INTRODUCTION:

Oral drug delivery systems have limitations such as incomplete absorption owing to physiological variations and fast emptying time, mostly unpredictable gastrointestinal transit and emptying times in addition to metabolic degradation in the lower gastrointestinal tract.^1-3. This scenario has led to a scientific undertaking to identify better alternatives. The development of gastro-retentive drug delivery systems (GRDDS) was brought into the limelight to overcome the above constraints by retaining drugs in the stomach for an extended period, ensuring optimal bioavailability.^4-6

The gastro-retentive floating tablet is a low-density system with adequate buoyancy to float above the stomach's gastric contents for a longer period without being affected by the GI tract's natural peristalsis.⁷ several methods have been used for GRDDS to delay the gastric emptying rate; such as bio-adhesive systems⁸, expanding and swelling⁹, and high /low-density^10-12. Recently, the use of 3D printing in the manufacture of pharmaceuticals prompted the creation of intra-gastric floating devices.¹³

The three-dimensional (3D) printer is a new method for manufacturing equipment, that can easily formulate 3D objects under computer software. It is commonly used in numerous fields, like aerospace, architecture, healthcare, and engineering.¹⁴ In the pharmaceutical field, since the shape and size of the object, are simply changed using 3D computer-aided design (CAD), a 3D printer is thought to be useful to fabricate a pharmaceutical dosage form whose dose and drug release rate is adjusted to meet individual patient characteristics and needs.¹⁵ So, 3D printing has usual a lot of attention in recent years as a suitable tool to improve personalized medicine.

Numerous printing technologies are included in 3D printing. For instance, in the 1990s, the development of powder bed inkjet printing¹⁶, which is employed in the production of the first licensed successful 3D-printed medicine (Spritam).¹⁷ Manufacturing 3D printed tablets with various drug release profiles has been done using selective laser sintering (SLS), a 3D printing powder bed technique that uses a laser beam to sinter and fuses the powder particles into a solid structure.¹⁸ The alternative technology, SLA is based on the solidifying of a resin by photopolymerization that has been evaluated to formulate oral dosage forms in addition to personalized facial masks designed for topical drug delivery.¹⁹

Of all of the 3DP technologies, fused deposition modeling (FDM) however, offers immediate production of printlets on demand and therefore is the most suitable type of 3D printing to be used in the production of patient-centric pharmaceuticals. In FDM 3DP a polymer filament is passed through a heated nozzle and the molten polymer is deposited onto a build plate creating the layers of the object to be printed.²⁰ FDM can be used with a wide range of different pharmaceutical grade excipients, both soluble²¹ and insoluble²²; for this reason, FDM is extremely versatile in the development of drug delivery systems, especially personalized oral medicines.

The feeding materials in FDM 3D printers must be thermoplastic polymers in the shape of filament. The majority of currently available filaments are unsuitable for pharmaceutical manufacturing, which is considered a major obstacle to FDM 3D printing being used as the dominant technique of pharmaceutical manufacturing.²³ To circumvent these issues and use FDM in the formulation of drug delivery dosage forms, the selected drug (s) should be loaded into the polymeric filament, which can be done in one of two ways: soaking or hot-melt extrusion.²⁴

HME has emerged as a novel processing technology in developing molecular dispersions of active pharmaceutical ingredients (APIs) into various polymer or/and lipid matrices through the application of heat and pressure which has led this technique to demonstrate time-controlled, modified, extended, and targeted drug delivery.²⁵ HME is the most popular technique in polymer processing and can be utilized to blend drugs with polymers and extrude the formulation through a circular orifice to form a rod-shaped filament for FDM 3D printing. Conjugating HME and FDM 3D printing is a viable approach for the formulation of medicines based on patient needs.²⁶

Baclofen is a centrally acting skeletal muscle relaxant used to treat spasticity.²⁷ Baclofen is rapidly and extensively absorbed and eliminated. The half-life of the drug is ~2.5 to 4 hr in plasma.²⁸ It has a narrow absorption window in the upper gastrointestinal system, resulting in reduced bioavailability (70% to 85%).²⁹ Baclofen is challenging to manufacture into sustained-release dosage forms since its absorption is reduced or non-existent once it reaches the colon (or even before).

This study aims to formulate baclofen gastro-retentive drug delivery dosage forms in two different approaches using HME and FDM 3D printers and then compare the effectiveness and select the best formula from the two approaches for further characterization.

The first approach is to formulate filaments by HME where baclofen and different polymeric blends were mixed and extruded, then these filaments were used in an FDM 3D printer to formulate tablets with different infill percentages which make the tablet float for various periods based on the low density of the 3D printed tablets.

In the second approach, sustained-release tablets of baclofen were formulated by HME of different polymers with baclofen and the resulting extrudate was ground and compressed into an ordinary tablet, meanwhile, a gastro-floating device (GFD) was designed and 3D printed by an FDM 3D printer using commercially available Polylactic acid (PLA) filaments where the floating ability of the device is attributed to the air pockets inside the device and the prepared tablets were inserted into the floating device and were evaluated.

The prepared formulas by the two approaches were assayed for drug content, in vitro floating study, and in vitro dissolution. The selected formula from the two approaches was further assayed for in vivo X-ray imaging, DSC, and FT-IR.

MATERIALS AND METHODS:

Materials:

Baclofen, Ethylcellulose, PEO 600K, Sodium starch glycolate, and Poloxamir 407 were purchased from Baoji Guokang Bio-Technology Co Ltd (Baoji, China). Eudragit® RS-100 was donated by Evonik (Darmstadt, Germany). PEG 4000 (Polyethylene glycol) was purchased from Himedia Laboratories Co Ltd (Mumbai, India). Polylactic acid filament (PLA filament, 1.75mm in diameter) was purchased from Prusa Research (Prague, Czech Republic).

Method:

Formulation of Baclofen 3D Printed Floating Tablets:

Preparation of Drug Loaded Filaments:

Baclofen and other excipients were mixed for 15 minutes in 30-gram batches with a mortar and pestle to ensure a uniform mixture. As granules, Eudragit RS-100 was ground using an electric coffee grinder before extrusion. The formulations' composition is shown in Table 1. The mixture was extruded using a single-screw Noztek Pro Filament Extruder (Noztek, Shoreham, UK) with a 1.75 mm nozzle at a screw speed of 15rpm.³⁰ Extrusion temperatures are shown in table 1.

Table 1: Composition of HME filaments and extrusion temperature.

Formulation Composition (%w/w)					Extrusion Temperature (°C)
Formula	Baclofen	Eudragit RS-100	PEO 600K	PEG 4000	Extrusion Temperature (°C)
I 1	10	80		10	140
I 2	20	75		5	140
I 3	10		90		125
I 4	10		80	10	130
I 5	10	10	80		145

Tablet Design and 3D Printing:

Before the printing step, the 3D models were designed in Fusion 360 software version 2.0.10244 (Autodesk, San Rafael, USA) and exported as STL files to the slicer software PrusaSlicer v 2.2.0 (Prusa Research, Prague, Czech Republic) then exported as gcode file to be printed. Cylindrical shape tablets were designed to be 10 mm in diameter and 4mm in height with three infill percentages: 50% infill, 30% infill, and 10% infill as shown in figure 1, and were symbolled as A, B, and C so formula I 1 with 50% infill was donated as (I 1 A) and so on for the other formulas. Slicing parameters were as follows: layer height, 0.15mm; printing speed, 50mm/s; two outer vertical shells, five top and bottom horizontal shells, and grid fill pattern.

Filaments produced from the HME process with sufficient mechanical properties were printed using a commercial FDM-3D printer (Prusa i3 MK3S, Prusa Research, Prague, Czech Republic) equipped with a 0.4 mm nozzle. The printing temperature was 180°C. Filaments produced from (I 4) were not printable as will be discussed later. To avoid adhesion of tablets to the printer bed and possible damage after removal, painting tape was sticked on the bed and printing was on this tape.³¹

Figure 1: Cross-section of tablets during slicing with (A) 50% infill, (B) 30% infill, and (C) 10% infill.

Preparation of Hot-Melt Extruded Tablets:

Baclofen and other excipients were mixed for 15 minutes in 30-gram batches with a mortar and pestle to ensure a uniform mixture. As granules, Eudragit RS-100 was ground using an electric coffee grinder before extrusion. The formulations' composition is shown in Table 2. The mixture was extruded using a single-screw Noztek Pro Filament Extruder (Noztek, Shoreham, UK) with a 3 mm nozzle at a screw speed of 15 rpm and an extrusion temperature of 140°C.³²

The resulting extrudate was ground using an electric coffee grinder then it was sieved through a size #35 USP mesh to eliminate any aggregated or agglomerated particles. Direct compression of the sieved extrudate with a 6mm round concave punch produced 150mg tablets equivalent to 15mg baclofen for F 1 and 30mg baclofen for the other formulas.

Table 2: Composition of HME tablets

3D Printing of The Gastro-Floating Device (GFD):

Fusion 360 software version 2.0.10244 (Autodesk, San Rafael, USA), a computer-aided design program, was used to create the structure of the GFD. The capsule shape device was made up of two parts: the body and the cap (Figure 2). The device was designed to have two air pockets, one in the body and the other in the cap, and the body contains a hollow compartment where the tablet is inserted. The central compartment was designed to have four windows for drug release, the size of each one is 2×5mm. Device dimensions were 20mm in height, 8 mm in inner diameter, and 0.5mm in thickness. The GFD devices were printed with a commercial polylactic acid filament using a Prusa i3 MK3S FDM 3D printer with a 0.4mm nozzle (Prusa Research, Prague, Czech Republic). Temperatures for the extruder and platform were set to 210°C and 600°C, respectively. The following was the printing configuration: Layer height is 0.1mm, printing speed is 50mm/s, and the infill percentage is 100%. The manufactured baclofen tablet was inserted into the middle compartment of the body after the devices were produced, and the cap was locked to form the complete gastro-floating system.

Figure 2. 3D design of the GFD, (A) Front view, (B) Side view, (C) Front sectional view, and (D) Side sectional view.

Characterization of Filaments and Tablets:

Weight and Dimensions:

The weights of the tablets were measured using an electronic balance (Kern and Sohn-G.m.b.H, Germany) (n = 3). The thickness and diameter of the tablets and the diameter of the filaments were measured using a digital caliper (Neiko, China) (n = 3).

Drug Content Determination:

The drug content in all the prepared formulas of 3D printed tablets and hot melt extruded tablets was determined spectrophotometrically, where the 3D printed tablets or the HME tablets were dissolved in 100 ml of 0.1N HCl and kept for 12hr under stirring and then filtered. Then serial dilutions were done with 0.1N HCl and spectrophotometric absorbance was taken at λmax of 220nm drug concentration was calculated and compared to theoretical concentration and drug content was calculated accordingly.³³

In vitro Buoyancy Studies:

The in vitro buoyancy was calculated using the Roy et al method where floating lag time and total floating time were calculated. The 3D-printed tablets and the GFD filled with hot melt extruded tablets (n = 3) were submerged in 100ml of 0.1 N HCl for 12 hr. Floating lag time is the time it takes for the tablet or the device to rise to the surface and float. The total floating time was calculated as the amount of time the dosage form remained on the surface at all times.³⁴

In-vitro Dissolution Studies:

The in vitro dissolution rates of baclofen were determined for the prepared formulas of the two approaches where the 3D-printed tablets and the GFD filled with HME tablet were placed in 900ml of 0.1 N HCL (pH 1.2) as a dissolution medium at 37±0.5°C. Drug release was performed using USP dissolution apparatus type II (paddle type) at 50rpm for 12hr. Aliquots of 5ml were withdrawn at the following time intervals: 5, 10, 15, 30, 60, 90, 120 min then every hour until 12 hr. The samples were filtered and the medium was replenished with a similar volume of fresh medium. Using the dissolution media as a blank, the quantity of baclofen was measured using spectrophotometry at 220 nm, and the percentage of drug release in total was computed. The outcome was calculated as the average of three runs.³³

Characterization of the Optimized Formula:

Differential Scanning Calorimetry (DSC):

Thermodynamic analysis of pure Baclofen, as well as the extrudate of a selected formula (F5) of the hot melt extruded tablet, were determined using a DSC 60 (Shimadzu, Japan). The samples (5-6 mg) were placed in an aluminum pan and heated at a rate of 10°C/min between 25°C and 300°C under a dry nitrogen purge. Indium/Zinc standards were used to calibrate the DSC temperature and enthalpy scale, while an empty aluminum pan served as the reference.³⁵

Fourier Transform Infrared Spectroscopy (FTIR):

The FTIR spectra of pure Baclofen and the selected formula (F5) were obtained by using an FTIR spectrophotometer (Lambda scientific 8300, Australia). Samples were ground and mixed with dry potassium bromide then pressed in the form of discs using a hydraulic press. The samples were analyzed at wave numbers (4000-500 cm^-1).³⁶

In vivo Radiographic Study:

In vivo animal study was performed using an X-ray imaging technique for evaluating the GFD of the optimized tablet formulation as per the protocol approved by the institutional ethical committee in the College of Pharmacy, University of Baghdad, Baghdad, Iraq. Barium sulfate was mixed with the sieved extrudate of the selected formula (F5) in a 1:2 ratio and the resulting mixture was compressed to produce a 150 mg tablet containing 50mg barium sulfate and was inserted into the GFD. Albino rabbit weighing 2.3kg was housed under standard laboratory conditions with a standard diet and tap water. Before the initiation of the study, the animal was kept overnight under fasting conditions to avoid difficulties during imaging. An X-ray image of the empty stomach was taken before experimentation. The animal was orally administered with the optimized radio label tablet formulation and was placed in the upright position for imaging to locate the GFD in the GI tract under an X-ray machine at different time intervals which are 10 min, 6, and 12 hr after ingestion.

RESULTS AND DISCUSSION:

Preparation of the 3D-printed Tablets:

For successful FDM 3D printing, filaments should have optimum mechanical properties, flexibility, and melt viscosity.³⁷ Generally, most pharmaceutical-grade polymers lack these properties and HME will produce filaments that are either brittle which break in the motor gear and prevents the forward movement of the filament toward the nozzle, or soft filaments that can’t be pushed by the motor gear due to pliability of the filament resulting in squeezed filaments out of the driving gear, thus printing fails.³⁸ Therefore, plasticizers and other additives are usually used to enhance the mechanical properties of the extruded filament and enable 3D printing.³⁹

In this study, all the prepared filaments were successfully printed except (I 4) due to over-plasticization where 10% PEG 4000 was used as a plasticizer and this results in sticky filament with reduced diameter because of the rapid flow of the extrudate from the nozzle. The diameter of (I 4) filament was 1.24±0.03. Filaments with a diameter of less than 1.3mm result in incomplete printing as the printer is optimized for filaments with 1.75mm in diameter.

The floating ability of the 3D printed tablets is attributed to the low density of the tablets since air is entrapped inside the tablets because of the low infill percentage selected during the slicing of the designed tablet. The infill percentage determines how densely the tablets will be, as increasing the infill percentage will increase the deposition of the filament inside the tablet.

Preparation of HME Tablets and 3D Printing of the Gastro-floating Device:

HME was successfully employed to produce sustained-release tablets of baclofen. Eudragit RS-100 was selected as the primary polymer for release retardation and PEG 4000 was selected as a plasticizer, other additives were added based on the dissolution profile of the previous formulas to produce tablets with sustained release of baclofen over 12 hr.

3D printing of the GFD was successfully done by the FDM 3D printer where PLA filaments were used as the printing material. The average weight of the printed devices was 490±0.1 mg. The printed dimensions of the device were similar to the design, indicating that the FDM 3D printer was precise and reliable.

Characterization of Filaments and Tablets:

Weight and Dimensions:

Regarding the FDM 3D printed tablets, filament preparation and printing involve various process parameters that determine the result of the object to be printed. One of the variables that had a significant effect on the final printed object was the uniformity of the filament diameter. Commercially prepared filaments are available in 1.75 mm and 3 mm diameters with deviations of ± 0.05 mm. However, prepared filaments were found to have a diameter ranging from 1.46 to 1.57 mm (table 3), which is thinner than the commercially available and recommended filament size. Variation in diameter between different points of the same filament is caused by the weight of the filament as the extruder is placed at a height and as long as the extrusion continues the filament weight increase which pulls the upcoming filament from the nozzle which causes variation in diameter, and this issue can be solved by using conveyor belt which collects and straighten the upcoming filament with specific speed to maintain a constant diameter along all the extruded filament.⁴⁰

This variation in filament diameter results in significant weight variation between the individual 3D printed tablets of the same formula and infill percentage, and between different formulas with the same infill percentage although they have the same design and printing setting, but the amount of melted and the deposited filament is different in each tablet thus results in weight variation (table 3).¹³

The diameter and height of the 3D printed tablets were close to the designed value and this indicates that variation in filament diameter does not significantly affect the dimensions accuracy of the 3D printed tablets as the nozzle is moving according to the design given but the deposition of melted filament inside the tablets varies between each tablet.

Regarding the HME tablets, all the compressed tablets showed acceptable weight variation and uniform dimensions (table 3) as the tablet machine adjusted to produce 150 mg tablets, and this is considered an advantage of ordinary tablet machines in the mass production of tablets with uniform size and weight.⁴¹

Table 3. Physical properties and floating behavior of the prepared tablets.

Formula	Filament diameter	Tablets Physical Characterization					Floating Behavior
Formula	Filament diameter	Infill %	Height	Diameter	Weight	Density	Floating Lag time	Total Floating Time
I 1	1.46 ± 0.03	50%	3.99 ± 0.01	10 ± 0.04	278 ± 14.14	0.89 ± 0.04	0	15 min
		30%	4.08 ± 0.08	10.12 ± 0.08	232 ± 2.12	0.71 ± 0.01	0	12 hr
		10%	4.01 ± 0.06	9.96 ± 0.03	227 ± 9.19	0.73 ± 0.01	0	12 hr
I 2	1.5 ± 0.08	50%	4.04 ± 0.04	10.07 ± 0.07	361 ± 14.85	1.12 ± 0.02	N/A	0
		30%	4.07 ± 0.03	10.1 ± 0.04	293 ± 3.54	0.9 ± 0.01	0	12 hr
		10%	7.05 ± 4.14	10.11 ± 0.06	241 ± 7.78	0.51 ± 0.29	0	12 hr
I 3	1.53 ± 0.1	50%	4.04 ± 0.02	10.01 ± 0.06	409 ± 10.61	1.29 ± 0.05	N/A	0
		30%	4.02 ± 0.06	10 ± 0.11	313 ± 3.54	0.99 ± 0.05	N/A	0
		10%	3.94 ± 0.06	10.04 ± 0.01	328 ± 8.49	1.05 ± 0.04	N/A	0
I 5	1.57 ± 0.02	50%	3.98 ± 0.02	10.04 ± 0.04	310 ± 6.36	0.98 ± 0.02	0	12 hr
		30%	4.03 ± 0.01	10.04 ± 0.08	312 ± 10.61	0.98 ± 0.05	0	12 hr
		10%	4 ± 0.04	9.93 ± 0.05	289 ± 4.95	0.93 ± 0.03	0	12 hr
F 1	N/A	N/A	5.25 ± 0.06	6.02 ± 0.02	150.35 ± 0.35	1.16 ± 0.03	0	12 hr
F 2			5.3 ± 0.08	6.04 ± 0.02	149.85 ± 0.49	1.13 ± 0.02	0	12 hr
F 3			5.26 ± 0.07	6.04 ± 0.02	150.85 ± 1.63	1.15 ± 0.02	0	12 hr
F 4			5.31 ± 0.05	6.05 ± 0.04	150.7 ± 0.42	1.13 ± 0.01	0	12 hr
F 5			5.27 ± 0.03	6.03 ± 0.02	150.55 ± 0.64	1.15 ± 0.01	0	12 hr

Drug Content Determination:

The content of baclofen in the formulas was analyzed using a UV– Visible spectrophotometer. Drug content was in the range of 97.3% to 100.4% as shown in figure 3 indicating no significant drug loss occurred during HME and 3D printing since the extrusion temperature was lower than the melting point of baclofen which is 208°C.²⁸

Figure 3. Drug content of 3D printed and HME tablets (mean±SD, n=3).

In vitro Buoyancy Studies:

The in vitro floating behavior was performed for all the prepared 3D printed tablets and the HME tablets filled in GFD The floating lag time and total floating time are illustrated in table 3. The floating capacity and duration of the 3D-printed tablets with different infill percentages were found to be dependent on the density of the tablets and the presence of the top/bottom layer. 3D printed tablets with incomplete top or bottom layers due to not continuous flow of the extruded filament from the nozzle as a result of filament diameter variation, failed to show floating properties and sank immediately to the bottom of the vessel, this includes I 1 A and I 3 B tablets. This occurs due to the void spaces formed where water enters and replaces the air inside and increases the density of the tablets, causing them to sink into the media.¹³ Tablets with higher density than the density of the gastric fluid (1.004 g/cm3) also sank immediately to the bottom of the vessel as seen in table 3.⁴²

Tablets with complete closure of the top and bottom layers and having a density lower than that of the gastric fluid showed excellent floating properties and remained floating for >12 hr.

All the HME tablets (F1 – F5) have a density higher than the density of the gastric fluid but when inserted into the GFD, they remained floating for more than 12 hr since 3D printing of the GFD was done through PLA filament which is manufactured specifically to be used for FDM 3D printers and the printing quality is better compared to the printing with HME filaments and the air pockets inside the GFD was able to maintain the device with the tablet inside it, floating for the whole time of the experiment.

In Vitro Dissolution Studies:

Since one of the aims of this study is to prepare floating sustained-release tablets of baclofen that release the drug over 12 hr, firstly insoluble polymer (Eudragit RS-100) was tried with the addition of PEG 4000 as a plasticizer as seen in (I 1). The resulting filament from (I 1) was slightly brittle and breaks easily but was still printable, so part of the filament was 3D printed to prepare floating tablets with different infill percentages, and the other part was ground and compressed to prepare HME tablets which are (F1), So (I 1) and (F 1) have the same composition but with different preparation method.

The dissolution profile of (I 1) with different infill percentages and of (F2) are shown in figures 4 and 6 respectively. Although the two formulas have the same composition, there is a significant difference in the release profile with a similarity factor (f2) equal to 10.3 between (I 1 A) and (F2), and this is attributed to the basic mechanism of FDM 3D printers where compact layer over layer solidification of the melted filament results in a rigid structure that does not disintegrate and dissolve by erosion only, as reported by Solanki et al.³⁸ Changing the infill percentage of (I 1) does not significantly affect the release profile and only 10% of the drug is released over 12 hr with 10% infill tablet (I 1 C), while (F 1) tablet released 94% of the drug in 12 hr.

(I 2) and (F2) have the same composition as seen in the previous formula but the drug loading was increased to 20% and the percent of PEG 4000 was reduced to 5%. Again there is a significant difference in the release profile between (I 2) and (F2) as seen in the previous formula and (F2) showed a slight decrease in the dissolution rate compared to (F 1) with 87% of the drug released in 12 hr (figure 4).

In order to prepare 3D-printed floating tablets that release the drug over 12 hr, a soluble hydrophilic polymer (PEO 600K) was used instead of Eudragit RS-100 as seen in (I 3). PEO is used for extending the drug release depending on the molecular weight, although its a hydrophilic polymer but the interaction of the polymer with water causes the hydration and swelling that develops a hydrogel layer and this drives the entry of water within the matrix which regulates the controlled release behavior of drugs from the dosage form.

The dissolution profile of (I 3) showed complete release of the drug in about 5 hr with a slight difference between the different infill percentages (figure 4) and this may be attributed to the difference in tablets weight which results from the variation in filament diameter.⁴³

The addition of Eudragit RS-100 in (I 5) instead of PEG 4000 in (I 1) results in filaments with better flexibility and good mechanical properties, and the dissolution profile of (I 5) 3D printed tablets showed sustained release of baclofen over 12 hr and this attributed to the insoluble and retardation effect of Eudragit RS-100.⁴⁴ Figure 5 depicts the influence of infill percentage on the drug release profile of the 3D printed tablets. 50% infill tablets (I 5 A) had a slower and extended drug profile compared with 10% infill tablets (I 5 C). This could be mainly due to the large cavities/holes and large, loose gaps between the successive layers formed as the infill decreased. The higher porosity allows for quick penetration of the dissolution media into the tablet core, leading to rapid dissolution and diffusion of the drug from the tablet. It has been reported that tablets with high infill percentages are harder and encounter a more intense retarding force that counteracts the positive effects of polymer dissolution, causing a delay in the drug release rate.^7,45

Regarding the HME tablets filled in GFD, the effect of replacing the plasticizer from PEG 4000 in (F 2) with Poloxamer 407 in (F 3) results in a similar dissolution profile (figure 4) with similarity factor (f2) equal to 75. The addition of 5% sodium starch glycolate in (F 4) results in a significant difference in the dissolution rate compared to (F 2) with complete release of the drug in about 5 hr and this is attributed to the super disintegrant effect of sodium starch glycolate that facilitate the tablet breakup and dissolution media entry thus faster drug release rate. The addition of 20% ethyl cellulose in (F 5) compared to (F 2) results in a relatively similar dissolution profile with a similarity factor equal to 56.3 and complete release of the drug occurred in 12 hr. Ethyl cellulose is an insoluble polymer and has been used in the formulation of sustained-release dosage forms.⁴⁶

Figure 4. The dissolution profile of 3D printed tablets with (A) 50% infill, (B) 30% infill, and (C) 10% infill, and the dissolution profile HME tablets (F 1 – F 5) filled in GFD.

Selection of the Optimized Formula:

Since this study aimed to compare the effectiveness of two approaches for the formulation of gastro-floating dosage form using FDM 3D printing, and from the previous tests we found that FDM 3D printing of floating tablets with different infill percentages is associated with some negative points which mainly related to the formulation of suitable filament with good mechanical properties which affect the printing quality, and the selection of suitable thermoplastic polymers that produce the required release profile and withstand the HME conditions. Some of the negative results for the 3D printed tablets were variation in weight, failure to float because of low printing quality, difficulty in predicting the weight of the tablets, and difficulty in predicting the release profile.

Formulation of sustained release tablets through HME and extrudate compression was found to produce tablets with acceptable weight variation and it's considered a more reliable method in terms of mass production of tablets as 3D printing of each tablet required about 10 min, while HME and tablet compression is a much faster manufacturing method.

3D printing of GFD was successfully printed and was able to hold the HME tablet and remain floating for more than 12 hr. This approach has the advantage of converting any tablet into a floating dosage form. So the formulation of HME tablets filled in GFD was selected as the optimized approach for the formulation of gastro-floating dosage form, and (F 5) was selected as the optimized formula since it gave a sustained release of baclofen over 12 hr.

Characterization of the Optimized Formula:

Differential Scanning Calorimetry (DSC):

The thermal behavior of pure Baclofen showed a sharp endothermic peak at 209.92°C corresponding to baclofen melting temperature with the onset of a peak at 200°C and end set at 220°C which indicates that the drug is present in a pure crystalline state as shown in figure 5 (A), this DSC study was in agreement with the reported one.⁴⁷

The thermogram of the extrudate of the selected formula (F5) which contains baclofen, Eudragit RS-100, ethylcellulose, and PEG 4000, is shown in figure 5 (B). PEG 4000 has shown a peak at 57.09°C that is attributed to the glass transition temperature of the polymer⁴⁸, the sharp endothermic peak of baclofen has disappeared and this may be attributed to the conversion of baclofen from the crystalline state to the amorphous state and also due to the dilution of baclofen concentration as its added in 20% of the total weight of the formula. The endothermic peak at 187.54°C is belong to the ethylcellulose after processing in HME.⁴⁹

Figure 5: DSC thermogram of (A) pure baclofen, (B) Extrdate of F 5

Fourier Transform Infrared Spectroscopy (FTIR)

Infrared spectroscopy has been used to investigate possible interactions between the drug and polymers in solid dispersion systems. The crystalline baclofen shows the primary amide N-H stretching vibration band at 3407 cm-1 (figure 6 A). A strong band of C=O stretching was seen at 1621.84 cm-1, for the O-H group of acid exhibited stretching frequencies at 2904 cm-1. The bands occurring in the 734 cm-1 were assigned for C-Cl stretching. The presence of C=C in the aromatic ring was seen in 1573 cm-1.⁵⁰

The spectrum of the ground extrudate of the selected formula (F 5) showed no significant differences from pure baclofen (figure 6 B), which indicated that no new chemical bonds were created during the formation of solid dispersion and proved that there was good compatibility between the drug and excipients.⁵⁰

Figure 6. FTIR spectrum of (A) pure baclofen, and (B) F 5 extrudate.

In vivo Radiographic Study:

The radiopaque tablet was successfully prepared by the same method as described in the experimental section using barium sulfate. For in-vivo radiographical contrast, a sufficient quantity of barium sulfate is required to be encapsulated in the tablet. The prepared extrudate of F 5 was mixed with barium sulfate and compressed and the amount of barium sulfate (50mg) in the radiopaque tablet was sufficient to be viewed in the X-ray image. An X-ray image of the rabbit stomach was taken before the experiment to confirm the emptiness of the stomach and the absence of any opaque object that interrupts the X-ray images. The radiopaque tablet was inserted into the GFD and administered to the rabbit. Figure 7 shows the gastric retention of the GFD filled with the radiopaque tablet in the rabbit's stomach after 10 min, 6 hr, and 12 hr. The floating tablet seen in the rabbit's stomach for 12 hr showed the confirmation of buoyancy of the floating tablet.

Figure 7. X-ray images of Albino rabbits' abdomen show the floating ability of GFD filled with a radiopaque tablet at different time intervals.

CONCLUSION:

The introduction of 3D printing in pharmaceutical manufacturing is considered a potential tool in the formulation of complex and personalized dosage forms that can’t be achieved by traditional manufacturing techniques. Formulation of 3D printed floating tablets with low infill percentage using an FDM 3D printer was successfully done but with some problems related to the preparation of suitable filament with good mechanical properties. Formulation of sustained-release tablets by HME and inserting them into 3D printed GFD was found more reliable and produced a floating dosage form. 3D printing of floating devices or other capsule shells could be the future in terms of manufacturing personalized dosage forms with the required release profile.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

We would like to thank the staff of the Department of Pharmaceutics / College of Pharmacy / University of Baghdad for their technical help in performing DSC and FTIR tests.

REFERENCES:

1. Mn D, Pp W, Ra B, et al. A Brief Review on Gastro Retentive System. Research Journal of Pharmaceutical Dosage Forms and Technology. 2010;2(1):28–31.

2. Asian B, Vol R. Emerging Trends in Floating Drug Delivery Systems. 2014;4(Jun):1–2.

3. Patel N, Nagesh C, Chandrashekhar S, et al. Floating drug delivery system: An innovative acceptable approach in Gastro retentive drug delivery. Research journal ofpharma sosage forms and technology. 2012;4(2):93–103.

4. Janhavi ZS, Pradnya SL, Darekar AB, et al. A Comprehensive Review on Gastro-Retentive Floating Drug Delivery Systems. Asian Journal of Pharmaceutical Research. 2015;5(4):211. doi :10.5958/2231-5691.2015.00033.7

5. Sneha SW, Trupti VK, Darekar AB, et al. A Review: Floatable Gastroretentive Drug Delivery System. Asian Journal of Pharmaceutical Research. 2015;5(1):51. doi :10.5958/2231-5691.2015.00008.8

6. Zope GL, Darekar AB, Saudagar RB. Glimpse of Floating Drug Delivery in Pharmaceutical Formulations: A Review. Asian Journal of Pharmaceutical Research. 2016;6(1):31–8. doi :10.5958/0975-4377.2016.00019.7

7. Giri BR, Song ES, Kwon J, et al. Fabrication of intragastric floating, controlled release 3D printed theophylline tablets using hot-melt extrusion and fused deposition modeling. Pharmaceutics. 2020;12(1):77. doi :10.3390/pharmaceutics12010077

8. Chavanpatil MD, Jain P, Chaudhari S, et al. Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin. International Journal of Pharmaceutics. 2006;316(1–2):86–92. doi :10.1016/j.ijpharm.2006.02.038

9. Klausner EA, Lavy E, Friedman M, et al. Expandable gastroretentive dosage forms. Journal of Controlled Release. 2003;90(2):143–62. doi :10.1016/S0168-3659(03)00203-7

10. Lokhande SS. Recent Trends in Development of Gastro-Retentive Floating Drug Delivery System: A Review. Asian Journal of Research in Pharmaceutical Science. 2019;9(2):91. doi :10.5958/2231-5659.2019.00014.6

11. Farooq SM, Sunaina S, Rao MDS, et al. Floating Drug Delivery Systems: An updated Review. Asian Journal of Pharmaceutical Research. 2020;10(1):39–47. doi :10.5958/2231-5691.2020.00009.x

12. Lodh H, FR S, Chourasia PK, et al. Floating Drug Delivery System: A Brief Review. Asian Journal of Pharmacy and Technology. 2020;10(4):103–22. doi :10.46624/ajptr.2020.v10.i4.010

13. Lamichhane S, Park JB, Sohn DH, et al. Customized novel design of 3D printed pregabalin tablets for intra-gastric floating and controlled release using fused deposition modeling. Pharmaceutics. 2019;11(11):1–14. doi :10.3390/pharmaceutics11110564

14. Schutter G De, Lesage K, Mechtcherine V, et al. Cement and Concrete Research Vision of 3D printing with concrete — Technical , economic and environmental potentials. Cement and Concrete Research. 2018;(June):1–12. doi :10.1016/j.cemconres.2018.06.001

15. Genina N, Holländer J, Jukarainen H, et al. Ethylene vinyl acetate (EVA) as a new drug carrier for 3D printed medical drug delivery devices. European Journal of Pharmaceutical Sciences. 2016;90:53–63. doi :10.1016/j.ejps.2015.11.005

16. Wu BM, Borland SW, Giordano RA, et al. Solid free-form fabrication of drug delivery devices. Journal of Controlled Release. 1996;40(1–2):77–87. doi :10.1016/0168-3659(95)00173-5

17. Pandey M, Choudhury H, Fern JLC, et al. 3D printing for oral drug delivery: a new tool to customize drug delivery. Drug Delivery and Translational Research. 2020;10(4):986–1001. doi :10.1007/s13346-020-00737-0

18. Fina F, Goyanes A, Gaisford S, et al. Selective laser sintering (SLS) 3D printing of medicines. International Journal of Pharmaceutics. 2017;529(1–2):285–93. doi :10.1016/j.ijpharm.2017.06.082

19. Goyanes A, Det-Amornrat U, Wang J, et al. 3D scanning and 3D printing as innovative technologies for fabricating personalized topical drug delivery systems. Journal of Controlled Release. 2016;234:41–8. doi :10.1016/j.jconrel.2016.05.034

20. Khaled SA, Burley JC, Alexander MR, et al. 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. Journal of Controlled Release. 2015;217:308–14. doi :10.1016/j.jconrel.2015.09.028

21. Goyanes A, Fina F, Martorana A, et al. Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing. International Journal of Pharmaceutics. 2017;527(1–2):21–30. doi :10.1016/j.ijpharm.2017.05.021

22. Holländer J, Genina N, Jukarainen H, et al. Three-Dimensional Printed PCL-Based Implantable Prototypes of Medical Devices for Controlled Drug Delivery. Journal of Pharmaceutical Sciences. 2016;105(9):2665–76. doi :10.1016/j.xphs.2015.12.012

23. Tan DK, Maniruzzaman M, Nokhodchi A. Advanced pharmaceutical applications of hot-melt extrusion coupled with fused deposition modelling (FDM) 3D printing for personalised drug delivery. Pharmaceutics. 2018;10(4):203. doi :10.3390/pharmaceutics10040203

24. Long J, Gholizadeh H, Lu J, et al. Review: Application of Fused Deposition Modelling (FDM) Method of 3D Printing in Drug Delivery. 2016;(March 2017). doi :10.2174/13816128226661610261

25. Maniruzzaman M, Boateng JS, Snowden MJ, et al. A Review of Hot-Melt Extrusion: Process Technology to Pharmaceutical Products. ISRN Pharmaceutics. 2012;2012:1–9. doi :10.5402/2012/436763

26. Awad A, Trenfield SJ, Gaisford S, et al. 3D printed medicines: A new branch of digital healthcare. International Journal of Pharmaceutics. 2018;548(1):586–96. doi :10.1016/j.ijpharm.2018.07.024

27. Trivedi R V., Borkar JH, Taksande JB, et al. Development and characterization of stomach specific mucoadhesive drug delivery system of baclofen. International Journal of Research in Pharmaceutical Sciences. 2017;8(4):608–15.

28. Gande S, Rao YM. Sustained-release effervescent floating matrix tablets of baclofen: Development, optimization and in vitro-in vivo evaluation in healthy human volunteers. DARU, Journal of Pharmaceutical Sciences. 2011;19(3):202–9.

29. Nirmala D, Aslesha E, Sudhakar M. Formulation and Evaluation of Baclofen Floating Tablets. Asian Journal of Research in Pharmaceutical Science. 2016;6(4):255. doi :10.5958/2231-5659.2016.00035.7

30. Zhang J, Feng X, Patil H, et al. Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. International Journal of Pharmaceutics. 2017;519(1–2):186–97. doi :10.1016/j.ijpharm.2016.12.049

31. Nober C, Manini G, Carlier E, et al. Feasibility study into the potential use of fused-deposition modeling to manufacture 3D-printed enteric capsules in compounding pharmacies. International Journal of Pharmaceutics. 2019;569(July):118581. doi :10.1016/j.ijpharm.2019.118581

32. Lu J, Obara S, Liu F, et al. Melt Extrusion for a High Melting Point Compound with Improved Solubility and Sustained Release. AAPS PharmSciTech. 2018;19(1):358–70. doi :10.1208/s12249-017-0846-6

33. Ibrahim M, Naguib YW, Sarhan HA, et al. Preformulation-Assisted Design and Characterization of Modified Release Gastroretentive Floating Extrudates Towards Improved Bioavailability and Minimized Side Effects of Baclofen. Journal of Pharmaceutical Sciences. 2021;110(3):1227–39. doi :10.1016/j.xphs.2020.10.025

34. Anjali Devi N, Hadi MA, Rajitha P, et al. Formulation and evaluation of floating controlled release tablets of Imatinib mesylate using hydrophilic matrix system. International Journal of Pharmacy and Pharmaceutical Sciences. 2013;5(1):271–7.

35. Ansari KA, Vavia PR, Trotta F, et al. Cyclodextrin-based nanosponges for delivery of resveratrol: In vitro characterisation, stability, cytotoxicity and permeation study. AAPS PharmSciTech. 2011;12(1):279–86. doi :10.1208/s12249-011-9584-3

36. Osmani RAM, Aloorkar NH, Ingale DJ, et al. Microsponges based novel drug delivery system for augmented arthritis therapy. Saudi Pharmaceutical Journal. 2015;23(5):562–72. doi :10.1016/j.jsps.2015.02.020

37. Nasereddin JM, Wellner N, Alhijjaj M, et al. Development of a Simple Mechanical Screening Method for Predicting the Feedability of a Pharmaceutical FDM 3D Printing Filament. Pharmaceutical Research. 2018;35(8). doi :10.1007/s11095-018-2432-3

38. Solanki NG, Tahsin M, Shah A V., et al. Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release, Drug-Polymer Miscibility and Printability. Journal of Pharmaceutical Sciences. 2018;107(1):390–401. doi :10.1016/j.xphs.2017.10.021

39. Korte C, Quodbach J. Formulation development and process analysis of drug-loaded filaments manufactured via hot-melt extrusion for 3D-printing of medicines. Pharmaceutical Development and Technology. 2018;23(10):1117–27. doi :10.1080/10837450.2018.1433208

40. Wang H, Dumpa N, Bandari S, et al. Fabrication of Taste-Masked Donut-Shaped Tablets Via Fused Filament Fabrication 3D Printing Paired with Hot-Melt Extrusion Techniques. AAPS PharmSciTech. 2020;21(7):1–11. doi :10.1208/s12249-020-01783-0

41. Wallis M, Al-Dulimi Z, Tan DK, et al. 3D printing for enhanced drug delivery: current state-of-the-art and challenges. Drug Development and Industrial Pharmacy. 2020;46(9):1385–401. doi :10.1080/03639045.2020.1801714

42. Chen D, Xu XY, Li R, et al. Preparation and In vitro Evaluation of FDM 3D-Printed Ellipsoid-Shaped Gastric Floating Tablets with Low Infill Percentages. AAPS PharmSciTech. 2020;21(1):1–13. doi :10.1208/s12249-019-1521-x

43. Alhijjaj M, Nasereddin J, Belton P, et al. Impact of processing parameters on the quality of pharmaceutical solid dosage forms produced by fused deposition modeling (FDM). Pharmaceutics. 2019;11(12):633. doi :10.3390/pharmaceutics11120633

44. Ibraheem FQ, Gawhri FJAL. Preparation and in- vitro evaluation of Baclofen as an oral microsponge tablets. Iraqi Journal of Pharmaceutical Sciences. 2019;28(1):75–90. doi :10.31351/vol28iss1pp75-90

45. Jiaxiang Zhang, Weiwei Yang, Anh Q. Vo, Xin Feng, Xingyou Ye, Dong Wuk Kim and MAR. Hydroxypropyl Methylcellulose-based Controlled Release Dosage by Melt Extrusion and 3D Printing: Structure and Drug Release Correlation. Carbohydrate Polymers. 2017;177(1):49–57. doi :10.1016/j.physbeh.2017.03.040

46. Crowley MM, Schroeder B, Fredersdorf A, et al. Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion. International Journal of Pharmaceutics. 2004;269(2):509–22. doi :10.1016/j.ijpharm.2003.09.037

47. Correa G, Montero AV. Development of sustained release tablets containing solid dispersions of baclofen. Journal of fundemental and applied science. 2013;5(2):220–39.

48. Horoz BB, Kiliçarslan M, Yüksel N, et al. Influence of aluminum tristearate and sucrose stearate as the dispersing agents on physical properties and release characteristics of Eudragit RS microspheres. AAPS PharmSciTech. 2006;7(1):1–7. doi :10.1208/pt070116

49. Wasilewska K, Winnicka K. Ethylcellulose-a pharmaceutical excipient with multidirectional application in drug dosage forms development. Materials. 2019;12(20). doi :10.3390/ma12203386

50. Ali MAM, Sabati AM, Ali BA. Formulation and evaluation of baclofen mucoadhesive buccal films. Fabad Journal of Pharmaceutical Sciences. 2017;42(3):179–90.

Received on 04.10.2022 Modified on 13.11.2022

Research J. Pharm. and Tech 2023; 16(1):363-372.

DOI: 10.52711/0974-360X.2023.00063

Formula

Baclofen

Eudragit RS 100

PEG 4000

Poloxamer 407

Sodium starch glycolate

Ethyl cellulose