3D printing of porous microfluidic drug delivery systems

Abstract

The invention relates to 3D-printed controlled-release solid oral pharmaceutical compositions comprising a hydrophobic matrix comprising cavities filled with air, allowing flotation in the stomach, one or more regions within the matrix comprising a pharmaceutical, one or more regions within the matrix comprising a swellable material, wherein optionally the one or more regions within the matrix comprise a swellable material and a pharmaceutical one or more fracture zones within the matrix with weaker or less dense structure, one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region within the matrix comprising the swellable material or the pharmaceutical.

Description

[0001] 3D PRINTING OF POROUS MICROFLUIDIC DRUG DELIVERY SYSTEMS FIELD OF THE INVENTION

[0002] The invention relation to controlled release of medicaments in the stomach.

[0003] BACKRGROUND OF THE INVENTION

[0004] Novel drug delivery systems are required to tailor the dosage and release of multiple active pharmaceutical ingredients (active pharmaceutical ingredients) to the patient, stepping away from an industrial "one-size-fits-all" tablet. A more recent technology is additive manufacturing, or 3D printing, to fabricate drugs equivalent in quality and efficacy to conventional manufacturing processes. However, most approaches, if not all, rely on breaking down matrix-based tablets through controlled erosion or dispersion, which often cannot last for hours to achieve a sustained release, or cannot release instantaneously.

[0005] SUMMARY OF THE INVENTION

[0006] In the present invention, a binder jetting 3D printing technology is used for the fabrication of drug-loaded reservoir- based tablets for controlled release through microfluidics. More specifically, the tablet consists of a naturally hydrophilic polymer powder (such as polymethyl methacrylate), where hydrophobically bound walls (i.e., shell) delineate porous hydrophilic channels filled with bare powder and regions containing one or more active pharmaceutical ingredients. Water, or hydrophilic liquids, can flow through the macroporous cavities through capillary action, enabling autonomous liquid flow. The design and geometry of the tablet, and internal 3D channels, determine the drug release profile.

[0007] The invention is further summarised in the following statements:

[0008] 1. A controlled-release solid oral pharmaceutical composition comprising:

[0009] - a matrix of a hydrophobic material,

[0010] - one or more regions within the matrix comprising a pharmaceutical,

[0011] - one or more regions within the matrix comprising a swellable material,

[0012] - one or more fracture zones,

[0013] - one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region within the matrix comprising the swellable material, wherein the swellable region is in contact with a fracture zone of weaker or less densestructure of the matrix, and wherein the fracture zone is further in contact with a region comprising a pharmaceutical.

[0014] 2. The composition according to statement 1, further comprising one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region comprising a pharmaceutical, wherein further adjacent to the region with the pharmaceutical or together with the pharmaceutical, a surfactant is present.

[0015] Surfactants can be non-ionic (such as polysorbates, sorbitan esters, sugar-based surfactants), zwitterionic (such as betaines), amphoteric (such as amino acid-based surfactants) or anionic (such as bile salts).

[0016] 3. The composition according to statement 1 or 2, further comprising one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region comprising a pharmaceutical.

[0017] 4. The composition according to any one of statements 1 to 3, wherein the matrix of hydrophobic material is a 3D matrix of hydrophilic particles coated with a hydrophobic binder.

[0018] 5. The composition according to any one of statements 1 to 4, wherein the matrix of a hydrophobic material is a layer-by-layer printed three-dimensional body of particulate material with cavities in-between the particulate material, wherein said particulate material is treated with a hydrophobizing agent making the cavities in between the particulate material impermeable for an hydrophilic fluid sample.

[0019] 6. The composition according to any one of statements 1 to 5, wherein the channels are regions of hydrophilic particulate material for transport of a hydrophilic fluid via the cavities between the hydrophilic particulate material.

[0020] 7. The composition according to any one of statements 1 to 6, wherein the channels are empty lumens within the matrix.

[0021] 8. The composition according to any one of statements 1 to 7, wherein the composition has a minimal diameter of 5 mm.

[0022] 9. The composition according to any one of statements 1 to 8, wherein the swellable material is a hydrogel, such as a cross-linked carboxymethylcellulose or sodium starch glycolate.

[0023] 10. The composition according to any one of statements 1 to 9, whereby the matrix comprises microporous cavities allowing flotation in the stomach.

[0024] 11. The composition according to any one of statements 1 to 10, wherein the pharmaceutical is formulated as a pellet or powder within a cavity in the matrix .

[0025] 12. The composition according to any one of statements 1 to 11, wherein the pharmaceutical is intermixed with the binder.13. The composition according to any one of statements 1 to 12, wherein the composition comprises different regions with the same pharmaceutical, or comprises different regions with a different pharmaceutical.

[0026] 14. The composition according to any one of statements 1 to 13, wherein the hydrophobizing agent is selected from the group consisting of waxes, silanes, alkyl and alkenyl ketene dimers, acid anhydrides, including alkylanhydrides and alkenyl succinic anhydride, hydrophobic polymers, hydrophobic particles, fluorinated molecules, molecules containing apolar hydrocarbon moieties and any combinations thereof.

[0027] 15. The composition according to statement 1 wherein the particulate material is selected from the group consisting of polymethyl methylacrylate (PMMA), acrylonitrile butadiene styrene (ABS), poly lactic acid (PLA), poly styrene (PS), poly vinyl alcohol (PVA), nylon, cellulose, nitrocellulose, cellophane, and copolymers or block copolymers thereof.

[0028] 16. A 3D-printed controlled-release solid oral pharmaceutical composition comprising: - a hydrophobic matrix comprising cavities filled with air, allowing flotation in the stomach,

[0029] - one or more regions within the matrix comprising a pharmaceutical,

[0030] - one or more regions within the matrix comprising a swellable material,

[0031] wherein optionally the one or more regions within the matrix comprise a swellable material and a pharmaceutical,

[0032] - one or more fracture zones within the matrix with weaker or less dense structure, - one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region within the matrix comprising the swellable material or the pharmaceutical,

[0033] wherein the region comprising the swellable material is in contact with a fracture zone of weaker or less dense structure of the matrix, and wherein the fracture zone is further in contact with a region comprising a pharmaceutical, such that upon swelling of the region comprising the swellable material, the matrix is fractured along the fracture zone, resulting in the release of the pharmaceutical from the region comprising a pharmaceutical,

[0034] or wherein, when the region comprising a swellable material also comprises a pharmaceutical, the region with the swellable material is in contact with a fracture zone of weaker or less dense structure of the matrix, such that upon swelling of the region comprising the swellable material, the matrix is fractured along the fracture zone,resulting in a release of the pharmaceutical from the region comprising the swellable material and the pharmaceutical.

[0035] 17. The composition according to statement 16, further comprising one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region comprising a pharmaceutical, wherein further adjacent to the region with the pharmaceutical or together with the pharmaceutical, a surfactant is present.

[0036] 18. The composition according to statement 16 or 17, wherein the hydrophobic matrix is made from hydrophobic particular material or from hydrophilic particular material coated with a hydrophobic agent.

[0037] 19. The composition according to any one of statements 16 to 18, wherein the hydrophobic matrix is a layer-by-layer printed three-dimensional body of particulate material with macroporous cavities in-between the particulate material, wherein said particulate material is hydrophobic or treated with a hydrophobizing agent, making the macroporous cavities inbetween the particulate material impermeable for a hydrophilic fluid sample.

[0038] 20. The composition according to any one of statements 16 to 19, wherein the channels are regions of hydrophilic particulate material or regions of hydrophobic particulate material coated with a hydrophilizing binder, allowing transport of a hydrophilic fluid via the macroporous cavities between the hydrophilic particulate material.

[0039] 21. The composition according to any one of statements 16 to 20, wherein the composition has a minimal diameter of 3 mm.

[0040] 22. The composition according to any one of statements 16 to 21, wherein the swellable material is a hydrogel, such as a cross-linked carboxymethylcellulose or sodium starch glycolate.

[0041] 23. The composition according to any one of statements 16 to 25, wherein the pharmaceutical is formulated as a pellet , powder or solid dispersion within a region in the matrix.

[0042] 24. The composition according to any one of statements 20 to 23, wherein the pharmaceutical is intermixed with the binder, or is intermixed with a solvent-based or aqueous ink not binding the powder material, or is intermixed with the particulate material.

[0043] 25. The composition according to any one of statements 16 to 24, wherein the composition comprises different regions with the same pharmaceutical, or comprises different regions with a different pharmaceutical.

[0044] 26. The composition according to statement 19, wherein the hydrophobizing agent is selected from the group consisting of waxes, silanes, ethyl cellulose, alkyl and alkenylketene dimers, acid anhydrides, including alkylanhydrides and alkenyl succinic anhydride, hydrophobic polymers, hydrophobic particles, fluorinated molecules, molecules containing apolar hydrocarbon moieties and any combinations thereof.

[0045] 27. The composition according to statement 26, wherein the hydrophilizing agent is selected from the group consisting of Polyethylene glycol / oxide (PEG / PEO), Polyvinylpyrrolidone (PVP), a polyelectrolyte, Polyvinyl alcohol (PVA),a Zwitterionic polymer, a hydrophilic polyurethane dispersion, a hydrophilic silane, gelatin, starch or a starch derivative, cellulose or a cellulose derivative.

[0046] 28. The composition according to any one of statements 18 to 27, wherein the hydrophilic particulate material is selected from the group consisting of polymethyl methylacrylate (PMMA), cellulose, nitrocellulose, polyvinyl alcohol, cellophane, polysaccharides, polyvinylpyrrolidone, polyacrylic acid, and polyethylene imine.

[0047] 29. The composition according to any one of statements 18 to 27, wherein the hydrophobic particulate material is selected from the group consisting of acrylonitrile butadiene styrene, polylactic acid, polystyrene, polycaprolactone, polyhydroxyalkanoate, nylon, polyglycolic acid, poly(lactic-co-glycolic acid), po lyca p ro I a cto n e, po ly hyd roxya I ka n oa te .

[0048] DETAILED DESCRIPTION OF THE INVENTION

[0049] Figures shows embodiments illustrating the invention

[0050] Figure 1: Print-pause-print concept. A 20x10x7 mm3hollow rounded tablet design (A) is printed, while halfway through the print holes are punched and filled with dye pellets (B). The tablet is visualized using micro-computed tomography (C).

[0051] Figure 2: Diffusive drug release mechanism for a single capillary channel. (A) Water enters and wicks into the channel until it reaches the drug-containing chamber. (B) The active pharmaceutical ingredient powder / pellet dissolves. (C) Diffusive release outwards through the same pathway.

[0052] Figure 3: Surfactant-aided diffusive release mechanism for a single capillary channel. (A) Water enters and wicks through the primary pathway to the drug-containing chamber with a surfactant back wall. (B) The active pharmaceutical ingredient powder / pellet dissolves, and the surfactant molecules break through the hydrophobic barrier. (C) Diffusive release through the secondary pathway.

[0053] Figure 4: Burst release mechanism for a single capillary channel with one active pharmaceutical ingredient. (A) Water enters and wicks to the swelling chamber. (B) The swelling agent absorbs water to expand into a hydrogel matrix and push both halvesapart. (C) The active pharmaceutical ingredient, in direct contact with the medium, dissolves and is immediately released.

[0054] Figure 5: Example of tartrazine diffusion out of a porous sphere with 1 cm radius. Theoretical diffusion in water is also shown on the graph.

[0055] Figure 6: A beam-shaped 10x10x20 mm3tablet with dye ink-jetted in the (A) complete, (B) back half, or (C) front half of the 6x6x18 mm2bare powder channel. (D) Diffusion profile of the ink-jetted tartrazine.

[0056] Figure 7 : 10x10x20 mm3tablet for the diffusive release of tartrazine dye out of a single channel with varying cross-sections.

[0057] Figure 8: 10x10x20 mm3tablet for the diffusive release of tartrazine dye through a surfactant plug with varying cross-sections at the end of a single channel.

[0058] Figure 9: Fragmentation-based burst release proof-of-concept experiment. (A) 20x13x10 mm3tablet with a 0.5 mm cut, swelling chamber, and isolated dye chamber. (B) Dataset of the conducted experiment in triplicate.

[0059] Devices of the present invention are typically made as follows. A powder is spread onto a moveable platform in layers of typically 100 - 200 pm, followed by ink-jetting the binder solution in a predetermined pattern to build the shell. Xaar 128 piezoelectric printheads can be used because of their ease of integration, and compatibility with solvent-based inks. The hydrophobic binder for example consists of acetophenone, polyethylene glycol 200 (viscosity enhancer), and an alkyl ketene dimer (hydrophobic molecule) to chemically functionalize the PMMA particles. Another example of hydrophobic binder is acetophenone and ethyl cellulose.

[0060] The active pharmaceutical ingredient content can be inserted by two different methods. The first method is ink-jetting the active pharmaceutical ingredient simultaneously with the binder, dissolved in a (non-binding) solvent-based ink. The drug-containing ink consists generally of dimethyl sulfoxide, polyethylene glycol 200 (viscosity enhancer), and isopropanol (surface tension diminisher). However, this method is mostly applied for precise low dosages in pg range. Therefore, the second method uses a print-pause-print concept, i.e., the printing process is paused at certain time points to perform other manipulations. During this pause, a hole is punctured with a custom 'powder punch', after which it is filled with the active pharmaceutical ingredient in powder or pelletized form. An example of a 3D printed tablet is shown in Figure 1, which looks solid from the outside, but contains one or more active pharmaceutical ingredients inside. Following the methods described above, more than one type of active pharmaceutical ingredientcan be inserted by integrating another printhead in parallel, or by alternating between active pharmaceutical ingredient powders or pellets.

[0061] The final printouts in their surrounding support powder are safely removed from the powder bed and cured in the oven at 80 °C overnight. Next, the tablets are manually de-powdered by hand and with compressed air before being placed in a desiccator. Vacuum is applied for at least 3 hours to remove all excess solvents.

[0062] In other embodiments the printouts in their surrounding support powder are safely removed from the powder bed and cured in a vacuum oven at 120 °C for 1.5 hours. Next, the tablets are manually de-powdered by hand and with compressed air.

[0063] Capillary wicking and drug release

[0064] As described above, the fabricated tablet is made of a hydrophobic shell delineating 3D-oriented channels and chambers filled with the dispensed active pharmaceutical ingredient and compacted hydrophilic macroporous powder. At least one opening on the side of the tablet is needed to connect the capillary network with the surrounding medium. When the tablet is ingested and enters the stomach, gastric fluid will autonomously start a series of predesigned events, depending on the required release profile. The latter is defined by three parameters: the time from ingestion until release start (i.e., lag time), the shape of the profile (i.e., release curve), and the time from release start until complete release (i.e., release time).

[0065] 1. For consistency and comparison reasons, different design approaches and their respective release mechanisms are based on a bean-shaped 1x1x2 cm3tablet size, comparable to a paracetamol tablet.

[0066] The first and simplest mechanism relies solely on diffusion. Water enters a single capillary channel through one opening and wicks to the drug-containing chamber (Figure 2A). The active pharmaceutical ingredient, being in its dispersed, powder or pellet form, dissolves (Figure 2B) and diffuses from a high to a low concentration, according to the laws of diffusion. As such, the active pharmaceutical ingredient is released following the same pathway into the surrounding medium (Figure 2C).

[0067] The lag time is determined on the one hand by the design parameters (i.e., wicking rate and channel size) and on the other hand by the active pharmaceutical ingredient properties (i.e., dissolution rate and diffusion coefficient). In other words, large short channels with highly soluble active pharmaceutical ingredients will result in a shorter lag time compared to small long channels with poorly soluble active pharmaceuticalingredients. However, these influencing parameters are known and can be exploited to predetermine and achieve accurate lag times, e.g. through simulations. The release curve and time are also determined by the design parameters, and can be adjusted accordingly. However, since the same pathway is being used for both drug dissolution and release, the parameters of the release profile depend on each other.

[0068] 2. The second mechanism is similar to the first, but includes a surfactant at the end of the channel. The amphiphilic nature causes the surfactant to bind with its hydrophobic tail to the hydrophobic PMMA, exposing its hydrophilic head to the porous cavity and allowing water to pass through the newly generated secondary pathway. Therefore, water enters the primary pathway to reach the drug-containing chamber (Figure 3A), the active pharmaceutical ingredient dissolves (Figure 3B), and is now released by diffusion through the secondary pathway (Figure 3C).

[0069] The lag time will mainly be determined by the design parameters of the primary pathway. The release curve and time, however, will now be independent and influenced by the design of the secondary pathway. The main purpose of this mechanism is to shorten the diffusive path, thus decreasing the release time.

[0070] 3. The third mechanism is a different approach to achieve a timed burst release. As can be seen in Figure 4A, multiple additional elements are integrated. In its most basic form, the tablet is split in two halves by a small unbound gap. However, the post-curing process creates a weak binding to keep the tablet whole. One half contains a chamber filled with the active pharmaceutical ingredient powder or pellet, directly adjacent to the gap. The other half contains the capillary channel leading to a chamber containing a swelling agent, bridging the gap. When water reaches the swelling agent, it starts to form a hydrogel (Figure 4B). The expansion pushes both halves apart, directly exposing the drug-containing chamber to the surrounding medium and causing an immediate release (Figure 4C).

[0071] The lag time is equal to the time necessary to split the pill, (thus the time between ingestion and fragmentation of the pill) while the release profile is an instant release curve depicting the dissolution rate of the active pharmaceutical ingredient.

[0072] Tartrazine is used in the following examples as a model compound to simulate the drug because of its high solubility and yellow color, which can be quantified using a UV-Vis spectrophotometer. Also, a simulated gastric fluid (SGF) will be used instead of water to mimic the gastric environment.EXAMPLES

[0073] Example 1. Tablet fabrication

[0074] Tablets have been prepared using 3D printing technology as described Persembe et al. (2021) Rev. Sci. Instr. 92, 125106.]. Software and hardware have gained an upgrade to reach an optimal print capacity of 50 tablet shells per hour, measuring 2x1x1 cm3with a layer height of 0.2 mm. Directly ink-jetting the active pharmaceutical ingredient simultaneously with the binder does not impact the printing time. Dispensing the active pharmaceutical ingredient pellet or powder separately depends on the number of active pharmaceutical ingredients, and prolongs the printing time. The active pharmaceutical ingredient pellets are fabricated using a custom mould containing cylindrical holes with a diameter of 3 mm. Depending on the height of the pellets, their weight lies between 10 and 30 mg.

[0075] Example 2. Wicking speed

[0076] Controlled capillary wicking allows to tune the drug release profile. Factors to achieve reliable and reproducible wicking speeds have been investigated, and are divided into external (i.e., fabrication and post-processing parameters, shown in Table 1) and internal (i.e., channel properties).

[0077] Table 1: Summary of the different external factors influencing the wicking speed, their effect, and the most effective setpoint to achieve the lowest variability.

[0078]

[0079]

[0080] The external factors are kept constant for consistency reasons and to properly characterize the effect of the internal factors, i.e. the channel properties, on the wicking speed. This is evaluated and compared by the time necessary to wick 40 mm. First, control wicking tests were conducted with a 2x2x40 mm3untampered powder-filled channel and blue-dyed SGF.

[0081] The first channel property to be varied is the cross-section, which theoretically should not affect the wicking speed according to Darcy's law and Richards equation. However, a recent study has shown that a linear contact angle gradient exists at the channel edges for ~250 pm (Piovesan et al. (2022) Microfluidics Nanofluidics 26, 21), causing smaller channels to have a higher contact angle on average. Therefore, cross-sections 0.6x0.6, 1x1, 1.6x1.6, and 3x3 mm2were tested, which reveals that the wicking speed decreases and variability increases as the channel gets smaller, and vice versa.

[0082] The second channel property is the channel dimension, i.e. wicking in ID (horizontal line), 2D (horizontal plane), or 3D (horizontal and vertical), to understand as long channels will get squeezed into a single tablet. Satellite drops of the binder during printing might influence the hydrophilicity depending on the channel orientation. Ideally, wicking in ID, 2D, or 3D results in the same wicking speed, as long as the cross-section remains unchanged.

[0083] Example 3. Diffusion coefficient

[0084] Another factor in tailoring the diffusive drug release profile is predicting the diffusion through the porous medium, which is characterized by the diffusion coefficient. These coefficients are widely available for most drugs in water, but for this approach, the effective diffusion coefficient in SGF needs to be known. Therefore, hydrophilic spheres of 1 cm radius were printed and saturated with tartrazine-containing SGF. Next, the spheres were placed into vials with clean SGF at specific time intervals, to mimic a sink behaviour of the tartrazine into the medium. Last, the vials were analysed, translated into concentrations, and numerically fit Fick's diffusion model for spheres to obtain the diffusion coefficient. An example of tartrazine diffusion through SGF in the pores can be seen in Figure 5, where it is compared to the theoretical diffusion in water. The effective diffusion coefficient in SGF is similar to the theoretical diffusion coefficient in water,being 4.78e-10 m2 / s and 4.95e-10 m2 / s, respectively. Following this procedure, the diffusion coefficient can be numerically calculated and used in future simulations.

[0085] Example 4. Ink-jetting drugs

[0086] Tablets can be fabricated by jetting a suitable drug-containing ink alongside the binder solution onto the powder bed. As the exact volume jetted per pixel is known, very precise dosages can be achieved, albeit in the pg range. A 10x10x20 mm3beam-shaped tablet was designed with a 6x6x18 mm3channel, partially or completely filled with a 10 g / L tartrazine ink (figure 5). A full dose will be around 231 pg, while a half dose results in about 115 pg. The tablets were immersed in water, and samples were taken over time to characterize diffusion and validate the printed dose. The results are shown in Figure 5D. The fully printed channel has a precision of 100.4%, the back half has 98.5%, and the front half has 92.0%. It can also be noted that the release from the completely filled channel is faster than from the partially filled channel, and that the front half is slower than the back half, which sounds counterintuitive. However, this can be explained because diffusion is slower than wicking, causing the dye particles to be dragged to the back of the channel first before diffusion backward.

[0087] Example 5. Diffusive release

[0088] The first release mechanism relies on diffusion (Figure 2), where the channel properties can be tuned to control the release profile using the effective diffusion coefficient as calculated before. A 50x10x6 mm3part was fabricated containing a reservoir leading to a single channel with 3 cylindrical chambers located at the beginning, middle, and end (Figure 6A). Tartrazine dye pellets were deposited in one of these chambers, as shown in Figure 6B. SGF was added to the reservoirs and wicking was observed. After 12 hours it is clear that wicking is the dominant factor in dye movement, as gradients are formed by dragging the dye particles along to the end of the channel (Figure 6C)

[0089] Next, the potential of diffusive release out of a porous microfluidic channel was tested. The print-pause-print concept was applied to insert one tartrazine pellet at the end of a single channel in a 10x10x20 mm3beam-shaped tablet (7A). The channel cross-section was varied between 2x2, 5x5, and 8x8 mm2, with each variation printed in triplicate. The tablets were submerged in SGF, yet they floated, and samples were taken to be analysed with the UV-Vis spectrophotometer. Data is shown in 7B.

[0090] Increasing the cross-section decreases the release time and variation, while the lag time (~10 hours) seems independent of the cross-section. This can be explained by thechannel length, which mainly influences the lag time, and is the same in all three designs. However, the increased cross-section causes a greater flow, thus the dye diffuses out faster. Nevertheless, the minimum observed release time is 180 hours, making diffusive release alone unusable for oral drug delivery.

[0091] Example 6. Diffusive release with shortened path length

[0092] To reduce the lag and release time, surfactant is implemented in the second mechanism to act as bridging molecules for water to cross a hydrophobic barrier. This way a secondary shorter pathway is created for the dye to diffuse outwards. The same tablet design is used with a fixed channel size of 8x8x16 mm3, and a surfactant plug of 4x4, 6x6, and 8x8 mm2in cross-section (8A). Again, tablets were submerged in SGF, and samples were taken to observe the dye diffusion. Tablets were printed in triplicate, but only one dataset for each variation is shown in 8B.

[0093] Both the lag and release time are significantly faster compared to the previous mechanism, being ~2.5 hours and minimum 7 hours, respectively. Also, since the length of the channel is equal in the three variations, the lag time shows to be equal. Furthermore, increasing the cross-section of the surfactant plug decreases the release time, since the secondary pathway becomes larger, allowing a greater flow, and dye diffusion. These data show the potential for this mechanism to be used in oral drug delivery with extended release.

[0094] Example 7. Burst release

[0095] The third mechanism relies on the timed fragmentation of the tablet to release the stored active pharmaceutical ingredient (or dye) as a burst. The fragmentation is initiated after the surrounding medium (or SGF) has reached a swelling agent stored in a predefined cut. Therefore, the capillary wicking time determines the lag time, while the release time only depends on the active pharmaceutical ingredient dissolution rate. The pro of- of- co nee pt design contains a 20x13x10 mm3tablet with a 0.5 mm cut in the middle, which proved to be a good balance between holding the parts together and the ability to fragment (9A). A single channel in one half connects the outside to the central swelling agent chamber, while a dye pellet is located in an isolated chamber in the other half. The experiment is conducted in triplicate, of which the data is shown in Figure 9B. These data shows a significant decrease in lag and release time compared to the diffusion approaches, so can be used in a controlled burst release delivery system.Example 8. Release of an active pharmaceutical ingredient (riboflavin) The diffusion-based concept was applied to the active pharmaceutical ingredient riboflavin to show its potential in drug therapy. A spatula tip of riboflavin powder (1-3 mg) was deposited in a beam-shaped dosage form of 10x10x20 mm3, which contained a thin shell (~1 mm) with two in- / outlets of 8x8 mm2. The experiment was performed in SGF while stirring, and a sustained release of riboflavin was observed over 5 days.

Claims

CLAIMS1. A 3D-printed controlled-release solid oral pharmaceutical composition comprising:- a hydrophobic matrix comprising cavities filled with air, allowing flotation in the stomach,- one or more regions within the matrix comprising a pharmaceutical,- one or more regions within the matrix comprising a swellable material, wherein optionally the one or more regions within the matrix comprise a swellable material and a pharmaceutical,- one or more fracture zones within the matrix with weaker or less dense structure, - one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region within the matrix comprising the swellable material or the pharmaceutical,wherein the region comprising the swellable material is in contact with a fracture zone of weaker or less dense structure of the matrix, and wherein the fracture zone is further in contact with a region comprising a pharmaceutical, such that upon swelling of the region comprising the swellable material, the matrix is fractured along the fracture zone, resulting in the release of the pharmaceutical from the region comprising a pharmaceutical,or wherein, when the region comprising a swellable material also comprises a pharmaceutical, the region with the swellable material is in contact with a fracture zone of weaker or less dense structure of the matrix, such that upon swelling of the region comprising the swellable material, the matrix is fractured along the fracture zone, resulting in a release of the pharmaceutical from the region comprising the swellable material and the pharmaceutical.

2. The composition according to claim 1, further comprising one or more hydrophilic channels within the matrix fluidly connecting the outside of the composition with a region comprising a pharmaceutical, wherein further adjacent to the region with the pharmaceutical or together with the pharmaceutical, a surfactant is present.

3. The composition according to claim 1 or 2, wherein the hydrophobic matrix is made from hydrophobic particular material or from hydrophilic particular material coated with a hydrophobic agent.

4. The composition according to any one of claims 1 to 3, wherein the hydrophobic matrix is a layer-by-layer printed three-dimensional body of particulate material with macroporous cavities in-between the particulate material, wherein said particulate material is hydrophobic or treated with a hydrophobizing agent, making the macroporous cavities inbetween the particulate material impermeable for a hydrophilic fluid sample.

5. The composition according to any one of claims 1 to 4, wherein the channels are regions of hydrophilic particulate material or regions of hydrophobic particulate material coated with a hydrophilizing binder, allowing transport of a hydrophilic fluid via the macroporous cavities between the hydrophilic particulate material.

6. The composition according to any one of claims 1 to 5, wherein the composition has a minimal diameter of 3 mm.

7. The composition according to any one of claims 1 to 6, wherein the swellable material is a hydrogel, such as a cross-linked carboxymethylcellulose or sodium starch glycolate.

8. The composition according to any one of claims 1 to 7, wherein the pharmaceutical is formulated as a pellet , powder or solid dispersion within a region in the matrix.

9. The composition according to any one of claims 5 to 8, wherein the pharmaceutical is intermixed with the binder, or is intermixed with a solvent-based or aqueous ink not binding the powder material, or is intermixed with the particulate material.

10. The composition according to any one of claims 1 to 9, wherein the composition comprises different regions with the same pharmaceutical, or comprises different regions with a different pharmaceutical.

11. The composition according to claim 4 , wherein the hydrophobizing agent is selected from the group consisting of waxes, silanes, ethyl cellulose, alkyl and alkenyl ketene dimers, acid anhydrides, including alkylanhydrides and alkenyl succinic anhydride, hydrophobic polymers, hydrophobic particles, fluorinated molecules, molecules containing apolar hydrocarbon moieties and any combinations thereof.1612. The composition according to claim 5, wherein the hydrophilizing agent is selected from the group consisting of Polyethylene glycol / oxide (PEG / PEO), Polyvinylpyrrolidone (PVP), a polyelectrolyte, Polyvinyl alcohol (PVA),a Zwitterionic polymer, a hydrophilic polyurethane dispersion, a hydrophilic silane, gelatin, starch or a starch derivative, cellulose or a cellulose derivative.

13. The composition according to any one of claims 3 to 12, wherein the hydrophilic particulate material is selected from the group consisting of polymethyl methylacrylate (PMMA), cellulose, nitrocellulose, polyvinyl alcohol, cellophane, polysaccharides, polyvinylpyrrolidone, polyacrylic acid, and polyethylene imine.

14. The composition according to any one of claims 3 to 12, wherein the hydrophobic particulate material is selected from the group consisting of acrylonitrile butadiene styrene, polylactic acid, polystyrene, polycaprolactone, polyhydroxyalkanoate, nylon, polyglycolic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyhydroxyalkanoate.

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