Tablet produced by selective laser sintering

Abstract

The invention relates to a tablet (2), wherein the tablet (2) has a plurality of precursor material particles (9) connected to one another by selective laser sintering, wherein the precursor material particles (9) have a granulate particle (6) with a granulate particle diameter (60), and an enveloping layer (27) that envelopes the granulate particle (6) and has a layer thickness (40), wherein the granulate particle (6) contains a medicament (5) and the enveloping layer (27) is formed from a coating agent (8) having a thermoplastic material (7), wherein the enveloping layers (27) form an enveloping layer matrix (64) in which the granulate particles (6) are embedded.

Description

[0001] Tablet manufactured by selective laser sintering

[0002] The invention relates to a tablet.

[0003] A wide variety of technologies and processes are used to manufacture tablets. Over the past 10 years, additive manufacturing processes have gained particular attention in order to improve the production of tablets with drug-delivery formulations.

[0004] Fina et al., in "Selective laser sintering (SLS) 3D printing of medicines," International Journal of Pharmaceutics, Volume 529, Issues 1-2, 30 August 2017, pages 285-293, https: / / doi.org / 10.1016 / j.i.pharm.2018.05.044, demonstrate that there are no reports of the use of SLS to manufacture tablets filled with oral medications. Therefore, the aim of this study was to investigate the suitability of SLS printing for the manufacture of pharmaceuticals. Two pharmaceutical-grade thermoplastic polymers, Kollicoat IR and Eudragit L100-55, with immediate and modified release, respectively, were selected to investigate the versatility of an SLS printer. Each polymer was tested with three different drug concentrations of paracetamol. To support the sintering process, 3% Candurin® Gold Luster was added to each of the powder formulations.A total of six solid formulations were successfully printed; the 3D-printed tablets were robust, and no signs of drug degradation were observed.

[0005] 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 / mal5062142, also describe that 3D printing of high-dose tablets containing pure, brittle, crystalline pharmaceutical ingredients by selective laser sintering (SLS) is possible but impractical. Currently used pharmaceutical excipients, including polymers, are primarily designed for powder compression to ensure good mechanical properties. The use of these excipients for SLS typically results in poor mechanical properties of the printed tablets. To overcome this problem, composite printed parts made of sintered, carbon-dyed polyamide and metronidazole were fabricated by SLS.The tablets were characterized using differential scanning calorimetry and infrared spectroscopy, and their mechanical properties were evaluated. This study highlights the need to define the requirements for excipients for 3D printing and to search for suitable materials for this purpose.

[0006] The object of the invention is therefore to provide a tablet.

[0007] This object is achieved in a tablet of the type mentioned at the outset in that the tablet has a large number of precursor material particles bonded to one another by selective laser sintering, the precursor material particles having a granule particle having a granule particle diameter and a coating layer enclosing the granule particle and having a layer thickness, the granule particle having a medicinal substance and the coating layer being made from a coating agent comprising a thermoplastic material, the coating layers forming a coating layer matrix in which the granule particles are embedded. As a result, tablets with a very high medicinal substance loading of greater than 40%, preferably greater than 60%, particularly preferably greater than 80% can be produced.

[0008] Thermoplastic materials are materials that can be thermoformed within a specific temperature range. This process is reversible. This means it can be repeated by cooling and reheating to the molten state, as long as thermal decomposition of the material does not occur due to overheating. For convenience, thermoplastic polymers and / or lipids are referred to as thermoplastic materials here.

[0009] Granule particles are small granular or spherical solid bodies which together form the granulate.

[0010] A medicinal substance—also called an active ingredient or medicinal product—is a substance used as a medicinally active ingredient in the manufacture of a drug. The medicinal substance is usually processed into a drug in combination with one or more pharmaceutical excipients, but occasionally also without excipients.

[0011] The method for producing tablets comprises a coating step and an additive manufacturing step following the coating step, wherein in the coating step, granulate particles comprising a drug are coated with a coating agent comprising a thermoplastic material in order to produce precursor material particles, and in the additive manufacturing step, a powdered precursor material comprising a plurality of precursor material particles is selectively laser sintered to form tablets.

[0012] The method is preferably carried out on a device for producing tablets, the device comprising a precursor material production device and an additive manufacturing device, the precursor material production device being designed to coat granulate particles comprising a medicinal substance with a coating agent comprising a thermoplastic material in order to produce precursor material particles, and the additive manufacturing device being designed to produce tablets from a powdered precursor material comprising a large number of precursor material particles by selective laser sintering. The precursor material production device is expediently fluidly connected to the additive manufacturing device to enable a transfer of the precursor material from the precursor material production device to the additive manufacturing device.

[0013] The powdered precursor material has a large number of precursor material particles, each precursor material particle having a granule particle with a granule particle diameter and a coating layer with a layer thickness that surrounds the granule particle, the granule particle having a drug and the coating layer being made from a coating agent comprising a thermoplastic material. In the case of non-spherical granule particles, the equivalent diameter of the corresponding granule particle is also regarded as the granule particle diameter. The equivalent diameter is a measure of the size of an irregularly shaped granule particle. It is calculated by comparing a property of the irregular granule particle with a property of a regularly shaped granule particle.Advantageously, the powdered precursor material simultaneously exhibits a low packing density and a large surface area, allowing more laser energy to be absorbed and allowing the precursor material particles to combine to form tablets during selective laser sintering. Another advantage is that the coating step with a thermoplastic material transforms the granulate particles into precursor material particles with improved flowability and spreadability. Both improved properties are important for achieving a thin powder bed layer for the additive manufacturing step.

[0014] In the additive manufacturing facility, the powdered precursor material is first distributed in a thin layer as a powder bed on a platform within a construction chamber of the additive manufacturing facility. The powdered precursor material, which contains a large number of precursor material particles, is then preheated to a temperature slightly below the melting point of the thermoplastic material. This makes it easier for the laser to increase the temperature of certain areas of the powder bed again, which solidifies the tablet by tracing its shape. The laser scans a cross-section of the 3D tablet model and heats the powdered precursor material to a temperature just below or exactly at the melting point, so that the precursor material particles are mechanically welded together to form a solid tablet.The welding of the precursor material particles is particularly advantageous due to the coating layer containing the thermoplastic material applied to the granulate particles. This is because the precursor material particles are well distributed and therefore also evenly distributed over the powder bed due to the coating layer applied evenly. Since the unsintered powdered precursor material supports the tablet during printing, no additional support structures are required for tablet production. The platform then lowers one layer into the construction chamber, usually between 50 and 200 cm². The whole process is then repeated for each layer until the tablet is finished.

[0015] The construction chamber is then preferentially cooled in a second step, first inside the additive manufacturing facility and then outside the additive manufacturing facility designed as a printer, to ensure optimal mechanical properties and prevent the tablet from deforming.

[0016] In the third step of the additive manufacturing process, the finished tablets are removed from the build chamber, separated, and freed of excess powdered precursor material. The excess powdered precursor material can be reused, and the tablets can be post-processed.

[0017] The process enables tablets with a very high drug loading of greater than 40%, preferably greater than 60%, particularly preferably greater than 80% to be produced. According to a first process variant, the process further comprises a granulation step in which granules consisting of a large number of granulate particles are produced, the granulation step taking place before the coating step. The granulation step is expediently carried out as a direct granulation process or as a vertical granulation process or as a spray-drying process. The granulation device assigned to the precursor material production device is expediently designed as an extruder, in particular as a twin-screw extruder, or as a vertical granulator or as a spray-drying apparatus. In the first process variant, the granulation device is preferably arranged upstream of the coating device.

[0018] In vertical granulation, also known as high-shear granulation or wet granulation, various powdered starting materials are formed into larger, evenly distributed, highly compact granulate particles by the addition of a liquid granulating agent through the high mechanical shearing action of the rotating mixing tools. In high-shear granulation, the larger granules are preferably additionally crushed by a laterally arranged chopper. The granulating agents are typically in the form of a dissolved adhesive or an aqueous-organic solvent mixture. Common adhesives are water, polyvinylpyrrolidone, cellulose ether, or gelatin.

[0019] In spray drying, a powdered starting material is dissolved, emulsified, or dispersed in a solvent or in a solution of a carrier material. The solution, emulsion, suspension, or dispersion is then atomized and sprayed into a drying chamber through which a hot drying gas stream flows, promoting the evaporation of the solvent. During spray drying, the granules produced vary greatly in size and have poor flow properties.

[0020] According to a further advantageous embodiment of the first process variant in this regard, a sieving step takes place between the granulation step and the coating step, wherein the granules with a monomodal granulate particle size distribution are produced for the coating step. To carry out the sieving step, the precursor material production device has a sieving device in which granules with a monomodal granulate particle size distribution can be produced. Accordingly, the sieving device of the precursor material production device is expediently arranged downstream of the granulation device. Due to the monomodal granulate particle size distribution after the sieving step, a uniform coating of the granulate particles can be achieved in the coating step.

[0021] For coating the granulate comprising a plurality of granulate particles, the precursor material production device has a coating device, wherein the coating device is expediently designed as a fluidized bed or spouted bed or drum coating apparatus.

[0022] In the first process variant, the coating step is preferably carried out as a drum coating process, in which the granulate particles are coated with the coating agent in a rotating drum. The drum coating process is particularly suitable for coating large, non-fluidic granulate particles. In the drum coating process, also called drum coating or drum coating, the granulate particles are moved gently and in a controlled manner in a drum and are coated with the coating layer comprising the thermoplastic material. The important thing here is to distribute the coating agent as evenly as possible over the granulate particles. This is ensured on the one hand by the appropriate spraying equipment and on the other hand by the homogeneous mixing of the granulate, which comprises a large number of granulate particles, in the drum.

[0023] In a second process variant which is an alternative to the first process variant, the process has a granulation step in which granules consisting of a large number of granulate particles are produced, the granulation step taking place simultaneously with the coating step. In particular, the granulation step taking place simultaneously with the coating step is carried out as a spray agglomeration process or as a spray granulation process. In this case, the granulation device assigned to the precursor material production device is expediently designed as a fluidized bed or spouted bed apparatus. The advantage of using the alternative second process variant is that the coating of the precursor material particles takes place simultaneously with their granulation / agglomeration.

[0024] During spray agglomeration, very small powdered starting particles are moved in a fluidized bed and sprayed with a binder liquid, whereby liquid bridges form between the starting particles and so-called agglomerate particles are created. In this case, the binder liquid is expediently also the coating agent. Due to the low kinetic energy during spray agglomeration in the fluidized bed, porous structures with many internal capillaries, i.e. cavities, are formed after the residual moisture has evaporated. The new structure is further consolidated by the hardened binder liquid. The dust-free, flowable agglomerate particles are easy to dose and can be optimally processed further. During agglomeration, finely dispersed starting particles are converted into granulate particles in the form of cohesive units by the introduction of the binder liquid.Therefore, the agglomerate particles are referred to below as granulate particles. Accordingly, the agglomerate produced in spray agglomeration, which contains a large number of agglomerate particles, is also referred to as granulate. By using the coating agent as a binder liquid, the agglomerate particles are coated simultaneously in the fluidized bed or spouted bed.

[0025] During spray granulation, parameters such as grain size, residual moisture, and solids content can be specifically influenced, and a wide variety of product properties of the granulate particles can be adjusted. The granulate particles produced by spray granulation have a dense surface structure and high bulk density; due to their small surface area, they are not very hygroscopic, meaning they hardly attract any ambient moisture. They are also very free-flowing, abrasion-resistant, non-flowing, easily soluble, and easy to dose. This means that the granulate particles are also coated in the fluidized bed or spouted bed. Compared to agglomerates, granules from spray granulation are denser and harder.

[0026] Advantageously, in the spray agglomeration or spray granulation process, the precursor material is produced in a fluidized bed or spouted bed apparatus, wherein the granules are initially introduced and the granule particles are sprayed with the coating agent. Alternatively, in the spray agglomeration or spray granulation process, the precursor material is produced in a fluidized bed or spouted bed apparatus, wherein the granules are introduced into the fluidized bed or spouted bed apparatus together with the coating agent as a solution, emulsion, suspension, or melt.

[0027] The coating specifically influences the surface structure of the granulate particles by applying a functional coating layer. Coating in fluidized and spouted beds is an effective coating process for applying coating layers. A very uniform application of the coating agent is important during the coating process. Coating in fluidized and spouted bed systems can be carried out in batch or continuous operation.

[0028] By means of the granulation step carried out before or at the same time as the coating step, the appropriate balance of precursor material particle size, morphology and size distribution can be adjusted in the coating step, which is required in the additive manufacturing step for the selective laser sintering.

[0029] The following applies to precursor material particles: the larger and rounder they are, and the more monomodal their particle size distribution, the better their flowability. Important factors that determine flowability include particle size distribution, particle shape, chemical composition of the particles, humidity, and temperature. One measure of flowability is the angle of repose methods listed in the European Pharmacopoeia - also known as the angle of repose or angle of friction - and the Hausner factor. The angle of repose of the granules is the steepest angle of inclination relative to a horizontal plane onto which the granules can be poured without sagging. The Hausner factor is calculated as a dimensionless key figure as the quotient of tapped density and bulk density, or as the quotient of bulk volume and tapped volume.The flow behavior of a powder is considered "excellent" with Hausner factors of 1.00-1.11. As the Hausner factor increases, the flow behavior deteriorates, with a value of 1.60 and above being considered "unsatisfactory." Accordingly, a precursor material with a low angle of repose and a Hausner factor close to 1 is considered the preferred precursor material. Good flowability is also beneficial for the dispersibility of the precursor material.

[0030] Thus, for selective laser sintering, the precursor material particles should not only have good flowability and dispersibility, but also a low packing density and a large surface area in order to absorb more laser energy and melt together into solid tablets under pressure. Small, round precursor material particles with a preferably monomodal precursor material particle size distribution are preferred. Accordingly, the precursor material particles preferably have a sphericity of greater than or equal to 0.75, expediently greater than or equal to 0.9, in particular greater than or equal to 0.93. Furthermore, the precursor material particles particularly preferably have a precursor material particle diameter of 20 / zm to 200 / zm, expediently from 50 / zm to 150 / zm. The shell layer expediently has layer thicknesses in the range from 0.1 / zm to 50 / zm, in particular in the range from 5 / zm to 20 / zm.The precursor material particles expediently have a ratio between the granulate particle diameter and the layer thickness of 2:1 to 15:1, in particular of 2:1 to 10:1. According to an additional advantageous embodiment of the method, the fluidized bed or spouted bed apparatus has a process chamber having a round cross-section and a nozzle arrangement spraying the coating agent in a main spray direction into the process chamber, wherein the main spray direction is formed parallel to a tangent to the round cross-section of the process chamber and is arranged within a circular segment of the round cross-section with a circular segment height of 30% of the cross-sectional radius, and wherein the coating agent or the suspension comprising the coating agent is sprayed or can be sprayed into the fluidized bed or spouted bed apparatus via the nozzle arrangement.It is sufficient for this purpose that one directional component of the main spray direction is parallel to the tangent. The nozzle arrangement mentioned above is also referred to as a so-called tangentially spraying nozzle arrangement, which generates a "tangential spray." With the aid of a tangentially sprayed coating agent containing the thermoplastic material, a very uniform application of the coating agent to the granulate particles is achieved, whereby a coating layer with a constant layer thickness can be created on the granulate particles.In addition to tangential spray, the coating agent can also be sprayed into the process chamber as a "bottom spray" - the main spray direction is in the flow direction of the process gas in the fluidized bed or spouted bed apparatus - from below and as a "top spray" - the main spray direction is opposite to the flow direction of the process gas in the fluidized bed or spouted bed apparatus - from above.

[0031] The coating agent comprising a thermoplastic material can, in addition to the thermoplastic material, comprise further substances, such as solvents, but can also consist of at least one thermoplastic material.

[0032] Advantageously, however, the coating agent used contains a solvent in addition to the thermoplastic material. A solvent is a substance that can dissolve gases, liquids or solids and dilute them in the process, creating a solution. This makes the coating agent easier to spray and therefore easier to apply to the granulate particles. Water and / or an organic solvent is or are preferably used as the solvent. Alcohols and / or ketones and / or alkanes and / or ethers are expediently used as the organic solvent. Water has the advantage as a solvent that it is cheaper and less harmful to the environment than organic solvents. The solvent evaporates or evaporates during the coating step because a heated process gas flows around the precursor material particles during the coating step.

[0033] In a further advantageous embodiment of the process, a thermoplastic polymer or lipid is used as the thermoplastic material, in particular polyvinylpyrrolidone (PVP), polyvinylpyrrolidone co-vinyl acetate (PVPVA), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), or methacrylate (Eudragite). Thermoplastic materials—as their name suggests—have thermoplastic properties, i.e., they soften when heated and solidify when cooled without undergoing chemical changes. Biocompatible materials, in particular biocompatible polymers or lipids, are particularly suitable for the process.

[0034] A precursor material comprising a plurality of precursor material particles is advantageously used for producing tablets, wherein, in an additive manufacturing step, selective laser sintering of precursor material particles to form tablets is carried out. In this process, a high-power laser sinters a material, in particular a thermoplastic material of the coating agent, into a solid structure based on a 3D model of the tablet.

[0035] In the additive manufacturing step of selective laser sintering the powdered precursor material to form tablets, a powder bed fusion system designed as a selective laser sintering printer is used in the additive manufacturing facility, wherein the powder bed fusion system preferably has at least one laser unit, and wherein the laser unit has a CO2 laser or a fiber laser, so that a CO2 laser or a fiber laser is expediently used for the selective laser sintering. In this case, the powder bed fusion system designed as a selective laser sintering printer has at least one laser unit, wherein each laser unit has a scanner system formed from at least one mirror which is controlled by at least one drive unit, so that each laser beam of a laser unit heats precursor material particles to or above their melting point in order to bond precursor material particles to one another.By using multiple laser units, tablet production is scalable, i.e. the number of tablets produced in one additive manufacturing step is adjustable. In the additive manufacturing process, selected areas of the precursor material particles forming the powder bed are fused or welded together by the heat energy introduced by the laser. For selective laser sintering, a wavelength of 10,600 nm at a power of 14 W is expediently used when using a CO2 laser, and a wavelength of 1,064 nm at a power of 10 W when using a fiber laser. CO2 lasers are gas lasers based on an electrically excited carbon dioxide gas mixture and have excellent beam quality. In contrast, the fiber laser has an efficiency that is around 30% better. Energy efficiency, service life and a compact design also speak in favor of the fiber laser.

[0036] The additive manufacturing device is further expediently designed to produce tablets from the precursor material by selective laser sintering in a protective gas atmosphere, wherein nitrogen or argon can expediently be used as the protective gas.

[0037] In particular, the tablet contains different precursor material particles, each of which contains granules containing different drugs. This allows the different drugs to exhibit different release profiles.

[0038] The tablet has a large number of precursor material layers consisting of precursor material particles. Advantageously in this regard, one precursor material layer of the large number of precursor material layers has precursor material particles that differ from the precursor material particles of a precursor material layer adjacent to the precursor material layer. The large number of precursor material layers turns the tablet into a multi-layer tablet. These combine different therapeutic loads in a single dosage form. Furthermore, it is advantageous that the drug contained in each precursor material layer can be provided with different release profiles. Furthermore, the precursor material layers expediently have different packing densities. This makes the precursor material layers denser and the tablet itself more compact and stronger in its stability.

[0039] A corresponding tablet is further characterized in that the tablet comprises auxiliary material particles, wherein the auxiliary material particles comprise an explosive particle having an explosive particle diameter and a coating layer enclosing the explosive particle and having a layer thickness, wherein the explosive particle comprises an explosive agent and the coating layer is formed from a coating agent comprising a thermoplastic material. This also makes it possible to specifically define release profiles for the drugs.

[0040] According to a further advantageous embodiment of the tablet, the tablet has at least one capillary channel designed to convey a liquid, such as gastric juice, into the interior of the tablet by capillary action. The release profile can also be adjusted and adjusted by the capillary channels.

[0041] The tablet produced by the process can, in particular in a post-treatment step, be coated with a coating layer which is advantageously gastric juice resistant.

[0042] The invention is explained in more detail below using the attached drawing, which shows

[0043] Figure 1 shows a first embodiment of the device for producing tablets, Figure 2 shows a second embodiment of the device for producing tablets,

[0044] Figure 3 shows a third embodiment of the device for producing tablets,

[0045] Figure 4 shows a fourth embodiment of the device for producing tablets,

[0046] Figure 5 shows a fifth embodiment of the device for producing tablets,

[0047] Figure 6 shows a sixth embodiment of the device for producing tablets,

[0048] Figure 7 shows a schematic structure of a fluidized bed apparatus of the device for producing tablets with a sectional plane AA through the conical part of the process chamber,

[0049] Figure 8 shows a section corresponding to the section plane AA of Fig . 7 through the conical part of the process chamber ,

[0050] Figure 9 shows a schematic structure of an additive manufacturing device in the form of a powder bed fusion system designed as a selective laser printer,

[0051] Figure 10 shows a schematic process of coating a granulate particle having a granulate particle diameter with a coating layer having a layer thickness ,

[0052] Figure 11 shows a multilayer tablet with two precursor material layers and a vertical section plane AA, Figure 12 shows a vertical section along the section plane AA through the multilayer tablet shown in Fig. 11, wherein the coating layers form a coating layer matrix in which the granulate particles are embedded, and

[0053] Figure 13 is a schematic representation of meandering capillary channels in the lower precursor material layer of the multilayer tablet shown in Fig. 11.

[0054] Unless otherwise stated, the following description refers to all embodiments of a device 1 according to the invention for producing tablets 2 illustrated in the drawing.

[0055] A method for producing tablets 2 is expediently carried out on the device 1. For this purpose, the device 1 has a precursor material production device 3 for carrying out at least one coating step and an additive manufacturing device 4 for carrying out an additive manufacturing step following the coating step. The precursor material production device 3 is expediently fluidly connected to the additive manufacturing device 4 in order to enable a transfer of the precursor material 10 comprising a plurality of precursor material particles 9 from the precursor material production device 3 to the additive manufacturing device 4.

[0056] In the coating step, granulate particles 6 comprising a drug 5 are coated with a coating agent 8 comprising a thermoplastic material 7 in order to produce a powdered precursor material 10 comprising a large number of precursor material particles 9. The coating agent 6 can contain, in addition to the thermoplastic material 7, a solvent 57, wherein in particular water and / or an organic solvent is or are used as the solvent, and wherein alcohols and / or ketones and / or alkanes and / or ethers are expediently used as the organic solvent. Polyvinylpyrrolidone (PVP), polyvinylpyrrolidone co-vinyl acetate (PVPVA), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) or methacrylate (Eudragite) is preferably used as the thermoplastic material 7.Thermoplastic materials 7, as their name suggests, have thermoplastic properties, i.e., they soften upon heating and solidify upon cooling without undergoing chemical changes. Biocompatible materials 7 are particularly suitable for the process. For this purpose, the precursor material production device 3 expediently has a coating device 11, which is designed, in particular, as a fluidized bed apparatus 12, a spouted bed apparatus 13, or a drum coating apparatus 14.

[0057] The precursor material production device 3 further comprises—as shown in the respective embodiments of Figs. 1 to 4—a granulation device 28 which produces granulate particles 6 containing a drug 5. The granulation device 28 is expediently designed as a vertical granulator 29, spray-drying device 30, fluidized bed device 12, or spouted bed device 13 and is preferably arranged upstream of the coating device 11.

[0058] According to a first embodiment of the device 1 shown in Fig. 1, the method carried out on this device 1 has a granulation step in which a granulate 31 consisting of a large number of granulate particles 6 is produced in a vertical granulation process by means of vertical granulation. The granulation step takes place before the coating step. In vertical granulation, which is also referred to as high-shear granulation or wet granulation, various powdered starting materials 32 containing the medicinal substance 5 are formed into larger, evenly distributed, very compact granulate particles 6 by adding a liquid granulating agent 33 through a high mechanical shear effect of the rotating mixing tools 34, in particular anchor mixers 69, wing mixers 70 or paddle mixers.The shape of the mixing tool 34 is preferably adapted to the contour of the mixing container of the vertical granulator 29. In vertical granulation, dissolved adhesive or an aqueous-organic solvent mixture is used as the granulation agent 33. Common adhesives are water, polyvinyl pyrrolidone, cellulose ether, or gelatin.

[0059] With the spray drying apparatus 30, an alternative embodiment of the granulation device 28 is shown in the second embodiment shown in Fig. 2, wherein the granulation step also takes place before the coating step. Accordingly, a spray drying process is carried out with the spray drying apparatus 30. During spray drying, a powdered starting material 32 comprising the medicinal substance 5 is dissolved, emulsified or dispersed in a solvent or in the solution of a carrier material. The solution, emulsion, suspension or dispersion containing the starting materials 32 is subsequently atomized and sprayed into a drying chamber 36 through which a hot drying gas stream 35 flows, which promotes the evaporation of the solvent.During spray drying, the granulate particles 6 produced are, on the one hand, very differently shaped in their granulate particle size and, on the other hand, the granulate particles 6 have poor flow properties.

[0060] According to the devices 1 shown in Figs. 1 and 2, a screening step takes place between the granulation step and the coating step, in which screening step the granules 31 with a monomodal granule particle size distribution are produced for the coating step. For this purpose, the precursor material production device 3 has a screening device 37, wherein the screening device 37 is expediently arranged downstream of the granulation device 28 and upstream of the coating device 11. In the screening device 37, the granules 31 consisting of a large number of granule particles 6 are conveyed through a sieve 38 with a desired mesh size, whereby screened granules 31 with a monomodal granule particle size distribution is produced.

[0061] After the screening step, in the two embodiments of Fig. 1 and 2, in a coating step designed as a drum coating process, the granulate particles 6 are coated with the coating agent 8 comprising the thermoplastic material 7 in the drum coating apparatus 14 having a rotating drum 39. In the drum coating apparatus 14, the granulate particles 6 are moved gently and in a controlled manner in the drum 39 and are coated with a coating layer 27 having a layer thickness 40. The important thing here is to distribute the coating agent 8 as evenly as possible. This is ensured on the one hand by the appropriate spraying equipment having nozzle arrangements 51 for spraying the coating agent 8 and on the other hand by homogeneous mixing.During the coating step , the drum 39 is also flowed through by a coating drying gas 41 , whereby the coating agent 8 comprising the thermoplastic material 7 applied to the granulate 31 having a plurality of granulate particles 6 is dried to form the coating layer 27 .

[0062] In contrast to the first two embodiments, which are shown in Figs. 1 and 2, the two embodiments shown in Figs. 3 and 4 do not have a screening step between the granulation step and the coating step. The vertical granulation or spray drying process carried out in the granulation step proceeds as already described in the first two embodiments. Subsequently, the granulate 31 produced in the vertical granulation process according to Fig. 3 or in the spray drying process according to Fig. 4 is coated in a fluidized bed apparatus 12 in the third embodiment and in a spouted bed apparatus 13 in the fourth embodiment, in each case after the granulation step. In both embodiments, the granulate 31 is placed as a template in the corresponding fluidized bed or spouted bed apparatus 12, 13 and sprayed with the coating agent 8 comprising the thermoplastic material 7.

[0063] The spouted bed is based - like the fluidized bed - on the basic principle of fluidization and the pneumatic transport of granulate particles 6 by process gas 45 flowing upwards through the fluidized bed apparatus 12 or the spouted bed apparatus 13, in particular process air or an inert gas such as nitrogen. The essential difference is the design of the process gas inlet. In the spouted bed apparatus 13, the process gas inlet is designed as slotted openings 71 in conjunction with special flow profiles and a greatly expanding process chamber 42. In the fluidized bed apparatus 13, the process gas inlet is designed as a perforated plate floor, also referred to as an inflow floor 46. The functional principle and the schematic structure of a fluidized bed apparatus 12 in Fig. 7 for the production of tablets 2 with a sectional plane AA through the conical part of the process chamber 42 is explained as an example below.In the fluidized bed apparatus 12, granulate particles 6 are coated to form precursor material particles 9.

[0064] The structure of the fluidized bed apparatus 12 comprises, from bottom to top, a distribution chamber 43, the process chamber 42 and an exhaust air part 44. The fluidized bed apparatus 12 expediently has a process chamber 42 having a round cross-section 50. The process gas 45 required for coating and drying the precursor material 10 to be produced, which precursor material has a large number of precursor material particles 9, is fed to the distribution chamber 43, where the process gas 45 is distributed and enters the process chamber 42 via an inlet plate 46. The process chamber 42 is delimited in the lower region by inclined side surfaces 49, so that it is conical in its lower region. The process gas 45 flows through the process chamber 42 in the direction of the outlet part 44 and leaves the fluidized bed apparatus 12 preferably as purified exhaust gas 48 through a dedusting system 47 arranged in the exhaust air part 44, in particular filter cartridges or textile filter elements.

[0065] In the process chamber 42, the granulate particles 6 are introduced or independently generated. They are carried upwards by the process gas 45 toward the dust extraction system 47 arranged in the exhaust air section 44 and are thereby fluidized. In the upper region of the process chamber 42, the process gas velocity decreases, so that the upward-flowing granulate particles 6 fall back into the lower region of the process chamber 42. This mechanism forms a very uniform fluidized bed of granulate particles 6 in the process chamber 42.

[0066] By way of example, three different nozzle arrangements 51, in particular single-component or multi-component nozzles, are shown in the fluidized bed apparatus 12 in Fig. 7, which nozzle arrangements can be installed alternatively to one another. The coating agent 8 is sprayed into the process chamber 42 in a main spray direction via the nozzle arrangement 51. If the coating agent 8 comprising the thermoplastic material 7 is sprayed by means of a nozzle arrangement 51 arranged in the lower region of the process chamber 42, the main spray direction being in the flow direction of the process gas 45 in the fluidized bed apparatus 12, the nozzle arrangement 51 generates a spray jet 56, also referred to as a "bottom spray".If, on the other hand, the nozzle arrangement 51 is arranged in the upper region of the process chamber 42 and the spraying takes place in a main spray direction directed counter to the flow direction of the process gas 45, the nozzle arrangement 51 generates a spray jet 56 referred to as a "top spray". According to a third preferred alternative, the arrangement of which is further shown in Fig. 8, the fluidized bed apparatus 12 has a nozzle arrangement 51 arranged laterally on the process chamber 42, wherein the main spray direction is formed parallel to a tangent 55 on the round cross-section 50 of the process chamber 42 and is arranged within a circular segment 52 of the round cross-section 50 with a circular segment height 53 of 30% of the cross-sectional radius 54, and wherein the coating agent 8 or a suspension comprising the coating agent 8 is sprayed into the fluidized bed apparatus 12 via the nozzle arrangement 51.It is sufficient for this purpose that a directional component of the main spray direction of the spray jet 56 is parallel to the tangent. Such a nozzle arrangement 51 is also referred to as a so-called tangentially spraying nozzle arrangement 51, which generates a "tangential spray." With the aid of a tangentially sprayed coating agent 8 containing the thermoplastic material 7, a very uniform application of the coating agent 8 to the granulate particles 6 is achieved, whereby a coating layer 27 having a substantially constant layer thickness 40 can be generated on the granulate particles 6, so that the precursor material particles 9 produced have very good flow properties.

[0067] The nozzle arrangement 51, preferably a two-component nozzle, is configured to spray very small droplets 62 with a droplet size of 1 / zm to 100 / zm, preferably from 1 / zm to 50 / zm, particularly preferably between 5 / zm and 10 / zm. By adjusting the droplet size using the nozzle arrangement 51 and the compressed air applied to the nozzle arrangement 51, the shear forces occurring during spraying can be precisely adjusted, so that a very homogeneous droplet size of the coating agent 8 to be sprayed can be achieved or achieved. The droplets 62 adhere to the granulate particles 6 containing the pharmaceutical substance 5, and when a solvent 57 is used, film evaporation of the solvent preferably takes place.

[0068] Due to the highly advantageous heat and mass transfer and the high granule particle circulation in the spray area 58 of the process chamber 42 of the fluidized bed apparatus 12, the coating agent 8 is largely deposited on the granule particles 6, thus uniformly wetting the granule particles' surfaces 59. The uniform wetting combined with a simultaneously high granule particle circulation in the spray area 58 results in a very uniform coating layer 27 being formed on the granule particles 6. The drying process causes the solvent 57 to evaporate and leave the fluidized bed apparatus 12 with the exhaust gas 48. The thermoplastic material 7 contained in the coating agent 8 remains as a coating layer 27 having a layer thickness of 40 on the granulate particle surface 59 of the granulate particles 6, so that the resulting precursor material particles 9 grow and are coated very uniformly and homogeneously.

[0069] Fig. 10 describes a schematic process of coating a granulate particle 6 having a granulate particle diameter 60 with a coating layer 27 having a layer thickness 40 to form a precursor material particle 9.

[0070] The discharge 61 of the coated granulate particles 6, referred to as precursor material particles 9, can be realized, for example, by an overflow or by a volumetric discharge device, in particular a rotary valve, or also by a gravity sifter, preferably a zigzag sifter charged with sifting gas or a riser pipe sifter.

[0071] Alternatively, in addition to the coating agent 8, additives or other components in liquid form can be sprayed into the process chamber 42 and thus homogeneously embedded into the granulate particle structure. The additives can also be contained in the coating agent 8.

[0072] In the fifth and sixth embodiments, shown in Figs. 5 and 6, the granulate 31 consisting of a plurality of granulate particles 6 is produced in the coating device 11 and simultaneously coated. Accordingly, the granulation step occurs simultaneously with the coating step. Preferably, the granulation step occurring simultaneously with the coating step is carried out as a spray agglomeration process or as a spray granulation process.

[0073] During spray agglomeration, very small powdered starting materials 32, also referred to as starting particles, are moved in a fluidized bed and sprayed with a binder liquid, whereby liquid bridges form between the starting materials 32 and so-called agglomerate particles are created. In this case, the binder liquid is expediently also the coating agent 8 at the same time. Due to the low kinetic energy during spray agglomeration in the fluidized bed, porous structures with many internal capillaries, i.e. cavities, are formed after the residual moisture has evaporated. The new structure is further consolidated by the hardened binder liquid. The dust-free, flowable agglomerate particles are easy to dose and optimally suitable for further processing. During agglomeration, finely dispersed starting materials 32 are converted into granulate particles 6 in the form of cohesive units by introducing the binder liquid.Therefore, the agglomerate particles are referred to below as granulate particles 6. Accordingly, the agglomerate comprising a large number of agglomerate particles produced in the spray agglomeration is also referred to as granulate 31. By using the coating agent 8 as a binder liquid, the agglomerate particles in the fluidized bed or spouted bed are coated simultaneously.

[0074] During spray granulation, parameters such as grain size, residual moisture, and solids content can be specifically influenced, and a wide variety of product properties of the granulate particles 6 can be adjusted. The granulate particles 6 produced by spray granulation have a dense surface structure and high bulk or packing density; due to their small granulate particle surface area 59, they are not very hygroscopic, meaning they hardly attract any ambient moisture. In addition, they are very free-flowing, abrasion-resistant, non-pourable, readily soluble, and optimally meterable. Thus, the granulate particles 6 are simultaneously coated in the fluidized bed or spouted bed. Compared to agglomerates, granules 31 from spray granulation are denser and harder.

[0075] In the precursor material production device 3 shown in Fig. 5, the precursor material 10 is produced in the coating device 11 designed as a fluidized bed apparatus 12 by the spray granulation process, wherein the granulate 31 is introduced and the granulate particles 6 are sprayed with the coating agent 8.

[0076] In a series of experiments, a process according to Fig. 5 was carried out with metoprolol succinate as the drug 5. The beta-blocker exhibits particularly poor flow properties. The angle of repose is 52° and the Hausner factor is 1.68. The drug was placed in the fluidized bed apparatus 12 and sprayed with the thermoplastic material 7, namely Kollidon VA 64 (PVPVA), in the form of a "tangential spray" because of its good solubility in water and organic solvents. The granulation and coating steps carried out simultaneously in the fluidized bed apparatus 12 significantly improve the flowability of the precursor material particles 9 produced. The angle of repose is now 31° and the Hausner factor is 1.21.A further advantage is the uniform distribution of the material 7 on the granulate particle surface 59, which creates a contact surface between the individual precursor material particles 9. Alternatively, the precursor material 10 is produced in the coating device 11 of the precursor material production device 3, designed as a spouted bed apparatus 13, according to Fig. 6, using the spray agglomeration process, wherein the granulate 31 is introduced into the spouted bed apparatus 13 together with the coating agent 8 as a solution, emulsion, suspension, or melt.

[0077] Each produced precursor material particle 9 has a granulate particle 6 having a granulate particle diameter of 60 and has a coating layer 27 surrounding the granulate particle 6 and having a layer thickness of 40. The granulate particle 6 contains the drug 5 and the coating layer 27 is formed from a coating agent 8 comprising a thermoplastic material 7. The precursor material particles 9 preferably have a sphericity of greater than or equal to 0.75, expediently greater than or equal to 0.9, in particular greater than or equal to 0.93.

[0078] Furthermore, the precursor material particles 9 have a precursor material particle diameter 63 of 20 / zm to 200 / zm, expediently from 50 / zm to 150 / zm. The precursor particle diameter 63 results from the granulate particle diameter 60 plus twice the layer thickness 40 of the coating layer 27. Preferably, the coating layer 27 has layer thicknesses 40 in the range from 0.1 / zm to 50 / zm, in particular in the range from 5 / zm to 20 / zm. The preferably selected precursor material particle diameter 63 ensures that the laser energy can penetrate through the precursor material particles 9 and that the coating layers 27 of the precursor material particles 9 made up of the thermoplastic material 7 can be connected to one another, in particular welded. In addition, smaller precursor material particle diameters 63 have a larger surface area, which means more laser energy can be absorbed.It has been found to be advantageous that the precursor material particles 9 should have a ratio between the granulate particle diameter 60 and the layer thickness 40 of 2:1 to 15:1, in particular of 2:1 to 10:1.

[0079] The precursor material 10, which has a plurality of precursor material particles 9, is used in particular for producing tablets 2, wherein, in an additive manufacturing step, selective laser sintering of precursor material particles 9 to form tablets 2 is carried out. In this process, a high-power laser sinters a material 7, in particular a thermoplastic material 7 of the coating agent 8, to form a solid shell layer matrix 64 based on a 3D model of the tablet 2.

[0080] In the additive manufacturing device 4, in the additive manufacturing step, a powdered precursor material 10 comprising a plurality of precursor material particles 9 is selectively laser sintered into tablets 2. For this purpose, the additive manufacturing device 4 is designed, in particular, as a powder bed fusion system 15 in the form of a selective laser sintering printer 16. The powder bed fusion system 15 designed as a selective laser sintering printer 16 expediently 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 scanner system 21 formed from at least one mirror 20, which is controlled by at least one drive unit (not shown), so that each laser beam 22 of a laser unit 17 heats precursor material particles 9 to or above their melting point in order to bond precursor material particles 9 to one another to form a tablet 2, in particular to weld them together. For this purpose, the CO2 laser 18 used expediently has a wavelength in the range of 9,600 nm to 10,600 nm at a power of 14 W, and the fiber laser 19 used has a wavelength of 1,064 nm at a power of 10 W.According to a particular embodiment of the laser sintering printer 16, it has a construction chamber housing 73, so that the laser sintering printer 16 is suitable for producing tablets 2 from the precursor material 10 by selective laser sintering under a protective gas atmosphere 23, wherein nitrogen or argon can be used as the protective gas.

[0081] The additive manufacturing step comprises in particular three steps, namely tablet printing, cooling of the printed tablets 2 and removal of the cooled tablets 2 from the additive manufacturing device 4 as well as separation of the tablets 2 from excess powdered precursor material 10.

[0082] Accordingly, in the additive manufacturing device 4, in the first step, the powdered precursor material 10 is distributed from a precursor material supply 71 in a thin layer as a powder bed 24 on a platform 25 within a construction chamber 26 of the additive manufacturing device 4 by means of a distribution device 74. The powder bed 24, which comprises the powdered precursor material 10 having a large number of precursor material particles 9, is preferably preheated by a preheating device (not shown here) to a temperature slightly below the melting point of the thermoplastic material 7. As a result, the temperature of certain regions of the powder bed 24 can be increased even more easily by the laser 18, 19 of the laser unit 17, which solidifies the tablet 2 by tracing the shape of the tablet.The laser 18, 19 scans a cross-section of the 3D tablet model and, in the process, heats the powdered precursor material 10 to a temperature just below or exactly at the melting point, so that the precursor material particles 9 are mechanically welded together and a solid tablet 2 is formed. The welding of the precursor material particles 9 is particularly advantageously carried out by the coating layer 27 comprising the thermoplastic material 7 applied to the granulate particles 6, since the latter is evenly distributed in the platform 25 over the powder bed 24 due to the good distribution of the precursor material particles 9 due to the good flow properties of the precursor material particles 9 and thus also the coating layer 27 evenly applied to them.Since the unsintered powdered precursor material 10 supports the tablet 2 during printing by the laser 18, 19, no additional support structures are required for tablet production in the additive manufacturing facility 4. The platform 25 then descends one layer into the construction chamber 26 corresponding to the precursor material particle diameter 63, typically between 50 / cm and 200 / cm. The entire process is then repeated for each layer until the tablet 2 is completed.

[0083] Thereafter, in the second step, the construction chamber 26 is preferably cooled, first within the additive manufacturing device 4 and then - if necessary - outside the additive manufacturing device 4 designed as a laser sintering printer 16, so that the optimal mechanical properties are ensured and the tablet 2 cannot deform.

[0084] In the third step of the additive manufacturing process, the finished tablets 2 are removed from the construction chamber 26, separated, and freed of excess powdered precursor material 10. The excess powdered precursor material 10 can be reused, and the tablets 2 can be reworked if necessary. The process performed on the device 1 makes it possible to produce tablets 2 with a very high drug loading of greater than 40%, preferably greater than 60%, and particularly preferably greater than 80%.

[0085] Accordingly, a tablet 2 produced according to the method for producing tablets 2 has a plurality of precursor material particles 9 bonded to one another by selective laser sintering, the precursor material particles 9 having the granulate particle 6 having the granulate particle diameter 60 and the coating layer 27 surrounding the granulate particle 6 and having a layer thickness 40. The granulate particle 6 has a medicinal substance 5 and the coating layer 27 is made of a coating agent 8 comprising a thermoplastic material 7. The coating layers 27 of the individual precursor material particles 9 form a coating layer matrix 64 as a result of the laser sintering, in which coating layer matrix the granulate particles 6 are embedded in the welded coating layers 27 of the individual precursor material particles 9.

[0086] In particular, the tablet 2 has different precursor material particles 9, wherein different precursor material particles 9 each have granulate particles 6 with different drugs 5. As a result, the different drugs 5 can have different release profiles.

[0087] The tablet 2 according to Fig. 11 has two precursor material layers 65, which are identified as the first precursor material layer 65a and the second precursor material layer 65b for easier differentiation. Two precursor material layers 65a, 65b turn the tablet 2 into a multi-layer tablet. The multi-layer tablet with two precursor material layers 65a, 65b and a vertical section plane AA is shown in Fig. 11. The precursor material layers 65 of the tablet 2 shown furthermore have different precursor material particles 9, which are identified accordingly as first precursor material particles 9a and second precursor material particles 9b for easier differentiation. In this regard, the precursor material layer 65a has precursor material particles 9a which differ from the precursor material particles 9b of the precursor material layer 65b adjacent to the precursor material layer 65a.

[0088] The multilayer tablet combines different therapeutic loads in a single dosage form due to the different precursor material particles 9a, 9b, since the drug 5 contained in the different precursor material particles 9a, 9b of the corresponding precursor material layer 65a, 65b can be provided with different release profiles.

[0089] Fig. 12 shows a vertical section along the section plane AA through the multi-layer tablet shown in Fig. 11. The precursor material layer 65b expediently has precursor material particles 9b with different packing densities. Thus, the precursor material layer 65b is packed more densely and the tablet 2 as a whole gains in compactness and stability. In the embodiment shown, the precursor material particles 9a, 9b are coated with the same coating agent 8. This offers the advantage that during selective laser sintering by the laser sintering printer 16, the thermoplastic material 7 forming the shell layer 27 is heated in the same way. The use of different coating agents 8 is possible, but when selecting the coating agents 8, care should be taken to ensure that the melting points of the thermoplastic material 7 are approximately the same.The coating layers 27 form a coating layer matrix 64 in each precursor material layer 65a, 65b, in which the granulate particles 6 containing the drug 5 are embedded. Here, the two coating layer matrices 64 of the precursor material layers 65a, 65b are also identified as a first coating layer matrix 64a and a second coating layer matrix 64b. Due to the selection of the same coating agent 8 for the different precursor material particles 9a, 9b, the two coating layer matrices 64a, 64b can also be optimally welded together.

[0090] Furthermore, the precursor material layer 65b is characterized in that it has auxiliary material particles 66, wherein the auxiliary material particles 66 have an explosive particle 67 having an explosive particle diameter and a coating layer 27 enveloping the explosive particle 67 and having a layer thickness of 40, wherein the explosive particle 66 has an explosive agent and the coating layer 27 is formed from a coating agent 8 comprising a thermoplastic material 7, in particular from the same coating agent 8 as the precursor material particles 9. This makes it possible to specifically define release profiles of the medicinal substances 5 in the tablet 2.

[0091] According to a further embodiment of the tablet 2, which is shown as a schematic representation in Fig. 13 as a section through the lower precursor material layer 65b of the multi-layer tablet shown in Fig. 11, the precursor material layer 65b of the tablet 2 has three meandering capillary channels 68, each of which is designed to convey a liquid, such as in particular gastric juice, into the interior of the tablet by capillary action. The release profile of the tablet 2a can also be adapted and adjusted by the capillary channels 68. Other shapes of the capillary channels are realized in embodiments not shown. These can also differ, for example, in the capillary channel diameter or the penetration depth into the interior of the tablet. Finally, there is the possibility of refining the produced tablets 2 in a post-treatment step. In the case of Fig .In the device 1 shown in Figure 4, the tablets 2 produced in the additive manufacturing device 4 in the additive manufacturing step are coated with a coating layer, which is expediently resistant to enteric juices, in a post-treatment step, here in a drum coating apparatus 14. The functionality of the coating process carried out in the post-treatment step corresponds to the coating in the drum coating apparatus 14 already described above.

Claims

Claims 1. Tablet (2), characterized in that the tablet (2) has a plurality of precursor material particles (9) bonded to one another by selective laser sintering, wherein the precursor material particles (9) have a granulate particle (6) having a granulate particle diameter (60) and a coating layer (27) enveloping the granulate particle (6) and having a layer thickness (40), wherein the granulate particle (6) has a medicinal substance (5) and the coating layer (27) is formed from a coating agent (8) comprising a thermoplastic material (7), wherein the coating layers (27) form a coating layer matrix (64) in which the granulate particles (6) are embedded.

2. Tablet (2) according to claim 1, characterized in that the tablet (2) has different precursor material particles (9), wherein different precursor material particles (9) each have granulate particles (6) with different medicinal substances (5).

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

4. Tablet (2) according to claim 3, characterized in that a precursor material layer (65) of the plurality of precursor material layers (65) comprises precursor material particles (9) which differ from the precursor material particles (9) of a ner precursor material layer (65) adjacent to the precursor material layer (65).

5. Tablet (2) according to claim 3 or 4, characterized in that the precursor material layers (65) have different packing densities.

6. Tablet (2) according to one of the preceding claims, characterized in that the tablet (2) has auxiliary material particles (66), wherein the auxiliary material particles (66) have an explosive particle (57) having an explosive particle diameter and a coating layer (27) enveloping the explosive particle (57) and having a layer thickness (40), wherein the explosive particle (66) has an explosive agent and the coating layer (27) is formed from a coating agent (8) comprising a thermoplastic material (7).

7. Tablet (2) according to one of the preceding claims, characterized in that the tablet (2) has at least one capillary channel (68) which is designed to convey a liquid, such as in particular gastric juice, into the interior of the tablet by capillary action.

8. Tablet (2) according to one of the preceding claims, characterized in that the tablet (2) is coated in a post-treatment step with a coating layer which is expediently gastric juice-resistant.

Images