Tablets manufactured by selective laser sintering

Abstract

The invention relates to a tablet (2), wherein the tablet (2) has a plurality of precursor material particles (9) which are connected to one another by selective laser sintering, wherein the precursor material particles (9) have granule particles (6) with a granule particle diameter (60) and a coating (27) with a layer thickness (40) which coats the granule particles (6), wherein the granule particles (6) have a pharmaceutical substance (5) and the coating (27) is formed from a coating agent (8) with a thermoplastic material (7), wherein the coating (27) forms a coating matrix (64) into which the granule particles (6) are embedded.

Description

Technical Field

[0001] This invention relates to a tablet. Background Technology

[0002] Tablets are manufactured using various technologies and methods. Over the past decade, additive manufacturing, in particular, has become a hot topic, aiming to improve the manufacture of tablets containing pharmaceutically effective release formulations.

[0003] Fina et al., in "Selective laser sintering (SLS) 3D printing of medicines," *International Journal of Pharmaceutics*, Vol. 529, Nos. 1-2, August 30, 2017, pp. 285-293, https: / / doi.org / 10.1016 / j.ijpharm.2018.05.044, noted that there are currently no reports on the use of SLS to manufacture tablets filled with oral medications; therefore, this study aims to investigate the applicability of SLS printing for drug manufacturing. To this end, two pharmaceutical-grade thermoplastic polymers, Kollicoat IR and Eudragit L100-55, with immediate-release and sustained-release properties respectively, were selected to investigate the versatility of the SLS printer. Each polymer was studied using three different concentrations of acetaminophen. To facilitate the sintering process, 3% Candurin® Goldglanz was added to each powder formulation. A total of six solid formulations were successfully printed; the 3D-printed tablets were robust and durable, and no signs of degradation of the pharmaceutical substances were observed.

[0004] Furthermore, Kulinowski et al., in “Development of Composite, Reinforced, Highly Drug-Loaded Pharmaceutical Printlets Manufactured by Selective Laser Sintering - In Search of Relevant Excipients for Pharmaceutical 3D Printing”, Materials 2022, 15(6), 2142; https: / / doi.org / 10.3390 / ma15062142, described that while it is feasible, it is impractical to 3D print high-dose tablets with pure, fragile, crystalline pharmaceutical active substances using selective laser sintering (SLS). Currently used pharmaceutical excipients, including polymers, are primarily designed for powder compression to ensure good mechanical properties. Using these excipients in SLS typically results in poor mechanical properties of the printed tablets. To overcome this problem, composite tablets consisting of sintered carbon-dyed polyamide and metronidazole were fabricated using SLS. The tablets were characterized using differential scanning calorimetry and infrared spectroscopy, and their mechanical properties were evaluated. The study indicates the need to define the excipient requirements for 3D printing and to identify suitable materials. Summary of the Invention

[0005] Therefore, the object of the present invention is to provide a tablet.

[0006] For the type of tablet mentioned at the beginning, this objective is achieved by having a plurality of precursor material particles connected to each other by selective laser sintering. Each precursor material particle has a particle diameter and a coating layer of a certain thickness encapsulating the particle. The particle contains a pharmaceutical substance, and the coating layer is formed by a coating agent of a thermoplastic material, forming a coating layer matrix into which the particle is embedded. This allows for the manufacture of tablets with very high drug loading, greater than 40%, preferably greater than 60%, and particularly preferably greater than 80%.

[0007] Thermoplastic materials are materials that can undergo thermoplastic deformation within a specific temperature range. This process is reversible. This means that, as long as the material does not undergo thermal decomposition due to overheating, the process can be repeated by cooling and reheating to a molten state. Suitablely, thermoplastic polymers and / or lipids are referred to herein as thermoplastic materials.

[0008] In this context, small granular or spherical solids are called granular particles, and these small granular or spherical solids together form particles.

[0009] A drug—also known as an active substance or pharmaceutical substance—is a substance used as a pharmaceutically active ingredient in the manufacture of a medicine. Typically, a pharmaceutical substance is combined with one or more pharmaceutical excipients to form a drug, but sometimes excipients are not used at all.

[0010] A method for manufacturing tablets includes a coating step and an additive manufacturing step following the coating step, wherein, in the coating step, granular particles having a pharmaceutical substance are coated with a coating agent having a thermoplastic material to produce precursor material particles, and in the additive manufacturing step, a powdered precursor material having multiple precursor material particles is selectively laser-sintered to form a tablet.

[0011] Preferably, the method is performed on equipment for manufacturing tablets, wherein the equipment has a precursor material manufacturing apparatus and an additive manufacturing apparatus, wherein the precursor material manufacturing apparatus is designed to coat granules containing a pharmaceutical substance with a coating agent having a thermoplastic material to produce precursor material granules, and wherein the additive manufacturing apparatus is designed to manufacture a powdered precursor material having multiple precursor material granules by selective laser sintering. Suitably, the precursor material manufacturing apparatus and the additive manufacturing apparatus are fluidly connected to enable the transport of precursor material from the precursor material manufacturing apparatus to the additive manufacturing apparatus.

[0012] The powdered precursor material has multiple precursor material particles, each of which has a particle diameter and a coating layer of a certain thickness. The particle contains a pharmaceutical substance, and the coating layer is formed by a coating agent of a thermoplastic material. For non-spherical particles, the equivalent diameter of the corresponding particle is also considered as the particle diameter. Here, the equivalent diameter is a measure of the size of irregularly shaped particles. This equivalent diameter is calculated based on a comparison of the characteristics of irregularly shaped particles with those of regularly shaped particles. Advantageously, the powdered precursor material simultaneously possesses low bulk density and a large surface area, enabling the absorption of more laser energy, and the precursor material particles are joined in selective laser sintering to form tablets. Furthermore, it is advantageous to obtain improved precursor material particles from the particles by a coating step with a thermoplastic material, resulting in improved properties related to flowability and spreadability. These two improved properties are important for achieving thin powder beds in additive manufacturing processes.

[0013] In an additive manufacturing apparatus, during the additive manufacturing process, in a first step, a thin layer of powdered precursor material is distributed as a powder bed on a platform within the forming cavity of the additive manufacturing apparatus. The powder bed, containing multiple precursor material particles, is then preheated to a temperature slightly below the melting point of the thermoplastic material. This allows for easier temperature amplification of specific areas of the powder bed by a laser that tracks the shape of the tablet to solidify it. The laser scans the cross-section of the 3D tablet model and heats the powdered precursor material to a temperature slightly below or exactly equal to its melting point, causing the precursor material particles to mechanically fuse together and form a solid tablet. Welding the precursor material particles using a thermoplastic coating applied to the granular particles is particularly advantageous because the precursor material particles, and consequently the uniformly distributed coating, are evenly distributed on the powder bed. Since the unsintered powdered precursor material supports the tablet during printing, no additional support structure is required for tablet manufacturing. The platform then descends one layer into the forming cavity, typically between 50 µm and 200 µm. The entire process is then repeated for each layer until the tablet is complete.

[0014] Then, in the second step, the forming cavity is preferably cooled, first inside the additive manufacturing apparatus and subsequently outside the additive manufacturing apparatus designed as a printer, in order to ensure optimal mechanical properties and prevent the tablet from deforming.

[0015] In the third step of the additive manufacturing method, the finished tablet is removed from the forming cavity, separated, and excess powdered precursor material is removed. The excess powdered precursor material can be reused, and the tablet can be post-processed.

[0016] This method enables the manufacture of tablets with very high drug loading, exceeding 40%, preferably exceeding 60%, and particularly preferably exceeding 80%.

[0017] According to the first method variant, the method further includes a granulation step in which granules are produced consisting of multiple granular particles, wherein the granulation step is performed prior to the coating step. Suitably, the granulation step is performed as a direct granulation process, a vertical granulation process, or a spray drying process. In this case, the granulation device associated with the precursor material manufacturing apparatus is suitably designed as an extruder (especially a twin-screw extruder), a vertical granulator, or a spray dryer. Preferably, in the first method variant, the granulation device is arranged upstream of the coating apparatus.

[0018] In vertical granulation (also known as high-shear granulation or wet granulation), with the addition of a liquid granulating agent, various powdered raw materials are granulated into large, uniformly distributed, and very dense particles by the high mechanical shearing action of a rotating mixing tool. In high-shear granulation, larger particles are preferably further shredded by a laterally arranged shredder. The granulating agent is particularly designed as a dissolved binder or a water-organic solvent mixture. Commonly used binders are water, polyvinylpyrrolidone, cellulose esters, or gelatin.

[0019] In spray drying, powdered raw materials are dissolved, emulsified, or dispersed in a solution of solvent or carrier material. The solution, emulsion, suspension, or dispersion is then atomized and sprayed into a drying chamber, through which a hot, drying gas stream promotes solvent evaporation. Spray drying produces granules that vary considerably in size and exhibit poor flowability.

[0020] According to another advantageous design related to the first method variant, a sieving step is performed between the granulation step and the coating step, wherein, for the coating step, granules with a unimodal particle size distribution are produced. To perform the sieving step, the precursor material manufacturing apparatus has a sieving device in which granules with a unimodal particle size distribution are produced. Accordingly, the sieving device of the precursor material manufacturing apparatus is suitably arranged downstream of the granulation device. Due to the unimodal particle size distribution after the sieving step, uniform coating of the granules can be achieved in the coating step.

[0021] For coating a granular material having multiple granular particles, the precursor material manufacturing apparatus has a coating device, wherein the coating device is suitably designed as a fluidized bed, a spray bed, or a roller coating device.

[0022] In a first method variant, the coating step is preferably performed as a roller coating process, wherein the granules are coated with a coating agent in a rotating roller. In a first process embodiment, the coating step is preferably performed as a roller coating process, wherein the granules are coated with a coating agent in a rotating roller. In the roller coating process (also known as roller coating or roller coating), the granules are gently and controlledly moved in the roller and coated with a coating layer of thermoplastic material. It is important here to distribute the coating agent as evenly as possible on the granules. This is ensured on the one hand by appropriate spraying equipment, and on the other hand by uniform mixing of the granules having multiple granules in the roller.

[0023] In a second method variant that replaces the first method variant, the method includes a granulation step in which granules composed of multiple granular particles are produced, wherein the granulation step is performed simultaneously with the coating step. In particular, here, the granulation step performed simultaneously with the coating step is carried out as a spray agglomeration process or a spray granulation process. In this case, the granulation apparatus associated with the precursor material manufacturing apparatus is suitably designed as a fluidized bed or spray bed apparatus. The advantage of using the alternative second method variant is that the coating of the precursor material particles occurs simultaneously with its granulation / agglomeration.

[0024] In spray agglomeration, extremely small, powdery raw particles move in a fluidized bed and are sprayed with a binder, thereby forming liquid bridges between the raw particles and creating so-called agglomerated particles. In this case, the binder is also suitably a coating agent. Due to the low kinetic energy during spray agglomeration in a fluidized bed, a porous structure with multiple internal capillaries, i.e., cavities, is formed after the residual moisture evaporates. The hardened binder further reinforces the new structure. The dust-free, highly fluid agglomerated particles can be easily metered and can be optimally further processed. During agglomeration, finely dispersed raw particles are transformed into granular particles in the form of binding units by introducing a binder. Therefore, agglomerated particles are subsequently referred to as granular particles. Correspondingly, agglomerates with multiple agglomerated particles produced in spray agglomeration are also called granules. By using a coating agent as a binder, agglomerated particles are simultaneously coated in a fluidized bed or spray bed.

[0025] In spray granulation, parameters such as particle size, residual moisture, and solids content can be selectively influenced, and various product characteristics of the granules can be set. Granules produced by spray granulation have a dense surface structure and high bulk density; due to their small surface area, these granules have very low hygroscopicity, meaning they absorb almost no ambient moisture. Furthermore, they exhibit excellent flowability, abrasion resistance, spray resistance, good solubility, and optimal metering. Therefore, granules can also be coated simultaneously in fluidized beds or spray beds. Compared to agglomerates, granules produced by spray granulation are denser and harder.

[0026] Advantageously, in spray agglomeration or spray granulation processes, the precursor material is manufactured in a fluidized bed or spray bed apparatus, wherein particles are pre-added and the granules are sprayed with a coating agent. Alternatively, in spray agglomeration or spray granulation processes, the precursor material is manufactured in a fluidized bed or spray bed apparatus, wherein the particles, together with the coating agent, are introduced into the fluidized bed or spray bed apparatus as a solution, emulsion, suspension, or melt.

[0027] Coating, specifically applying functional coatings, can target and influence the surface structure of granular particles. Fluidized bed and spray bed applications are effective coating processes for creating these coatings. A crucial aspect of coating is achieving highly uniform application of the coating agent. Coating in fluidized bed and spray bed systems can be performed either batch-wise or as a continuous process.

[0028] By performing a granulation step before or concurrently with the coating step, it is possible to establish an appropriate balance in the coating step based on the particle size, morphology, and size distribution of the precursor material, which is essential for selective laser sintering in the additive manufacturing step.

[0029] In principle, for precursor material particles, the larger and rounder the particles, and the more unimodal their size distribution, the better the flowability. Key parameters determining flowability include particle size distribution, particle shape, particle chemical composition, moisture content, and temperature. Flowability is measured using the angle of repose method (also known as the angle of repose or friction angle) and the Hausner factor, as listed in the European Pharmacopoeia. The angle of repose of a particle is the maximum angle of inclination relative to the horizontal plane at which it can be tilted without settling. The Hausner factor is a dimensionless number, calculated here as the ratio of tapped density to bulk density, or bulk volume to tapped volume. Powder flow behavior is considered "excellent" when the Hausner factor is between 1.00 and 1.11. As the Hausner factor continues to increase, the flow behavior deteriorates, with values ​​above 1.60 considered "inadequate." Correspondingly, precursor materials with small angles of repose and Hausner factors close to 1 are evaluated as preferred precursor materials. Good fluidity also facilitates the distribution of precursor materials.

[0030] Therefore, for selective laser sintering (SLS), precursor material particles, in addition to good flowability and distribution, should also have low packing density and large surface area to absorb more laser energy and fuse together to form a solid tablet during printing. Thus, small, round precursor material particles with a preferred unimodal particle size distribution are preferred. Correspondingly, the precursor material particles preferably have a sphericity greater than or equal to 0.75, suitably greater than or equal to 0.9, and especially greater than or equal to 0.93. Furthermore, it is particularly preferred that the precursor material particles have precursor material particle diameters of 20 µm and 200 µm, and suitably from 50 µm to 150 µm. Here, the coating layer suitably has a layer thickness in the range of 0.1 µm to 50 µm, and especially in the range of 5 µm to 20 µm. Suitablely, the precursor material particles have a particle diameter to layer thickness ratio of 2:1 to 15:1, particularly 2:1 to 10:1.

[0031] According to an additional advantageous design of the method, the fluidized bed or spray bed device has a process chamber with a circular cross-section and a nozzle device that sprays the coating agent into the process chamber along a main spray direction. The main spray direction is designed to be parallel to the tangent of the circular cross-section of the process chamber and is arranged within an arc segment of the circular cross-section, the height of which is 30% of the cross-sectional radius. The coating agent or a suspension containing the coating agent is sprayed into the fluidized bed or spray bed device through the nozzle device, or is capable of being sprayed into the fluidized bed or spray bed device. For this purpose, it is sufficient that one directional component of the main spray direction is parallel to the tangent. The aforementioned nozzle device is also called a so-called tangentially sprayed nozzle device, which produces "tangential spraying". By means of tangentially sprayed coating agents with thermoplastic materials, a very uniform coating of the coating agent on the granular particles is achieved, thereby creating a coating layer of substantially constant thickness on the granular particles. In addition to tangential spraying, the coating agent can also be sprayed into the process chamber from below as "bottom spraying" (the main spraying direction is along the flow direction of the process gas in the fluidized bed or spray bed device), and can be sprayed into the process chamber from above as "top spraying" (the main spraying direction is opposite to the flow direction of the process gas in the fluidized bed or blower bed device).

[0032] In addition to the thermoplastic material, the coating agent containing the thermoplastic material may also contain other substances, such as a solvent, if suitable; however, the coating agent may also consist of only at least one thermoplastic material.

[0033] However, advantageously, the coating agent used, in addition to the thermoplastic material, also contains a solvent. A solvent is a substance capable of dissolving and diluting gases, liquids, or solids to form a solution. This makes the coating agent easier to atomize and therefore easier to coat onto the granular particles. Preferably, water and / or organic solvents are used as solvents. Suitablely, alcohols, ketones, alkanes, and / or ethers are used as organic solvents. Water has the advantage of being cheaper and less environmentally harmful than organic solvents. During the coating step, the solvent evaporates or dissipates because heated process gases flow around the precursor material particles during the coating step.

[0034] In a further advantageous design of this method, thermoplastic polymers or lipids, particularly polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), or methyl methacrylates (Eudragite), are used as the thermoplastic material. As the name suggests, thermoplastic materials possess thermoplastic properties, meaning they soften upon heating, solidify upon cooling, and do not undergo chemical changes. Biocompatible materials, especially biocompatible polymers or lipids, are particularly suitable for this method.

[0035] Suitablely, tablet manufacturing uses a precursor material having multiple precursor material particles, wherein, in an additive manufacturing step, the precursor material particles are selectively laser-sintered to form the tablet. In this case, a high-power laser sintersects the material, particularly the thermoplastic material of the coating agent, into a solid structure based on a 3D model of the tablet.

[0036] In an additive manufacturing step of selectively laser sintering powdered precursor materials into tablets, a powder bed melting system designed as a selective laser sintering printer is used in the additive manufacturing apparatus. This powder bed melting system preferably has at least one laser unit, and this laser unit has a CO2 laser or a fiber laser, making it suitable to use a CO2 laser or fiber laser for selective laser sintering. In this case, the powder bed melting system designed as a selective laser sintering printer has at least one laser unit, wherein each laser unit has a scanning system formed by at least one mirror controlled by at least one drive unit, such that each laser beam of the laser unit heats the precursor material particles to or above their melting point, thereby connecting the precursor material particles to each other. By using multiple laser units, tablet manufacturing can be scaled up, i.e., the number of tablets manufactured in a single additive manufacturing step can be adjusted. In this additive manufacturing method, selected regions of the precursor material particles constituting the powder bed are fused or welded together by the thermal energy introduced by the laser. Suitable for selective laser sintering, when using a CO2 laser, a wavelength of 10600 nm is used at a power of 14 W; when using a fiber laser, a wavelength of 1064 nm is used at a power of 10 W. CO2 lasers are gas lasers based on electrically excited carbon dioxide mixtures and possess excellent beam quality. In contrast, fiber lasers are approximately 30% more efficient. Fiber lasers also offer higher energy efficiency, longer lifespan, and a more compact form factor.

[0037] Furthermore, the additive manufacturing apparatus is suitably designed to manufacture tablets from precursor materials by selective laser sintering in a protective gas atmosphere, wherein nitrogen or argon can suitably be used as the protective gas.

[0038] In particular, the tablets contain different precursor material particles, each containing granules of a different pharmaceutical substance. This allows different pharmaceutical substances to have different release profiles.

[0039] The tablet has multiple precursor material layers composed of precursor material particles. Advantageously, one of the multiple precursor material layers contains precursor material particles that are different from the precursor material particles of the adjacent precursor material layers. Through these multiple precursor material layers, the tablet becomes a multilayer tablet. These layers combine different therapeutic doses in a single form of administration. It is also advantageous that the pharmaceutical substance contained in each precursor material layer can be configured with a different release profile.

[0040] Furthermore, the precursor material layers are suitably configured with different packing densities. Therefore, the precursor material layers are more compact, and the tablets themselves are more compact and stable.

[0041] The corresponding tablets are further characterized by having excipient particles, wherein the excipient particles are disintegrating particles with a diameter equivalent to disintegrating particles, and having a coating layer of a certain thickness that covers the disintegrating particles, wherein the disintegrating particles contain a disintegrant, and the coating layer is formed by a coating agent of a thermoplastic material. This allows for the targeted setting of the release profile of the pharmaceutical substance.

[0042] According to another advantageous design of the tablet, the tablet has at least one capillary channel designed to deliver liquids (e.g., gastric juices, in particular) into the tablet interior via capillary action. The release profile can also be adjusted and set via the capillary channel.

[0043] Tablets manufactured according to this method can be coated with a shell layer in a post-processing step, preferably a shell layer resistant to gastric juice. Attached Figure Description

[0044] The invention will then be described in more detail with reference to the accompanying drawings, in which:

[0045] Figure 1 A first embodiment of an apparatus for manufacturing tablets is shown;

[0046] Figure 2 A second embodiment of an apparatus for manufacturing tablets is shown;

[0047] Figure 3A third embodiment of an apparatus for manufacturing tablets is shown;

[0048] Figure 4 A fourth embodiment of an apparatus for manufacturing tablets is shown;

[0049] Figure 5 A fifth embodiment of an apparatus for manufacturing tablets is shown;

[0050] Figure 6 A sixth embodiment of an apparatus for manufacturing tablets is shown;

[0051] Figure 7 A schematic structure of a fluidized bed apparatus for manufacturing tablets is shown, wherein section AA passes through the conical portion of the process chamber;

[0052] Figure 8 It shows the relationship with Figure 7 The section corresponding to section AA of the conical part passing through the process chamber;

[0053] Figure 9 A schematic structure of an additive manufacturing apparatus in the form of a powder bed melting system designed as a selective laser printer is shown;

[0054] Figure 10 A schematic process is shown for coating granules with a particle diameter and a coating layer of a certain thickness.

[0055] Figure 11 A multilayer tablet with two precursor material layers and a vertical section AA is shown;

[0056] Figure 12 It shows the passage along Figure 11 The diagram shows a vertical cross-section AA of a multilayer tablet, wherein a coating layer forms a coating layer matrix, and granular particles are embedded in the coating layer matrix; and

[0057] Figure 13 It shows in Figure 11 The diagram shows a meandering capillary channel in the lower precursor material layer of a multilayer tablet.

[0058] Unless otherwise stated, the following description refers to all embodiments of the apparatus 1 for manufacturing tablets 2 according to the present invention, as illustrated in the accompanying drawings. Detailed Implementation

[0059] On the apparatus 1, a method for manufacturing tablet 2 is suitably performed. For this purpose, the apparatus 1 includes: a precursor material manufacturing device 3 for performing at least one coating step; and an additive manufacturing device 4 for performing an additive manufacturing step following the coating step. Suitably, the precursor material manufacturing device 3 is fluidly connected to the additive manufacturing device 4 so that a precursor material 10 having a plurality of precursor material particles 9 can be transferred from the precursor material manufacturing device 3 to the additive manufacturing device 4.

[0060] In the coating step, granular particles 6 containing pharmaceutical substance 5 are coated with a coating agent 8 containing thermoplastic material 7 to produce a powdered precursor material 10 having a plurality of precursor material particles 9. In addition to the thermoplastic material 7, the coating agent 6 may contain a solvent 57, wherein, in particular, water and / or organic solvents are used as solvents, and wherein, suitably, alcohols and / or ketones and / or alkanes and / or ethers are used as organic solvents. Preferably, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), or eudrasite is used as the thermoplastic material 7. As the name suggests, the thermoplastic material 7 has thermoplastic properties, i.e., it softens upon heating, solidifies upon cooling, and does not undergo chemical changes. Biocompatible material 7 is particularly suitable for this method. Suitablely, the precursor material manufacturing apparatus 3 has a coating device 11 for this purpose, which is particularly designed as a fluidized bed device 12, a spray bed device 13, or a roller coating device 14.

[0061] Precursor material manufacturing apparatus 3 – such as in Figures 1 to 4 As shown in the corresponding embodiment, it also includes a granulation device 28 that produces granules 6 containing the pharmaceutical substance 5. Suitably, the granulation device 28 is designed herein as a vertical granulator 29, a spray dryer 30, a fluidized bed device 12, or a jet bed device 13, and is preferably arranged upstream of the coating device 11.

[0062] According to Figure 1The first embodiment of the apparatus 1 shown in the figure includes a granulation step performed on the apparatus 1, in which granules 31 composed of multiple granular particles 6 are produced by means of a vertical granulation method. Here, the granulation step is performed before the coating step. In vertical granulation (also known as high-shear granulation or wet granulation), with the addition of a liquid granulating agent 33, various powdered raw materials 32 containing pharmaceutical substances 5 are formed into large, uniformly distributed, and very dense granular particles 6 by the high mechanical shear action of a rotating mixing tool 34 (especially an anchor mixer 69, a wing mixer 70, or a paddle mixer). Here, the shape of the mixing tool 34 is preferably adapted to the profile of the mixing container of the vertical granulator 29. In vertical granulation, dissolved binders or water-organic solvent mixtures are used in particular as the granulating agent 33. Commonly used binders are water, polyvinylpyrrolidone, cellulose esters, or gelatin.

[0063] exist Figure 2 In the second embodiment shown, an alternative implementation of the granulation apparatus 28 is illustrated using a spray drying apparatus 30, wherein the granulation step is also performed prior to the coating step. Accordingly, the spray drying process is performed using the spray drying apparatus 30. In spray drying, a powdered raw material 32 containing the pharmaceutical substance 5 is dissolved, emulsified, or dispersed in a solution of a solvent or carrier material. The solution, emulsion, suspension, or dispersion containing the raw material 32 is then atomized and sprayed into a drying chamber 36, through which a hot drying gas stream 35, promoting solvent evaporation, flows. In spray drying, the resulting granules 6 vary considerably in size and have poor flowability.

[0064] According to Figure 1 and Figure 2 The apparatus 1 depicted includes a sieving step between the granulation and coating steps, wherein, for the coating step, granules 31 with a unimodal particle size distribution are produced. For this purpose, the precursor material manufacturing apparatus 3 has a sieving device 37, which is suitably arranged downstream of the granulation apparatus 28 and upstream of the coating apparatus 11. In the sieving device 37, the granules 31, composed of multiple granular particles 6, are conveyed through a sieve 38 with the desired mesh size, thereby forming sieved granules 31 with a unimodal particle size distribution.

[0065] exist Figure 1 and Figure 2In both embodiments, after the screening step, in a coating step designed as a roller coating process, the granular particles 6 are coated with a coating agent 8 having a thermoplastic material 7 in a roller coating apparatus 14 having a rotating roller 39. In the roller coating apparatus 14, the granular particles 6 are gently and controlledly moved in the roller 39, thereby being coated with a coating layer 27 having a layer thickness 40. It is important here to distribute the coating agent 8 as uniformly as possible. This is ensured on the one hand by a corresponding spraying device having a nozzle device 51 for spraying the coating agent 8, and on the other hand by uniform mixing. During the coating step, a coating drying gas 41 also flows through the roller 39, thereby drying the coating agent 8 having the thermoplastic material 7 coated on the granules 31 having a plurality of granular particles 6 to form the coating layer 27.

[0066] and Figure 1 and Figure 2 The first two implementations shown are different, in Figure 3 and Figure 4 The two embodiments shown do not have a sieving step between the granulation and coating steps. The vertical granulation or spray drying process performed in the granulation step is the same as the vertical granulation or spray drying process already described in the previous two embodiments. Subsequently, in accordance with Figure 3 In the vertical granulation process or according to Figure 4 The granules 31 produced in the spray drying process are coated in a fluidized bed apparatus 12 in the third embodiment and in a spray bed apparatus 13 in the fourth embodiment, respectively, after the granulation step. In both embodiments, the granules 31 are pre-added as a base material to the corresponding fluidized or spray bed apparatus 12, 13 and sprayed with a coating agent 8 having a thermoplastic material 7.

[0067] Similar to fluidized beds, jet beds are based on the fundamental principles of fluidization and the pneumatic conveying of granular particles 6 by process gas 45 (especially process air or inert gases such as nitrogen) flowing upwards through the fluidized bed device 12 or jet bed device 13. The main difference lies in the implementation of the process gas inlet. In the jet bed device 13, the process gas inlet is designed as a gap opening 71, combined with a special streamlined shape and a significantly expanded process chamber 42. In the fluidized bed device 13, the process gas inlet is designed as a perforated plate base with perforations, also known as an inflow base 46.

[0068] Subsequently, using section AA of the conical portion passing through process chamber 42, the process for manufacturing tablet 2 is illustrated exemplary. Figure 7 The working principle and schematic structure of the fluidized bed device 12 are shown. In the fluidized bed device 12, granular particles 6 are coated to form precursor material particles 9.

[0069] The fluidized bed apparatus 12 comprises, from bottom to top, a distribution chamber 43, a process chamber 42, and an exhaust section 44. Suitably, the fluidized bed apparatus 12 has a process chamber 42 with a circular cross-section 50. Process gas 45 required for coating and drying the precursor material 10 having multiple precursor material particles 9 is supplied to the distribution chamber 43, where it is distributed and enters the process chamber 42 via an inflow base 46. The process chamber 42 is defined in its lower region by inclined side surfaces 49, such that the lower region of the process chamber is designed to be conical. The process gas 45 flows through the process chamber 42 toward the exhaust section 44 and preferably exits the fluidized bed apparatus 12 as exhaust gas 48 purified by a dust removal system 47 (especially a cartridge or fabric filter element) arranged in the exhaust section 44.

[0070] In process chamber 42, granular particles 6 are pre-added or generated independently. These particles are carried upward by process gas 45 toward a dust collection system 47 arranged in exhaust section 44 and thereby fluidized. In the upper region of process chamber 42, the process gas velocity decreases, causing the upwardly flowing granular particles 6 to fall back into the lower region of process chamber 42. Through this mechanism, a very uniform fluidized bed is formed on the granular particles 6 in process chamber 42.

[0071] exist Figure 7 In the fluidized bed apparatus 12, three different nozzle devices 51 are exemplarily shown, particularly single-material nozzles or multi-material nozzles, which can be installed interchangeably. The coating agent 8 is sprayed into the process chamber 42 along the main spray direction through the nozzle devices 51. If the coating agent 8 having the thermoplastic material 7 is sprayed by means of the nozzle devices 51 arranged in the lower region of the process chamber 42, where the main spray direction is along the flow direction of the process gas 45 in the fluidized bed apparatus 12, the nozzle devices 51 produce a jet flow 56 also known as "bottom spray". On the other hand, if the nozzle devices 51 are arranged in the upper region of the process chamber 42 and spray along the main spray direction opposite to the flow direction of the process gas 45, the nozzle devices 51 produce a jet flow 56 also known as "top spray". According to a preferred third alternative, its arrangement further includes... Figure 8As shown, the fluidized bed apparatus 12 has a nozzle device 51 arranged on the side of the process chamber 42, wherein the main spray direction is parallel to the tangent 55 of the circular cross-section 50 of the process chamber 42 and is arranged within an arc segment 52 of the circular cross-section 50, the arc segment height 53 of which is 30% of the cross-sectional radius 54, and wherein the coating agent 8 or a suspension having the coating agent 8 is sprayed into the fluidized bed apparatus 12 through the nozzle device 51. For this purpose, it is sufficient that one directional component of the main spray direction of the jet stream 56 is parallel to the tangent. This nozzle device 51 is also called a so-called tangential spray nozzle device 51, which produces "tangential spray". By means of the tangentially sprayed coating agent 8 having thermoplastic material 7, a very uniform coating of the coating agent 8 on the granular particles 6 is achieved, thereby producing a coating layer 27 with a substantially constant layer thickness 40 on the granular particles 6, so that the resulting precursor material particles 9 have very good flow characteristics.

[0072] The nozzle device 51, preferably a dual-substance nozzle, is configured to spray very small droplets 62 with a liquid size of 1 µm to 100 µm, preferably 1 µm to 50 µm, and particularly preferably between 5 µm and 10 µm. By setting the droplet size using the nozzle device 51 and the compression space acting on it, the shear force generated during spraying can be precisely set, enabling the achievement or attainment of a very uniform droplet size for the coating agent 8 to be sprayed. The droplets 62 adhere to the granular particles 6 containing the pharmaceutical substance 5, and when using the solvent 57, film evaporation of the solvent preferably occurs.

[0073] Due to the highly favorable heat and mass transfer and high-speed circulation of the granules in the spray zone 58 of the process chamber 42 of the fluidized bed apparatus 12, the coating agent 8 is substantially deposited on the granules 6, and these granules are thus uniformly wetted on the granule surface 59. This uniform wetting, occurring simultaneously with the high-speed circulation of the granules in the spray zone 58, results in the formation of a very uniform coating layer 27 on the granules 6. During the drying process, the solvent 57 evaporates and exits the fluidized bed apparatus 12 with the exhaust gas 48. The thermoplastic material 7 contained in the coating agent 8 remains on the granule surface 59 of the granules 6 as a coating layer 27 with a layer thickness of 40, resulting in very uniform and homogeneous growth and coating of the precursor material particles 9.

[0074] Figure 10 A schematic process is described in which a coating layer 27 with a thickness of 40 is applied to a granular particle 6 having a particle diameter of 60 to form a precursor material particle 9.

[0075] The discharge 61 of the coated granular particles 6, referred to as precursor material particles 9, can be achieved, for example, by overflow or by a volumetric discharge device (especially a rotary valve), or by a gravity classifier (preferably a zigzag classifier or a riser classifier loaded with sieving gas).

[0076] Alternatively, in addition to the coating agent 8, liquid additives or other components may be sprayed into the process chamber 42 and thus uniformly embedded in the granular structure. The additives may also be included in the coating agent 8.

[0077] exist Figure 5 and Figure 6 In the fifth and sixth embodiments shown, granules 31 composed of a plurality of granular particles 6 are generated in the coating apparatus 11 and coated simultaneously. Accordingly, the granulation step and the coating step are performed simultaneously. Preferably, the granulation step performed simultaneously with the coating step is performed as a spray agglomeration process or a spray granulation process.

[0078] In spray agglomeration, extremely fine powdery raw material 32 (also called raw particles) moves in a fluidized bed and is sprayed with a binder, thereby forming liquid bridges between the raw material 32 and forming so-called agglomerated particles. In this case, the binder is also suitably a coating agent 8. Due to the low kinetic energy during spray agglomeration in a fluidized bed, a porous structure with multiple internal capillaries, i.e., cavities, is formed after the residual moisture evaporates. The hardened binder further strengthens the new structure. The dust-free, highly fluid agglomerated particles can be easily metered and can be optimally further processed. During agglomeration, the finely dispersed raw material 32 is transformed into granular particles 6 in the form of binding units by introducing the binder. Therefore, the agglomerated particles are subsequently referred to as granular particles 6. Correspondingly, the agglomerate with multiple agglomerated particles produced in spray agglomeration is also referred to as granules 31. By using the coating agent 8 as a binder, the agglomerated particles are simultaneously coated in a fluidized bed or spray bed.

[0079] In spray granulation, parameters such as particle size, residual moisture, and solids content can be selectively influenced, and various product characteristics of the granules 6 can be set. The granules 6 produced by spray granulation have a dense surface structure and high packing or filling density; due to their small surface area 59, these granules have very low hygroscopicity, i.e., they absorb almost no ambient moisture. Furthermore, they exhibit excellent flowability, abrasion resistance, spray resistance, good solubility, and optimal metering. Therefore, the granules 6 can also be coated simultaneously in a fluidized bed or spray bed. Compared to agglomerates, the granules 31 from spray granulation are denser and harder.

[0080] exist Figure 5In the precursor material manufacturing apparatus 3 shown, the precursor material 10 is manufactured by spray granulation process in the coating apparatus 11, which is designed as a fluidized bed apparatus 12, wherein granules 31 are added in advance and the granule particles 6 are sprayed with a coating agent 8.

[0081] In a series of experiments, metoprolol succinat was used as pharmaceutical substance 5 to perform the procedures according to... Figure 5 The method. β-blockers have particularly poor flow characteristics. The angle of repose is shown to be 52°, and the Hausner factor is shown to be 1.68. The pharmaceutical substance has been pre-added to the fluidized bed apparatus 12 and sprayed in the form of a thermoplastic material 7, namely Kollidon VA 64 (PVPVA), in a "tangential spraying" manner because this thermoplastic material has good solubility in water and organic solvents. By performing the granulation and coating steps simultaneously in the fluidized bed apparatus 12, the flowability of the resulting precursor material particles 9 is significantly improved. Now, the angle of repose is shown to be 31°, and the Hausner factor is shown to be 1.21. Another advantage is the uniform distribution of material 7 on the surface 59 of the granules, thereby increasing the contact area between the individual precursor material particles 9.

[0082] Instead of this, in accordance with Figure 6 The precursor material manufacturing apparatus 3 is designed as a coating apparatus 11 of the spray bed apparatus 13 to manufacture the precursor material 10 by a spray agglomeration process, wherein the granules 31 are introduced into the spray bed apparatus 13 together with the coating agent 8 as a solution, suspension or melt.

[0083] Each manufactured precursor material particle 9 has a granular particle 6 with a particle diameter of 60, and a coating layer 27 with a thickness of 40 covering the granular particle 6, wherein the granular particle 6 has a pharmaceutical substance 5, and the coating layer 27 is formed of a coating agent 8 having a thermoplastic material 7. Preferably, the precursor material particle 9 has a sphericity greater than or equal to 0.75, suitably greater than or equal to 0.9, and particularly greater than or equal to 0.93.

[0084] Furthermore, the precursor material particles 9 have a precursor material particle diameter 63 of 20 µm to 200 µm, suitably 50 µm to 150 µm. The precursor particle diameter 63 is derived by adding twice the thickness 40 of the coating layer 27 to the particle diameter 60. Preferably, the coating layer 27 has a thickness 40 in the range of 0.1 µm to 50 µm, particularly in the range of 5 µm to 20 µm. By preferably selecting the precursor material particle diameter 63, it is ensured that laser energy can penetrate the precursor material particles 9, and that the coating layers 27 of the precursor material particles 9, composed of thermoplastic material 7, can connect to each other, particularly fused together. Furthermore, a smaller precursor material particle diameter 63 has a larger surface area, thereby absorbing more laser energy. It has proven advantageous that the ratio of the particle diameter 60 to the layer thickness 40 of the precursor material particles 9 should be 2:1 to 15:1, particularly 2:1 to 10:1.

[0085] The tablet 2 is manufactured using a precursor material 10 having multiple precursor material particles 9, wherein, in an additive manufacturing step, the precursor material particles 9 are selectively laser-sintered to form the tablet 2. In this case, a high-power laser sinters the material 7, especially the thermoplastic material 7 of the coating agent 8, into a solid coating matrix 64 based on a 3D model of the tablet 2.

[0086] In the additive manufacturing apparatus 4, during the additive manufacturing step, a powdered precursor material 10 having multiple precursor material particles 9 is selectively laser sintered to form a tablet 2. For this purpose, the additive manufacturing apparatus 4 is particularly designed as a powder bed melting system 15 in the form of a selective laser sintering printer 16. Suitably, the powder bed melting system 15, designed as a selective laser sintering printer 16, has at least one laser unit 17, wherein the laser unit 17 has a CO2 laser 18 or a fiber laser 19. Each laser unit 17 has a scanning system 21 formed by at least one reflector 20 controlled by at least one drive unit (not shown), such that each laser beam 22 of the laser unit 17 heats the precursor material particles 9 to or above their melting point, so as to connect, and in particular fuse, the precursor material particles 9 together to form the tablet 2. Therefore, suitably, the CO2 laser 18 used has a wavelength in the range of 9600 nm to 10600 nm at a power of 14 W, and the fiber laser 19 used has a wavelength of 1064 nm at a power of 10 W. According to a specific design of the laser sintering printer 16, which has a forming cavity housing 73, the laser sintering printer 16 is suitable for manufacturing tablets 2 from the precursor material 10 by selective laser sintering in a protective gas atmosphere 23, wherein, suitably, nitrogen or argon can be used as the protective gas.

[0087] The additive manufacturing process includes three steps: printing the tablet, cooling the printed tablet 2 and removing the cooled tablet 2 from the additive manufacturing apparatus 4, and separating the tablet 2 from the excess powdered precursor material 10.

[0088] Correspondingly, in the additive manufacturing apparatus 4, in the first step, powdered precursor material 10 is distributed in a thin layer as a powder bed 24 from the precursor material reserve 71 onto the platform 25 within the forming cavity 26 of the additive manufacturing apparatus 4 by means of a dispensing device 74. Preferably, the powder bed 24 containing the powdered precursor material 10, having a plurality of precursor material particles 9, is preheated to a temperature slightly below the melting point of the thermoplastic material 7 by a preheating device not shown here. Thus, the temperature of a specific area of ​​the powder bed 24 can be further and more easily increased by the lasers 18, 19 of the laser unit 17, which solidify the tablets by tracking the shape of the tablets 2. The lasers 18, 19 scan the cross-section of the 3D tablet model and accordingly heat the powdered precursor material 10 to a temperature slightly below or exactly equal to the melting point, causing the precursor material particles 9 to mechanically fuse together and form a solid tablet 2. Welding the precursor material particles 9 using a coating layer 27 of thermoplastic material 7 applied to the granules 6 is particularly advantageous because the precursor material particles 9, due to the good flow properties of the precursor material particles 9 and the coating layer 27 uniformly coated on them, are evenly distributed in the platform 25 on the powder bed 24. Since the unsintered powdered precursor material 10 supports the tablet 2 during printing by lasers 18 and 19, no additional support structure is required for tablet manufacturing in the additive manufacturing apparatus 4. The platform 25 then descends one layer into the forming cavity 26, corresponding to the precursor material particle diameter 63, typically between 50 µm and 200 µm. The entire process is then repeated for each layer until the tablet 2 is completed.

[0089] Then, in the second step, the forming cavity 26 is preferably cooled, first within the additive manufacturing apparatus 4 and subsequently—if necessary—outside the additive manufacturing apparatus 4, which is designed as a laser sintering printer 16, in order to ensure optimal mechanical properties and prevent the tablet 2 from deforming.

[0090] In the third step of the additive manufacturing method, the finished tablet 2 is removed from the molding cavity 26, separated, and excess powdered precursor material 10 is removed. The excess powdered precursor material 10 can be reused, and the tablet 2 can be post-processed if necessary.

[0091] By performing this method on device 1, it is possible to manufacture tablets 2 with a very high drug loading, greater than 40%, preferably greater than 60%, and particularly preferably greater than 80%.

[0092] Accordingly, the tablet 2 produced according to the method for manufacturing tablet 2 has a plurality of precursor material particles 9 connected to each other by selective laser sintering, wherein the precursor material particles 9 have: granular particles 6 with a particle diameter of 60; and a coating layer 27 with a layer thickness of 40 covering the granular particles 6. In this case, the granular particles 6 have a pharmaceutical substance 5, and the coating layer 27 is formed by a coating agent 8 having a thermoplastic material 7. The coating layer 27 of each precursor material particle 9 forms a coating layer matrix 64 by laser sintering, and the granular particles 6 are embedded in the coating layer matrix in which the respective precursor material particles 9 are fused together.

[0093] In particular, tablet 2 has different precursor material particles 9, wherein the different precursor material particles 9 each have granular particles 6 containing different pharmaceutical substances 5. Thus, the different pharmaceutical substances 5 can have different release profiles.

[0094] according to Figure 11 Tablet 2 has two precursor material layers 65, which, for better distinction, are labeled as first precursor material layer 65a and second precursor material layer 65b. Through the two precursor material layers 65a and 65b, tablet 2 becomes a multilayer tablet. Figure 11 The diagram illustrates a multilayer tablet having two precursor material layers 65a and 65b and a vertical cross-section AA. The precursor material layer 65 of the tablet 2 shown also has different precursor material particles 9, which are respectively labeled as first precursor material particle 9a and second precursor material particle 9b for better distinction. In this respect, the precursor material particles 9a of the precursor material layer 65a are different from the precursor material particles 9b of the precursor material layer 65b adjacent to the precursor material layer 65a.

[0095] Multilayer tablets combine different therapeutic doses in a single administration form by using different precursor material particles 9a and 9b, because the pharmaceutical substance 5 contained in the different precursor material particles 9a and 9b of the corresponding precursor material layers 65a and 65b can be equipped with different release profiles.

[0096] Figure 12 It shows the passage along Figure 11The diagram shows a vertical cross-section AA of a multilayer tablet. Here, suitably, the precursor material layer 65b has precursor material particles 9b with different packing densities. Therefore, the precursor material layer 65b is more densely packed, and the tablet 2 as a whole achieves compactness and stability. In the illustrated embodiment, the precursor material particles 9a, 9b are coated with the same coating agent 8. This provides the advantage that the thermoplastic material 7 forming the coating layer 27 is heated in the same manner during selective laser sintering by the laser sintering printer 16. Different coating agents 8 can be used; however, when selecting the coating agent 8, care should be taken to ensure that the melting points of the thermoplastic materials 7 are approximately the same. In each precursor material layer 65a, 65b, the coating layer 27 forms a coating layer matrix 64 into which the granular particles 6 containing the pharmaceutical substance 5 are embedded. In this case, the two coating layer matrices 64 of the precursor material layers 65a, 65b are also designated as the first coating layer matrix 64a and the second coating layer matrix 64b. Since the same coating agent 8 is selected for different precursor material particles 9a and 9b, the two coating matrixes 64a and 64b can also be optimally fused to each other.

[0097] Furthermore, the precursor material layer 65b is characterized in that it has excipient particles 66, wherein the excipient particles 66 have disintegrating particles 67 with a disintegrating particle diameter, and has a coating layer 27 with a layer thickness of 40 covering the disintegrating particles 67, wherein the disintegrating particles 66 contain a disintegrant, and the coating layer 27 is formed by a coating agent 8 having a thermoplastic material 7, particularly by a coating agent 8 identical to that of the precursor material particles 9. This allows for the targeted setting of the release profile of the pharmaceutical substance 5 in the tablet 2.

[0098] According to another design scheme for tablet 2, the tablet in Figure 13 The diagram is shown as passing through Figure 11 The cross-section of the lower precursor material layer 65b of the multilayer tablet shown is illustrated. The precursor material layer 65b of tablet 2 has three meandering capillary channels 68, each designed to deliver liquids (such as gastric juice, in particular) into the tablet interior via capillary action. The release profile of tablet 2a can also be adjusted and set even through the capillary channels 68. In embodiments not shown, other shapes of the capillary channels are implemented. These capillary channels may also differ, for example, in terms of capillary channel diameter or penetration depth into the tablet interior.

[0099] Finally, the manufactured tablets 2 can still be refined in the post-processing steps. Figure 4In the apparatus 1 shown, the tablet 2 manufactured in the additive manufacturing step in the additive manufacturing apparatus 4 is coated with a shell layer in the post-processing step, here in the roller coating apparatus 14, which is suitably resistant to gastric juice. The working principle of the coating process performed in the post-processing step corresponds to the coating in the roller coating apparatus 14 already described above.

Claims

1. A tablet (2), characterized in that, The tablet (2) has a plurality of precursor material particles (9) connected to each other by selective laser sintering, wherein the precursor material particles (9) have granules (6) with a particle diameter (60) and a coating layer (27) with a layer thickness (40) covering the granules (6), wherein the granules (6) have a pharmaceutical substance (5), and the coating layer (27) is formed by a coating agent (8) having a thermoplastic material (7), wherein the coating layer (27) forms a coating layer matrix (64), and the granules (6) are embedded in the coating layer matrix.

2. The tablet (2) according to claim 1, characterized in that, The tablet (2) has different precursor material particles (9), wherein the different precursor material particles (9) have granules (6) with different pharmaceutical substances (5).

3. The tablet (2) according to claim 1 or 2, characterized in that, The tablet (2) has multiple precursor material layers (65) consisting of precursor material particles (9).

4. The tablet (2) according to claim 3, characterized in that, The precursor material layer (65) of the plurality of precursor material layers (65) has precursor material particles (9) that are different from the precursor material particles (9) of the precursor material layer (65) adjacent to the precursor material layer (65).

5. The tablet (2) according to claim 3 or 4, characterized in that, The precursor material layer (65) has a different packing density.

6. The tablet (2) according to any one of the preceding claims, characterized in that, The tablet (2) has excipient particles (66), wherein the excipient particles (66) have disintegrating particles (57) with a disintegrating particle diameter, and have a coating layer (27) with a layer thickness (40) covering the disintegrating particles (57), wherein the disintegrating particles (66) have a disintegrant, and the coating layer (27) is formed of a coating agent (8) having a thermoplastic material (7).

7. The tablet (2) according to any one of the preceding claims, characterized in that, The tablet (2) has at least one capillary channel (68) designed to deliver liquid, such as gastric juice, into the tablet via capillary action.

8. The tablet (2) according to any one of the preceding claims, characterized in that, The tablet (2) is coated with a shell layer in a post-processing step, which is suitably resistant to gastric juice.

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