Method and system for forming dosage form within packaging

Abstract

To provide a method and system of forming a pharmaceutical dosage form within a portion of a blister packaging 1.SOLUTION: The method includes a step of providing a blister packaging for the dosage form with depressions 4. A predetermined amount of a drug-containing powder material comprising drug-containing particles is deposited into a substantially uniform powder layer within the depressions 4. A binding liquid is then deposited in a pattern on the powder layer within the depressions 4, to bind the particles of the powder layer and form an incremental wetted layer. Excess solvent in the binding material can be removed to form an incremental bound layer. These steps are repeated in sequence at least one or more times to form the pharmaceutical dosage form within the blister packaging 1.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to the field of manufacturing dosage or tablet forms for pharmaceuticals or other active ingredients. [Background technology]

[0002] In recent years, pharmaceutical producers have turned to the use of blister packs for use in both forming and dispensing pharmaceutical tablets. These blister packs typically consist of a blister sheet or blister film and a lid sheet. The blister sheet contains spatial recesses for containing individual doses, including tablets, capsules, pills, etc.

[0003] In a standard process for producing freeze-dried tablets, a single liquid dose is introduced into each well of a blister sheet. The blister sheet with the liquid dose is then placed in a refrigerated environment where the dose is frozen by exposure to low temperatures. The blister sheet is then conveyed to a freeze dryer where the ice is removed by sublimation. Once freeze-drying is complete, the sheet is removed from the drying chamber and covered with an adhesive lid sheet, which seals the solid doses into the individual wells. US Pat. No. 5,999,333 is incorporated herein by reference, inter alia, for its teaching of the well-known process for producing freeze-dried tablets in blister packages.

[0004] Nevertheless, freeze-drying or lyophilization methods can have a significant negative impact on product activity, storage stability, and batch consistency and reproducibility.The process is inherently expensive in terms of energy and manpower resources, and presents additional challenges in terms of quality control and regulatory requirements.In some cases, freeze-drying or lyophilization methods are completely inappropriate for certain drugs or pharmaceuticals.

[0005] Rapid prototyping refers to various techniques for producing a three-dimensional prototype of an object from a computer model of that object. One technique is 3D printing, in which a printer is used to produce a 3D prototype from multiple two-dimensional layers. In particular, a digital representation of the 3D object is stored in a computer memory. Computer software segments this representation of the object into multiple separate 2D layers. Alternatively, a stream of instructions (sequential succession), e.g., a series of images, for each incremental layer can be input directly. The 3D printer then produces a thin layer of binding material for each 2D image layer segmented by the software. These layers are printed together on top of each other and adhere to each other to form the desired prototype.

[0006] Powder-liquid three-dimensional printing technology has been used to prepare articles such as pharmaceutical dosage forms, mechanical prototypes and conceptual models, molds for casting mechanical components, bone growth promotion implants, electronic circuit boards, scaffolds for tissue engineering, responsive biomedical composites, tissue growth promotion implants, dental restorations, jewelry, fluid filters, and other such articles.

[0007] Three-dimensional printing can include solid freeform fabrication / rapid prototyping techniques in which a thin layer of powder is spread onto a surface and selected areas of the powder are bound together by the controlled deposition of liquid ("printing"). This basic operation is repeated layer by layer, with each new layer forming and adhering to the previously printed layer, ultimately creating a three-dimensional object in the unbound powder bed. When the printed objects have sufficient cohesion, they can be separated from the unbound powder.

[0008] Systems and equipment assemblies for three-dimensional printing of articles are commercially available or used by others, such as: Massachusetts Institute of Technology Three-Dimensional Printing Laboratory (Cambridge, MA), 3DP and HD3DP™ systems from Z Corporation (now part of 3D Systems) (Burlington, MA), The Ex One Company, LLC (Irwin, PA), Soligen (Northridge, CA), Specific Surface Corporation (Franklin, MA), TDK Corporation (Chiba Prefecture, Japan), Therics LLC (Akron, OH, now part of Integra Lifesciences), Phoenix Analysis & Design Technologies (Tempe, AZ), Stratasys, Inc.'s Dimension™ system (Eden Prairie, MN), Objet Geometries (Billerica, MA or Rehovot, Israel), Xpress3D (Minneapolis, MN), and 3D Systems' Invision™ system (Valencia, CA).

[0009] Three-dimensional printing systems using powder and binding liquid typically form articles by depositing binding liquid on individual sequentially applied layers of powder. The binding liquid is applied in a pattern to predetermined areas of the powder in each powder layer, leaving unbound powder material at the periphery of the pattern. The unbound powder typically surrounds the printed article being formed. The printed article, including the bound powder, is then separated from a significant amount of the unbound powder. Such a process is undesirable as it requires the waste or recycling of the unbound powder. It would be a substantial improvement in the art to provide equipment assemblies, systems, and methods for substantially reducing or eliminating the waste or need for recycling of unbound powder.

[0010] US Patent No. 5,999,943, the disclosure of which is incorporated herein by reference, describes a manufacturing system, an equipment assembly, and its use for preparing an article by cavity 3D printing. The cavities can be part of a building module on a machine, and within those cavities, an article is formed that mimics the periphery of the cavity. The article is formed by a succession of multiple incremental layers formed within the cavity. Once completed, the 3DP article is released from the cavity. The 3DP article is optionally dried, optionally de-dusted, and / or optionally packaged. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication WO / 1994 / 012142 [Patent Document 2] US Patent Application Publication No. 2018 / 0141275 Summary of the Invention [Problem to be solved by the invention]

[0012] Thus, there is a continuing need for improved and more convenient pharmaceutical dosage forms and methods for making them. [Means for solving the problem]

[0013] The present invention provides methods and systems for forming bonded powder or bonded particle articles within the cavity volume of a packaging material, and manufactured articles formed in situ within the cavity of the packaging. In some embodiments, the article is a dosage form and can be a drug, medication, or pharmaceutical tablet or pill, including solid oral prescription drugs. The methods described herein are also referred to as cavity three-dimensional printing or cavity 3DP. The packaging can include one or more cavities, and in some embodiments, can include a pattern of multiple cavities. The methods and systems can be used for high throughput continuous, semi-continuous, or batch manufacturing with minimal product loss, high efficiency, and high product reproducibility.

[0014] The embodiments and configurations described herein provide methods for forming pharmaceutical and drug-containing tablets directly into packaging such as blister packs, and in certain embodiments, methods for making rapidly disintegrating pharmaceutical tablets into disposable, single-dose blister packs.

[0015] The embodiments described herein can provide a significant reduction or elimination of waste or reusable unbound powder when compared to other three-dimensional printing (3DP) processes. Dimple 3DP provides that most, substantially all, or all of the particulate material that enters a cavity is incorporated into a corresponding single 3D printed dosage form.

[0016] Embodiments described herein provide a method of forming a dosage form in a dosage portion of a package, the method comprising: 1) providing a dosage portion of a package including at least one recess; 2) depositing a predetermined amount of powder material including particles into the at least one recess into a powder layer; 3) depositing a binding liquid in a pattern onto the powder layer in the at least one recess to bind at least a portion of the particles of the powder layer to form an incrementally bound layer; and 4) repeating steps 2) and 3) in sequence at least one or more times, thereby forming a dosage form in the dosage portion of the package.

[0017]

[0013] Embodiments described herein also provide a method of forming a dosage form in a dosage portion of a package, the method comprising the steps of: 1) providing a dosage portion of a package including at least one empty recess; 2) depositing a predetermined amount of powder material including particles into the at least one recess into a powder layer; 3) depositing a binding liquid in a pattern onto the powder layer in the at least one recess to bind at least a portion of the particles of the powder layer to form an incrementally wetted layer; and 4) repeating steps 2) and 3) in sequence at least one or more times, thereby forming a dosage form in the dosage portion of the package.

[0018] In some embodiments, the deposited powder layer is a substantially uniform powder layer.

[0019] In either or both of the above methods, the powder material can be deposited in at least one recess in a powder deposition area (or system) of the apparatus or system assembly, and the powder material can be layered or formed into incremental layers of powder material in the powder deposition area (or system) or a dedicated powder flattening area (or system) of the apparatus or system assembly. The binding fluid can be added to the incremental powder layer when the receptacle is in the binding fluid addition area (or system) of the apparatus or system assembly. Shaping or compaction of the powder material or wet material layer can be completed in the powder deposition area (or system) or powder flattening area (or system) of the apparatus or system assembly, or in a dedicated forming area (or system) of the apparatus or system assembly.

[0020] The dosage form package containing one or more recesses can be movable between any two or more of the above-mentioned regions (or systems) in any order. In some non-limiting embodiments, the receptacle: a) repeatedly moves from the powder deposition region to the binder liquid application region and then optionally to the molding region; b) moves from the powder layering region to the molding region and then to the binder liquid application region; c) moves from the powder layering region to the binder liquid application region and then again to the powder layering region and then to the molding region; or d) moves from the powder layering region to the flattening region and then to the binder liquid application region and then to the drying region. The release region can be located after the powder layering region, the binder liquid application region, the molding region, and / or the drying region.

[0021] The product package has one or more recesses, and the one or more recesses may include a film material that contains a preformed, bound powder dosage form formed within one or more recesses, and a peelable or removable cover sheet adhered to the film material so as to enclose the dosage form within the one or more recesses.

[0022] In one embodiment, the dosage form is a bound powder matrix formed in one or more cavities by binding powder deposited in the one or more cavities with a binding liquid.

[0023] In one embodiment, a portion of the molded bonding powder matrix conforms to the interior surface of the one or more depressions.

[0024] An embodiment may also provide a package including a film material having one or more recesses containing a preformed binding powder matrix formed within the one or more recesses, and a peelable cover sheet adhered to the film material to enclose the binding powder matrix within the one or more recesses.

[0025] In one embodiment, the bonded powder matrix is ​​formed in the one or more recesses by bonding the powder deposited in the one or more recesses with a bonding liquid. A portion of the formed bonded powder matrix can conform to the inner surface of the one or more recesses. A peripheral portion of the bonded powder matrix facing the inner surface of the one or more recesses can include an additional amount of bonding liquid.

[0026] In one embodiment, a bound powder matrix can be formed in one or more cavities by binding the powder deposited in the one or more cavities with a binding liquid, comprising a 3D printed fast dispersing dose.

[0027] In one embodiment, the bound powder matrix includes an active pharmaceutical ingredient (API).

[0028] In another embodiment, a peripheral portion of the binding powder matrix facing the inner surface of one or more recesses includes an additional amount of binding liquid.

[0029] In one embodiment, the at least one cavity has a fixed shape and volume that does not change or fluctuate under normal use and handling conditions of the package.

[0030] In one embodiment, the package includes one or more blisters, cups, pods, or other receptacles.

[0031] In one embodiment, the packaging is pre-formed and / or pre-cut prior to the dosage formation process.

[0032] In one embodiment, the package includes a sheet including a plurality of recesses formed therein, the recesses including sidewalls extending from the sheet to a closed end.

[0033] In one embodiment, step 4) is repeated at least three times.

[0034] In one embodiment, a portion of the powder material includes particles of a binding material, and the binding liquid bonds the particles of the binding material.

[0035] In one embodiment, the method further comprises the step of applying a bonding liquid to at least the closed end of the well prior to step 2). The method can include depositing an amount of

[0036] In one embodiment, at least one recess includes an interior surface that includes a release agent.

[0037] In one embodiment, the bonding liquid comprises a volatile solvent, and the method can include removing a portion of the volatile solvent from the incremental bonding layer by evaporation.

[0038] In one embodiment, the sidewall has a recess depth and the thickness of each powder layer is at least 5% up to about 100%, and in some embodiments up to about 50%, of the recess depth.

[0039] In some embodiments, the number of powder layers deposited into the depressions and formed into the incrementally bonded powder layer can be one or more layers, including 2 or more layers, 3 or more layers, 4 or more layers, 5 or more layers, 6 or more layers, 7 or more layers, or 8 or more layers, up to 50 or less layers, 40 or less layers, 30 or less layers, 20 or less layers, 18 or less layers, 16 or less layers, 14 or less layers, 12 or less layers, 10 or less layers, 8 or less layers, 6 or less layers, or 4 or less layers, in any combination.

[0040] The incremental powder layers can have a target or weight average thickness of a predetermined thickness (vertical height). In some embodiments, the predetermined thickness can vary from 0.005-0.015 inches, 0.008-0.012 inches, 0.009-0.011 inches, about 0.01 inches, 100-300 μm, 100-500 μm, about 200 μm, or about 250 μm. In some embodiments, the incremental powder layer thickness ranges from 100-400 microns, 150-300 microns, or 200-250 microns. In one embodiment, the powder layer thickness is 200 microns. In another embodiment, the powder layer thickness is 250 microns.

[0041] In some embodiments, the predetermined thickness is at least 0.05 inches, at least 0.008 inches, at least 0.010 inches, at least 0.012 inches, at least 0.014 inches, or at least 0.016 inches, up to 0.020 inches, up to 0.018 inches, up to 0.016 inches, up to 0.014 inches, up to 0.012 inches, or up to 0.010 inches. The thicker the incremental layer used, the greater the amount of printing fluid deposited on that layer to ensure sufficient bonding both within the plane of the layer and between the layers. Conversely, the thinner the incremental layer, the smaller the amount of printing fluid deposited to achieve the same degree of bonding. For a given amount of printing fluid deposited per layer, using a larger layer thickness reduces (worsens) the handling of the dosage form and reduces (improves) the dispersion time. If too thick a layer is used for a given amount of fluid, layer defects may form that cause the dosage form to easily break along the plane of the layer (delamination), or the dosage form itself may simply not be strong enough to be handled.

[0042] Dosage forms made by the 3DP process described herein can range in diameter (equivalent diameter of non-circular area) from about 13-14 mm to about 20-25 mm, and height (total thickness) from about 5-6 mm to about 8-10 mm.

[0043] In one embodiment, the pattern of binding liquid deposited on the powder layer has a perimeter that is positioned against or in contact with the sidewall of the package.

[0044] In one embodiment, the pattern of binding liquid deposited on the powder layer is selected from the group consisting of rings and circles. The shape is selected from:

[0045] In one embodiment, the method can include the step of adding a lidding layer over the dosage form and the at least one recess to form a sealed package for the dosage form.

[0046] In one embodiment, the binding liquid is deposited by inkjet printing to form a wet or binding powder layer.

[0047] In one embodiment, the step 2) of depositing a predetermined amount of powder material comprising particles into the at least one recess into a substantially uniform powder layer comprises: 1) depositing a predetermined amount of powder material comprising particles into the at least one recess; and 2) forming the deposited predetermined amount of powder material into a substantially uniform powder layer within the at least one recess.

[0048] In one embodiment, the forming step includes molding and / or compacting the deposited quantity of powder material into a formed powder layer having a top surface, while in another embodiment, the forming step includes compacting the final deposited quantity of powder material into a final formed powder layer having a top surface.

[0049] In one embodiment, the method includes depositing a binding liquid in a pattern onto the powder layer in at least one recess, followed by shaping and / or compacting the incremental wet layer into a shaped or compacted wet layer. The top surface of the formed wet layer is flat or planar in one embodiment, and convex or concave in another embodiment.

[0050] In one embodiment, the method includes forming a plurality of incremental wet layers into a wetter structure comprising a plurality of wet layers followed by molding and / or compacting the plurality of wet layers into a molded or compacted wet structure.

[0051] In one embodiment, the shaping and / or compacting step utilizes a stamp or tamper, hi some embodiments, the stamp has a concave underside.

[0052] In one embodiment, the powder material may contain one or more types of drug-containing particles.

[0053] The present invention can also provide 3DP equipment systems and assemblies that provide and position depressions or patterns of depressions, for example in connection with dosage form packaging, and form 3DP dosage forms within the depressions. The equipment systems and assemblies can include, but are not limited to, a powder deposition system disposed within the powder deposition region, a powder flattening system disposed within the powder flattening region, a binder liquid addition system disposed within the binder liquid addition region, a molding system disposed within the molding region, and a drying system disposed within the drying region.

[0054] In some embodiments, the 3DP equipment assembly can include a control system including one or more computerized controllers, one or more computers, and one or more user interfaces for the one or more computers. In some embodiments, one or more components of the equipment assembly are computer controlled. In some embodiments, one or more components of the 3DP build system are computer controlled. In some embodiments, the powder deposition system, the powder flattening system, the binder fluid addition system, the molding system disposed in the molding area, and the drying system are computer controlled.

[0055] In some embodiments, the 3DP instrument assembly also includes one or more harvesters. The 3DP equipment assembly, device, or system may include a sting system, one or more liquid removal systems, one or more powder recovery systems, one or more article delivery systems, and one or more inspection systems. A 3DP equipment assembly, device, or system may include some or all of the above systems. For example, in certain embodiments of a hollow cavity 3DP equipment assembly, device, or system, it is not necessary to have a harvesting system because substantially all of the powder material that enters the cavity is incorporated into the respective dosage form formed within the cavity, and there is little or no excess powder for separation. [Brief description of the drawings]

[0056] [Figure 1] FIG. 1 shows a blister pack with a portion of the lid sheet peeled away to reveal dosage forms disposed within the recesses. [Diagram 2] FIG. 2 is a cross-sectional view of a dosage form in a cavity covered by a lid sheet. [Diagram 3] FIG. 2 is a cross-sectional view of a dosage form in a cavity with the lid sheet removed. [Figure 4] FIG. 2 is a cross-sectional view of a cavity from which a dosage form has been removed. [Diagram 5] FIG. 13 shows a bonding liquid being deposited onto the closed end of a well. [Figure 6] FIG. 13 illustrates depositing a pile of powder material from a powder source into a cavity. [Figure 7] FIG. 1 illustrates an example of a dosing device capable of delivering a predetermined amount of powder material into a cavity of a blister-type package, including but not limited to a predetermined mass weight and a predetermined volume. [Figure 8] 8 is a cross-sectional view of the dispensing device of FIG. 7 positioned to deposit a predetermined amount of powder material onto a bonded powder layer in a cavity of a blister-type package. [Figure 9] FIG. 8 shows the dosing device of FIG. 7, in which the fill cavity containing a predetermined amount of powder material is separated from the powder supply. [Figure 10]FIG. 8 shows the dosing device of FIG. 7 with a predetermined amount of powder material deposited into the cavity. [Figure 11] FIG. 2 shows a rotary dispensing device for dispensing powder material into cavities in a blister sheet 2. [Figure 12A] FIG. 12 is an enlarged cross-sectional view of the rotary dispenser and blister sheet of FIG. [Figure 12B] FIG. 13 is an enlarged cross-sectional view of another embodiment of a rotary dispenser and blister sheet. [Figure 13] FIG. 1 illustrates an automated dosing device for filling multiple cavities in a dosing package, including volumetric dispensing pockets. [Figure 14] FIG. 14 is an enlarged cross-sectional view of the automated dosing device and volumetric dispensing pocket of FIG. [Figure 15] FIG. 15 is an enlarged cross-sectional view of the automated dosing device and volumetric dispensing pocket of FIG. 14, with the powder bottle and fill pocket filled with powder material. [Figure 16] 16 shows the automated dosing device of FIG. 15 with the filled pocket moved from the filling position towards the dispensing position, such that the filled pocket partially overlaps the dispensing opening. FIG. [Figure 17] FIG. 17 shows the automatic dosing device of FIG. 16 with the powder material being emptied from the fill pocket and dispensed into the aligned cavity. [Figure 18] FIG. 18 shows the automated dosing device of FIG. 17 with the empty recess in the blister sheet aligned with the dispensing opening. [Figure 19] 13A-13C show another embodiment of an automated dosing device for filling multiple cavities in a dosing package, including a volumetric dispensing pocket and a tamper. [Figure 20] FIG. 20 is an enlarged cross-sectional view of the automated administration device and volumetric dispensing pocket of FIG. [Figure 21] FIG. 21 is an enlarged cross-sectional view of the automatic dosing device and volumetric dispensing pocket of FIG. 20, with the powder bottle and fill pocket filled with powder material. [Figure 22]FIG. 22 shows the automated dosing device of FIG. 21 with the powder material substantially emptied from the fill pocket and dispensed into the aligned cavity. [Figure 23] FIG. 23 shows the automatic dosing device of FIG. 22 with the tamper extending through the fill pocket and the dispensing opening. [Figure 24] FIG. 24 shows the automated dosing device of FIG. 23 with the tamper retracted and the empty recess in the blister sheet aligned with the dispensing opening. [Diagram 25] FIG. 13 illustrates various means for spreading the pile of powder material into a substantially uniform layer by shaking and / or vibrating the cavity. [Figure 26] FIG. 1 shows a support plate having openings aligned with a pattern of recesses for a blister pack. [Figure 27] FIG. 1 shows a support plate having openings aligned with the pattern of recesses for the blister packs, and a vacuum means for securing the blister sheet to the support plate. [Figure 28] FIG. 13 shows a laterally vibrating vibration device for flattening powder material within cavities in a blister sheet. [Figure 29] FIG. 29 illustrates a brush assembly for use in flattening the pile of powder in the recess of FIG. 28. [Diagram 30] FIG. 30 shows the brush assembly of FIG. 29 being lowered into a pile of powder. [Diagram 31] FIG. 30 shows the brush assembly of FIG. 29 moving particles of powder radially outward toward the wall of the recess. [Diagram 32] FIG. 13 shows the brush assembly being removed from within the cavity after the pile of powder has been formed into a substantially uniform powder layer. [Diagram 33] FIG. 1 shows a layer deposition apparatus positioned to collect an amount of powder material from a powder hopper. [Diagram 34] FIG. 34 illustrates the application of a vacuum to the interior of the layer deposition apparatus of FIG. 33 to fill the inlet end with a volume of powder from the powder hopper. [Diagram 35] FIG. 13 shows that an applied vacuum holds the volume of powder in the inlet of the layer deposition apparatus after the layer deposition apparatus is lifted off the powder hopper. [Diagram 36] FIG. 13 shows the layer deposition device positioned above the cavity while retaining the volume of powder. [Figure 37] FIG. 13 shows the layer deposition device positioned within the cavity with the volume of powder held at the inlet. [Figure 38] FIG. 13 shows that after the vacuum is removed and the layer deposition apparatus is lifted out of the cavity, the volume of powder is deposited as a uniform powder layer within the cavity. [Figure 39] FIG. 13 illustrates an alternative embodiment of a layer deposition apparatus providing additional powder volume on the periphery of the powder entrapment volume. [Diagram 40] FIG. 40 shows the layer deposition apparatus of FIG. 39 positioned within a recess. [Diagram 41] FIG. 13 shows that after the vacuum is removed and the layer deposition apparatus is lifted out of the recess, the volume of powder and an additional surrounding volume are deposited as a uniform layer of powder within the recess. [Diagram 42] FIG. 1 illustrates the addition of a binding liquid onto a uniform powder layer to form a wet powder layer. [Diagram 43] FIG. 1 illustrates several means of applying heat to the wet powder layer to remove excess solvent liquid and dry the wet powder layer to form a bonded powder layer. [Diagram 44] FIG. 1 shows a heated air dryer for evaporating moisture and solvent from a wet powder layer. [Diagram 45] FIG. 13 illustrates depositing powder material into the depressions to form a second substantially uniform powder layer on the first bonded powder layer. [Figure 46] FIG. 13 illustrates adding a binding liquid onto the second substantially uniform powder layer to form a second wet powder layer. [Figure 47] FIG. 1 illustrates the formation of an uppermost substantially uniform powder layer on top of a previously deposited, wetted and dried incrementally bonded powder layer. [Figure 48]FIG. 13 illustrates the addition of a binder liquid to the top substantially uniform powder layer to form a top wet powder layer. [Figure 49] FIG. 13 shows the drying of the top wet powder layer into a top bonded layer and the addition of a lid sheet onto the completed dosage form in the cavity to seal it. [Figure 50] FIG. 13 illustrates an alternative embodiment in which binding liquid is added only to the peripheral portions of the second substantially uniform powder layer, leaving a central portion of the powder unwetted / unbound. [Figure 51] FIG. 51 illustrates the addition of a third substantially uniform layer of powder over the second layer having a center portion of wetted and unbound powder shown in FIG. [Figure 52] FIG. 13 illustrates adding a binding liquid over the third substantially uniform powder layer to form a third wet powder layer over the second layer having a central portion of wetted and unbound powder. [Diagram 53] FIG. 13 illustrates the drying of the third, topmost wet powder layer into a third bonding layer. [Figure 54] FIG. 13 illustrates an alternative embodiment in which the binder liquid is added only to the peripheral portion of the first powder layer to form an outer coating on the peripheral portion or edge of the first powder layer. [Figure 55] FIG. 13 illustrates adding binding liquid onto a central portion of a first powder layer to form a first wet powder portion surrounded by a peripheral or edge coating of the first powder layer. [Figure 56] FIG. 13 illustrates the addition of a binding liquid to a peripheral portion of a topmost substantially uniform powder layer to form an outer coating on the peripheral portion or edge of the topmost powder layer. [Figure 57] FIG. 13 illustrates adding a binding liquid to the top portion of the topmost substantially uniform powder layer to form a topmost wet powder layer with a peripheral outer coating. [Figure 58] FIG. 13 illustrates the drying of the top wet powder layer into a top binder layer and adding binder liquid to the top portion of the top powder layer to form a wet coating. [Figure 59]FIG. 13 shows the finished dosage form after the wet coating on the top portion of the uppermost powder layer has been dried or cured to form an outer coating that surrounds the incrementally bound powder layer. [Figure 60] FIG. 13 illustrates a tamper having a concave bottom surface that sits above the top layer of powder material in the recess. [Figure 61] FIG. 13 shows the tamper located in the well and pressing down on the top surface of the powder layer. [Figure 62] FIG. 13 shows the convex top surface of the topmost powder layer formed by the tamper. [Figure 63] FIG. 13 illustrates the deposition of binding liquid on top of the convex powder material to form the final shaped wet powder layer. [Figure 64] FIG. 13 illustrates wetting the top powder layer to form a top wet powder layer. [Figure 65] FIG. 65 shows the tamper used to mold the top wet powder layer of FIG. [Figure 66] FIG. 13 shows a rotary compaction device having a tamper for compacting a powder layer into a pattern of depressions in a blister sheet. [Figure 67] FIG. 67 is an enlarged cross-sectional view of the rotary compactor and blister sheet of FIG. [Figure 68] FIG. 1 illustrates a linear 3DP equipment assembly including a powder bin and rotary dosing apparatus, a powder flattening device, a printing device, and a drying apparatus. [Figure 69] FIG. 1 illustrates a 3DP equipment assembly having two assemblies in series, each arranged in a continuous loop including a powder bin and rotary dosing device, a powder flattening device, a printing device, and a drying device. [Figure 70] FIG. 1 illustrates a 3DP equipment assembly having a continuous loop conveyor, including powder bins and a rotary dosing device, a powder flattening device, a printing device, and a drying device on different parts of the looped conveyor. [Figure 71]FIG. 1 shows a 3DP equipment assembly having first and second continuous loops, with a common conveyor portion including a powder bin and rotary dosing device, and a printing device, with a powder flattening device and a drying device located along the outer loops of the first and second continuous loops, respectively. [Figure 72] FIG. 5 shows a 3DP equipment assembly 505 having first and second continuous loops sharing a common conveyor section, where the first continuous loop includes a powder dispensing device and a flattening device along an outer portion, and the second continuous loop includes a printing device and a pair of drying devices. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] definition As used herein, the term "well" refers to a spatial cavity formed in a portion of a package for a dosage form. Non-limiting examples of well portions of a package include blisters, cups, pods, or other package receptacles capable of receiving and containing a flowable material, such as a powder or liquid.

[0058] As used herein, "3DP" means three-dimensional printing, three-dimensional printed, or other such applications.

[0059] As used herein, the term "compaction" refers to the action of reducing the porosity or pore volume of a powder mass under a force that reduces the volume of the powder mass. Compaction can be performed by a tamper system, which shapes and / or reduces the volume of one or more incrementally formed powder layers formed within a recess.

[0060] As used herein, "shaping" refers to the act of changing the shape of one or more surfaces of an incremental layer of material, or the shapes of one or more layers. The shape can be changed in the shaping process to the entire surface or only a portion of the surface, typically the top surface. The changed shape can be flat or planar, convex, concave, or any other shape as desired. The changed shape of the top surface can be different from the shape of the bottom surface.

[0061] The process of the present invention may include one or more compacting steps, one or more shaping steps, and / or one or more marking steps.

[0062] As used herein, a "three-dimensional printing build system" or "3DP build system" generally includes a powder layering system (area) that deposits and / or layers powder material into incremental powder layers within recesses, as well as a printing system (area) that applies binding liquid to the incremental powder layers according to a predetermined pattern, thereby forming a partial or complete bound powder layer (incremental printed layer).

[0063] FIG. 1 shows a blister pack 1 including a blister sheet 2, in which a desired number of cavities 4 are formed in a sheet 6 of a desired film or laminate material by conventional cold forming. A lid sheet 8 is shown sealed to the sheet 6, which includes spots 3 over the cavities that house the dosage forms 10 (also shown in cross section in FIG. 2). The front of the blister pack 1 shows the lid sheet 8 peeled away from the sheet 6, exposing the dosage forms 10 located in the cavities 4 (as shown in cross section in FIG. 3) or removing the dosage forms 10 from the cavities 4 (as shown in cross section in FIG. 4). The size and shape of the cavities 4 is a matter of choice that can be determined by the size and nature of the tablets to be formed and other considerations well known to those skilled in the art. The number and arrangement of the cavities 4 in the blister sheet 2 is a matter of choice that can be made based on the tablet dosage and duration of administration, economic aspects, and the type of API available in the case of a drug or pharmaceutical tablet, as well as other considerations well known to those skilled in the art. The film or laminate sheet 6 comprises a formable material in which one or more depressions can be formed. In one embodiment, the film or The film or laminate sheet 6 may comprise a thermoformable plastic layer, such as a polymeric material including polyamide, polyvinyl chloride, polypropylene, or other such materials. In another embodiment, the film or laminate sheet 6 may comprise a cold-formable metal foil, such as an aluminum film. The laminate material may comprise two or more layers that may be made of the same or different materials and the same or different thicknesses. The film or laminate material may have a thickness of 25 to 100 microns (μm).

[0064] FIG. 4 shows a single portion of a blister-type package for a dosage form, the portion consisting of a cavity 4 formed in a sheet 6, the cavity 4 having a closed end 7 and an outer wall 9 that define a space 5 within the cavity 4. In a non-limiting embodiment, the cavity 4 in the blister sheet 2 is shown to have a circular planar shape and an outer wall that tapers inwardly from the sheet toward the closed end 7. Some embodiments of the cavity in the blister sheet package have elongated or complex shapes. Some embodiments have outer walls that are circular, arcuate, or perpendicular to the packaging sheet. Those skilled in the art will recognize and understand that any embodiment of packaging material or cavity of any type, shape, or size can be directly and unambiguously combined with any other embodiment of the invention described herein.

[0065] FIG. 5 shows an initial step, which is optional in some embodiments, of depositing an initial layer 31 of binding liquid at the bottom or closed end 7 of the recess 4 to provide a bond for the initial powder material 20 deposited into the recess 4. The initial layer 31 of binding liquid may be deposited, for example, by spraying droplets 30 of binding liquid from a print nozzle 32 of an inkjet print nozzle assembly 33. The initial layer or film of binding liquid ensures that the bottom surface of the dosage form 10 is tightly bonded to the particles along the bottom surface 12. In some embodiments, an excess amount of binding liquid, at least more than sufficient to bond the particles of the powder material together, is used to form a wet coating that, when dried or cured, forms a firm, resilient bottom coating. In some embodiments, the binding liquid used to form the wet coating is a different liquid than the binding liquid used to form the bonded powder layer.

[0066] 6-24 show a method and apparatus for depositing powder material into one or more cavities of a blister-type package.

[0067] FIG. 6 illustrates a process of depositing a first predetermined amount 40 of powder material 20 including particles in a cavity 4 or in each of a plurality of cavities 4. The powder 20 is discharged from a supply container or hopper 22 through a powder dosing device 24. The powder dosing device 24 is designed and configured to dispense a predetermined amount 40 of powder from a supply container 22, which may contain a predetermined volumetric amount or a predetermined mass of powder. In the illustrated embodiment, the predetermined amount 40 of powder is deposited in the form of a pile 40 of powder onto the closed end 7 of the cavity 4. As seen in FIG. 5, the bottom of the first pile 40 of powder 20 is wetted with an optional first layer 31 of binding liquid to form a coating 50 on the bottom 12 of the dosage form.

[0068] In one embodiment, the predetermined amount 40 of powder can be a predetermined volume of powder material, where the powder material may have a substantially uniform powder density, such that the predetermined volume delivers a substantially fixed mass weight of the powder material. Accurate and reproducible mass weight of the deposited powder material amount is important to ensure that a finished dosage form consisting of two or more deposits of powder material has a consistent and accurate amount of total powder material. In embodiments where the powder material includes an active ingredient in particulate form, such as a particulate medicine or drug, and the powder material includes one or more other particulate materials, it is preferred that the particulate active ingredient does not separate from the other particulate materials.

[0069] In another embodiment, the predetermined amount of powder can be a predetermined mass weight of powder material. Again, assuming a substantially uniform powder density, the predetermined mass weight delivers a substantially fixed volume of powder material. In the illustrated embodiment, the predetermined mass weight of powder material provides a volume of powder material sufficient to form a fixed volume of a substantially uniform powder layer in the bottom of the available space in the recess 4. Depending on the size and shape of the bottom of the available space in the recess 4, a first powder layer of a substantially uniform powder layer of a predetermined depth is formed.

[0070] A representative example of a dosing apparatus 24 is shown in FIG. 7 as a manual dosing device 75. The manual dosing device 75 includes a supply container or hopper 71 containing a bulk supply of powdered material 20, an outer cylinder 73 attached to the bottom of the hopper 71 and having an upper opening communicating with the hopper 71 and a lower opening 173, and an inner cylinder 79 axially rotating within the outer cylinder 73 as indicated by rotation arrow RR in FIG. 7. The inner cylinder 79 is configured to rotate within the outer cylinder 73 between a fill rotation position shown in FIG. 8 and a dispense rotation position shown in FIG. 10. The inner cylinder 79 has a cylindrical fill cavity 77 formed within the cylindrical wall of the inner cylinder 79 that opens into the volume of the supply hopper 71 when rotated to the fill rotation position shown in FIG. 8 and opens into the lower opening 173 of the outer cylinder 73 when rotated to the dispense rotation position shown in FIG. 10.

[0071] FIG. 8 shows a cross-sectional view taken along line 8-8 of the manual dosing device 75 of FIG. 7. In the filling position, the filling cavity 77 of the inner cylinder 79 communicates with the interior space of the hopper 71, allowing the powder 20 to flow by gravity into the volume of the filling cavity 77 with a predetermined volume of powder 177 for complete filling. The volume of the filling cavity 77 is a predetermined volume for holding the required volume of powder material required for one powder deposition layer. In some embodiments, the inner cylinder 79 and its filling cavity 77 can be replaced with another inner cylinder with a different size filling cavity for depositing different predetermined volumes of powder. In another embodiment of the invention, the system can include a second (or more) manual dosing device with a filling cavity of different volume size to accommodate the formation of initial and incremental powder layers of different predetermined volumes or to achieve a target mass of powder material corresponding to powder materials having different specific densities.

[0072] FIG. 9 shows the inner cylinder 79 in a separated rotational position between the filling rotational position and the dispensing rotational position, where the powder material 177 in the filling cavity 77 is separated from the hopper 71. FIG. 10 shows the inner cylinder 79 rotated to the dispensing rotational position to release a predetermined volume of powder 177 (dashed line) by gravity from the filling cavity 77 through the opening 173 at the bottom of the outer cylinder 73 to the bottom of the space 5 of the recess 4 as a pile 40 of powder material. The manual dosing device 75 can then be repositioned and the filling cavity 77 refilled with powder 20 by rotating the inner cylinder 79 and the emptied filling cavity 77 again to the separated rotational position and then again to the filling rotational position shown in FIG. 8. The deposition of powder by gravity into the recess 4 creates a pile 40 of powder, typically, but not necessarily, in a consistent and reproducible shape, on the top surface of the first bonded powder layer 61, as shown in FIG. 6, where the pile 40 typically has a tapered shape based on the repose angle of the powder material. The top of the pile 40 of powder material is typically located below the discharge opening 173 of the powder dosing device 24 and the powder surface tapers towards the outer wall 9 of the cavity 4 .

[0073] One example of an automated dosing device for filling multiple cavities in a dosing package is the rotary dosing device shown in Figure 11. The rotary dosing device 224 includes a hopper 271 that contains a supply of powder material 20 and a rotating drum 275 having an outer surface 276 with a number of filling cavities 277 formed therein sufficient to fill the multiple cavities 4 in the blister sheet 2. The blister sheet 2 is moved beneath the rotary dispenser 224 at a speed synchronized with the rotation of a rotating drum 275 having ports 277 aligned with the recesses 4 (arrow).

[0074] The bin 271 includes multiple dispensing ports, shown as three dispensing ports, that feed the powder material into the filling cavities 277. FIG. 12A shows a cross-sectional view of the hopper 271 and the rotating drum 275, showing the dispensing gate 278. A sliding gate 279 dispenses the powder material through the dispensing gate 278, which is located at the filling point 272 of the device 224. As the rotating drum 275 rotates, each filling cavity 277 turns towards the filling point 272. As the filling cavity 277 approaches the filling point 272, the sliding gate 279 opens (small arrow) in a slot in the dispensing gate 278 to allow a portion of the powder material to pass through and fill the filling cavity 277. The sliding gate 279 can be oriented to open transversely (as shown) to the rotation axis 100 of the rotating drum 275, in the opposite (or same) direction to the direction of movement of the blister sheet 2, or parallel to the rotation axis 100.

[0075] The rotary dosing device 224 also includes a shell 274 having an arcuate inner surface opposing a cylindrical outer surface 276 between a sliding gate 279 and a discharge point 273 of the device 224, and covering the filled cavity 277f (filled cavity 277 filled with powder material 20) to prevent the powder material from spilling out. The leading edge of the shell 274 provides a means for sweeping away excess powder dispensed into the filled cavity 277 and for leveling the surface of the powder within the filled cavity 277f.

[0076] Some embodiments of the rotary dosing device can include a vacuum system that applies a vacuum to the inner surface of the fill cavity 277 to help maintain the powder material loaded into the fill cavity 277.

[0077] In some embodiments, each fill cavity is of sufficient size and depth to hold and dispense a layer of powder material 20 into each recess 4 of the blister sheet 2 to form the powder layer 61. FIG. 12B illustrates a rotary dosing device 375, where each fill cavity 377 is of sufficient size to hold a volume of powder in excess of the amount of powder required to form a powder layer in the recess. In such embodiments, the device 224 also includes a volumetric dispensing pocket to meter a predetermined volume of powder material into the oversized fill cavity. An example of a volumetric dispensing pocket is shown in FIGS. 13-18 and discussed later in this specification.

[0078] In some embodiments, the volume of powder material into the fill cavity 377 can be throttled using a sliding gate or other well known means for restricting the flow of powder material from the bin 271. A non-limiting example of a restricting means is a dispensing gate 278.

[0079] After each filled cavity 277f (or 377f) deposits its powder material into the empty recess 4 of the blister sheet 2, the filled cavity 277 (or 377) of the rotating drum 275 and the blister sheet 2 are aligned and advance at the same linear speed. After being emptied, the filled cavity advances towards the fill point 272. In some embodiments, the rotation of the rotating drum 275 and the advancement of the blister sheet 2 are constantly progressing, and in some embodiments, the rotation of the rotating drum 275 and the advancement of the blister sheet 2 are temporarily stopped when a filled cavity reaches a fill point and / or a discharge point.

[0080] Figures 13 to 18 show another embodiment of an automatic dosing device 225 for filling multiple cavities in a dosing package. Figure 13 shows an elongated bottle 271 containing powder material 20. The bottle 271 is oriented transversely to the direction of movement of the blister sheet 2 below the dosing device 225, along the width of the blister sheet 2. Figure 14 shows an empty bottle 271 with a bottom dispensing opening that feeds into a volumetric dosing pocket 282. The volumetric dosing pocket 282 is 15 and a dispensing position shown in FIG. 17. In FIG. 15, the powder material 20 flows under gravity and completely fills the pocket hole 287. In parallel, the blister sheet 2 is positioned under the volumetric dispensing pocket 282 so as to align the empty recess 4 under the elongated cavity 284 of the support frame 283. In FIG. 17 ... FIG. 17, the powder material 20 flows under gravity and completely fills the pocket hole 287. In parallel, the blister sheet 2 is positioned under the volumetric dispensing pocket 282 so as to align the empty recess 4 under the elongated cavity 284 of the support frame 283

[0081] In FIG. 16 , the operating means is shown as a force applied to the shaft 288, moving (sliding) the pocket gate 286 and the filled pocket hole 287 distally. As the pocket gate 286 moves distally, the top surface of the proximal portion of the body of the pocket gate 286 covers and closes the dispensing opening in the bottom portion of the elongated vial 271. As the pocket gate 286 continues to move distally, the filled pocket hole 287 of the pocket gate 286 moves toward alignment with the dispensing opening 284. As shown in FIG. 16 , once the filled pocket 287 begins to overlap and align with the dispensing opening 284 of the frame, the powder material in the pocket hole 287 begins to empty and pass through the dispensing opening 284 into the aligned recess 4. As shown in FIG. 17 , after the pocket gate 286 aligns with the dispensing opening 284, essentially the entire powder material has fallen from the pocket hole 287 through the dispensing opening 284 into the recess 4. After the pocket hole 287 is emptied, the blister sheet 2 advances to align the next empty cavity 4 under the dispensing opening 284, as shown in Figure 18. Simultaneously or contemporaneously, an operating means, shown as a force applied to an axis 288, moves (slides) the pocket gate 286 and the now emptied pocket hole 287 proximally back to the filling position shown in Figure 15.

[0082] It should be understood that alignment and filling of the recesses, and movement of the pocket holes between the filling and dispensing positions, occurs simultaneously or contemporaneously within other recesses and volume dispensing pockets 282 laterally along the elongated vial 271.

[0083] Figures 19-24 show another embodiment of an automatic dosing device 226 for filling a plurality of cavities in a dosing package. In Figure 19, similar to the embodiment shown in Figure 13, an elongated bin 271 containing powder material 20 is oriented transversely to the direction of movement of the blister sheet 2 below the dosing device 226 along the width of the blister sheet 2. Figure 20 shows an empty bin 271 with a bottom portion dispensing opening feeding a volumetric dispensing pocket 292 similar to the volumetric dispensing pocket 282, similar to the embodiment shown in Figure 14. The volumetric dispensing pocket 292 comprises a support frame 293 having an elongated cavity 295 and a dispensing opening 294 at its distal end. A pocket gate 296 is arranged in the elongated cavity 295, which has a pocket hole 297 in a distal portion and an operating means extending from a proximal portion, which is shown as a shaft 298 extending through a rear opening in the support frame 293. The pocket gate 296 is movable within the elongated cavity 295 via an operating means between a filling position shown in Figure 21 and a dispensing position shown in Figure 22. In Figure 21, the powder material 20 flows under gravity to completely fill the pocket holes 297. In parallel, the blister sheet 2 is positioned below the volumetric dispensing pockets 292 so as to align the empty recesses 4 below the cavities 294 of the support frame 293.

[0084] 22 as a force applied to shaft 298 moves (slides) pocket gate 296 and filled pocket hole 297 distally into alignment with dispensing opening 294. As pocket gate 296 moves distally, the top surface of the proximal portion of the body of pocket gate 296 covers and closes the dispensing opening in the bottom portion of elongated vial 271. After pocket gate 296 is aligned with dispensing opening 294 as shown in FIG. The entire powder material has fallen from the pocket hole 297 through the dispensing opening 284 into the recess 4. In some embodiments and circumstances, a portion of the powder material in the emptied pocket hole 297 remains and sticks or adheres to the edge of the pocket hole 297. To ensure that the entire powder material is dispensed into the recess, a tamper 88 having a lip 89 and a lower surface 87 is provided, the tamper 88 being vertically disposed above the dispensing opening 294 in axial alignment with the dispensing opening 294. As shown in FIG. 23 , when the tamper 88 is aligned and lowered through the pocket hole 297 and the dispensing opening 294, the lip 89 and lower surface 87 sweep all the powder material from within the pocket hole 297 into the recess 4. In some embodiments, the lip 89 of the tamper 88 extends sufficiently to extend the lower surface 87 into the recess 4 to contact the powder layer 61. In some embodiments, the tamper 88 is sufficient to flatten and / or compact the powder layer, as described in more detail herein below.

[0085] After the pocket hole 297 is emptied, the blister sheet 2 advances to align the next empty cavity 4 under the dispensing opening 294, as shown in Figure 24. Simultaneously or contemporaneously, an operating means, shown as a force applied to an axis 298, moves (slides) the pocket gate 296 and the now emptied pocket hole 297 proximally back to the filling position shown in Figure 21.

[0086] In some embodiments, the 3DP systems and devices can include a second or more dosing devices for dispensing a second powder material into the cavity, including a different second powder material, to form a dosage form containing two (or more) sources, types, and compositions of powder material.

[0087] Other non-limiting examples of mechanical dosing and / or metering devices are described in U.S. Patent Nos. 9,409,699 and 9,828,119, and U.S. Patent Application Publication Nos. 2017 / 0322068 and 2018 / 0031410, the disclosures of which are incorporated by reference in their entirety. Piezoelectric needle dispensing devices use standing waves driven by a piezoelectric actuator to dispense powder that is moved by forcing the powder material through a stainless steel tube. At the dispensing tip of the needle, the standing waves act to expel the powder material. These devices are effective in precisely delivering fixed, low levels of powder material.

[0088] Other non-limiting examples of mechanical dosing and / or metering devices can include gravimetric powder dispensing / powder dosing devices available from ChemSpeed ​​Technologies (https: / / www.chemspeed.com / flex-powderdose / ), the disclosure of which is incorporated by reference in its entirety.

[0089] In some embodiments, the method and system includes a means for flattening the pile of powder material in the recess. FIG. 25 illustrates a process for flattening a pile 40 of a predetermined amount of powder material 20 in the recess 4 into a substantially uniform powder layer 41. Using the flattening means, the pile 40 of powder material 20 or other shaped deposit is transformed into a substantially uniform powder layer 41. In the illustrated embodiment of FIG. 25, the flattening means includes a method including any one or combination of laterally, orbitally, and vertically vibrating the recess 4 and the pile 40 of powder contained therein at a frequency and speed sufficient to disperse and spread the pile 40 of powder outwardly over the entire base area of ​​the space 5 of the recess 4, in some embodiments into a substantially uniform powder layer 41. This method forms a first substantially uniform powder layer 41 having a predetermined layer thickness or height "h". In a manual system, the package and the recess portion can be shaken manually or with a vibration table. Non-limiting examples of mechanical vibratory tables, conveyors are available from Tinsley Equipment Company, https: / / www.tinsleycompany.com / bulk-process-equipment / vibratory-process-equipment / vibrating-tables / , the disclosures of which are incorporated by reference.

[0090] In some embodiments, the powder material layer prepared in the depression has a flat plane parallel to the bottom surface of the depression. In some embodiments, the powder material layer prepared in the depression can have a uniform thickness with tolerance. In such embodiments, the powder material layer thickness with a slightly non-uniform thickness but within the tolerance can be bound by a binding liquid into a bound powder formulation. In some embodiments, the non-uniformity of the planarization of the powder material layer can be defined by the variance of the powder layer thickness from the weight average or target thickness. The minimum powder layer thickness and the maximum powder layer thickness can have a variance relative to the weight average thickness, where the variance is up to about 25% variance. In some embodiments, the variance is up to about 20% variance, up to about 15% variance, in some embodiments up to about 10% variance, where the variance can be at least 5%, at least 10%, at least 15%, or at least 20% variance. For example, a powder material layer having a weight average (target) thickness of 0.50 mm can have a thickness with a tolerance of 20%, with the powder layer having a minimum and maximum thickness of 0.40 mm to 0.6 mm, so long as the bonding of the powder material by the binding liquid remains effective. In another example, a powder material layer having a weight average (target) thickness of 1.0 mm can have a thickness with a tolerance of 15%, with the powder layer having a minimum and maximum thickness of 0.85 mm to 1.15 mm, so long as the bonding of the powder material by the binding liquid remains effective. FIG. 26 illustrates a support plate 15 that can be used to secure and support one or more recesses 4 of a blister pack 1, including but not limited to during powder deposition and layering, deposition of binding liquid, removal of solvent, and any other process steps of the method and system. A port or opening 16 in the support plate 15 provides a receptacle for receiving and supporting the recesses 4 and the blister pack 1 on the upper surface 17 of the support plate 15. In some embodiments, the pattern of recesses can be aligned with a pattern of openings 16 in support plate 15. In some embodiments, the pattern of openings 16 includes multiple rows and multiple columns. In some embodiments, openings 16 extend through the entire thickness of support plate 15.In some embodiments, the openings 16 extend only partially through the thickness of the support plate 15, providing blind holes.

[0091] 27 shows one embodiment of a support plate 115 including a pattern of openings 116 through a top surface 117 forming blind holes in the support plate 115. The support plate 115 has three columns and four rows of blind holes 116 with a series of longitudinal inlet holes 118 extending from an edge 114 of the support plate 115 and intermediate holes 119 extending through the thickness along a row of four blind holes 116 and through the material between each adjacent opening 116 such that the inlet holes 118 and intermediate holes 119 communicate with each blind opening 116 in the row. Application of a vacuum to the inlet holes 118 communicates with each blind opening 116 through the intermediate holes 119, drawing and securing the blister pack 1 to the top surface 117 of the support plate 115.

[0092] In FIG. 28, a non-limiting example of a powder flattening means is shown as a vibration device 230 for use in providing lateral vibration of the depressions 4 in the blister sheet 2. In the illustrated embodiment, the blister sheet 2 is supported in the support plate 15. The device has a tapping arm 232 having a u-shape, the proximal end of which is attached to a pivot post 231 which oscillates about an axis "a" thereby vibrating a base 233 of the U-shaped tapping arm 232 in a lateral direction "b" to a side edge of the support plate 15. The lateral tapping provides flattening and improves uniformity of the powder material to the powder layer in the depressions. The frequency and degree of rotational vibration "a" of the pivot post 231 is controlled to provide a frequency and impact force of vibration of the base 233 against the support plate 15 to provide effective leveling of the powder layer without expelling the powder from the cavity or causing the powder to suspend unevenly within the cavity.

[0093] An alternative apparatus for leveling the pile of powder within the cavity into a substantially uniform layer of powder comprises: As shown in Figures 29 to 32.

[0094] 29-32 show an alternative flattening apparatus for flattening the pile 40 of powder 20 into a substantially uniform powder layer in the depression 4. A flattening device 80 is shown positioned above an open-ended depression 4 in which a predetermined amount of the pile 40 of powder material 20 is deposited in the center of a first bonded powder layer 61. The flattening device 80 is used to form a substantially uniform layer of powder material from the unevenly disposed pile 40 of powder material. The layering device 80 includes a vertical rotating shaft 82 driven by a motorized rotating means (not shown). Non-limiting examples of such motorized rotating means include servo motors. The powder flattening member extends horizontally and radially from a bottom of the rotating shaft 82 to a distal end that is substantially the radius of the depression 4. The powder flattening member rotates about the axis of the rotating shaft 82 while descending into the pile 40 of powder material to form a substantially uniform layer of powder in the depression 4.

[0095] As shown in FIG. 29, the powder flattening member can include a brush assembly including a circular disk 84 attached at its center to the lower end of a rotating shaft 82 and configured to rotate about the axis of the rotating shaft 82. In one non-limiting embodiment, the circular disk 84 includes a plurality of brushes 86 attached to and extending downward from the lower surface 81 of the circular disk 84. The plurality of brushes 86 are typically positioned in a pattern to maintain the center of gravity of the circular disk 84 at its attachment point to the rotating shaft 82. In an alternative embodiment, a single circular pad can be attached to the lower surface 81 of the circular disk 84. The plurality of layering brushes 86 are made from a material that avoids adhesion of particles of the powder material to avoid sticking during operation. In one embodiment, the top view diameter defined by the plurality of layering brushes 86 is the same or substantially the same diameter size as the top view surface area of ​​the bottom of the space 5 in the recess 4.

[0096] The rotating shaft 82 may also be integrally assembled within a housing or shroud (not shown) that extends around the periphery of the circular disk 84 to create a dust barrier during flattening of the powder material.

[0097] As the brush assembly rotates and descends into the recess 4, as shown in Figs. 30 and 31, a plurality of brushes or paddles 86 in a central area 85 of the rotating circular disk 84 contact the crest and top of the pile 40, partially moving the particles of powder 20 radially outward toward the wall 9 of the recess 4. After the rotating circular disk 84 descends toward the end height shown in Fig. 31, the elevated portion of the pile 40 of powder material in the center of the recess 4 is moved or dispersed toward the wall 9, and the top surface of the powder material in the pile 40 is substantially flattened to a plane to form a substantially uniform powder layer 42. The type and restoring force of the brushes or other material contacting the particles of powder, the rotational speed of the rotating circular disk 84, and the descent speed of the flattening device 80 into the recess should be selected and controlled to avoid moving an excessive amount of particles toward the inner surface of the wall 9 of the recess, which may cause an excessive accumulation of powder along the wall 9. After a substantially uniform layer of powder material 42 is formed, the layering device 80 can be lifted from the space 5 within the recess 4, as shown in FIG. 32.

[0098] In an alternative embodiment, the powder flattening member may include a single horizontal member, including using a vane or rod.

[0099] In another embodiment, the powder flattening member can have a curvature in the plane of rotation.

[0100] In another embodiment, the powder flattening member may have a curved, non-linear, e.g., concave or curved surface, to sweep the surface of the pile of powder material into a layer of powder material having the same surface profile. It may have a convex lower edge.

[0101] In some embodiments, the dispensing device 24 can include a device for dispensing a predetermined amount of powder material and forming the powder into a substantially uniform layer of powder within the cavity, an example of such a device is shown in Figures 33-41.

[0102] 33-38 illustrate an alternative apparatus for dispensing a predetermined amount of powder material 20 and forming the powder into a substantially uniform powder layer within cavity 4. The illustrated layer deposition apparatus 90 is capable of simultaneously dispensing a predetermined amount of powder material 20 and forming the powder into a substantially uniform powder layer within cavity 4. An example of a layer deposition apparatus is described in U.S. Pat. No. 10,071,372 and U.S. Patent Application Publication No. 2017 / 0312179, the disclosures of which are incorporated herein by reference in their entireties.

[0103] The layer depositing apparatus 90 is shown in FIG. 33 in a position for collecting a required volume of powder material from a powder hopper 91 filled with powder. The layer depositing apparatus 90 includes a cylindrical suction body 92 having an outlet suction end 93 and an inlet powder end 94 with an inlet edge 96. Within the body 92, at the powder end 94, is located a porous plate 95 that extends across a cross section of the interior of the body 92. The porous plate 95 can be a woven or non-woven screen material or a material with porosity, and has a number of passages leading from its inlet facing surface to its vacuum facing surface, forming a breathable medium. These passages are of a size small enough to prevent the powder material 20 from entering therein while allowing free air flow during operation.

[0104] The inlet-facing surface of the porous plate 95 is spaced axially from the inlet edge 96 a distance or depth "h" so as to define a cylindrical powder entrapment volume 97. In one embodiment, the axial position of the porous plate 95 can be moved toward or away from the inlet edge 96 to vary the cylindrical powder entrapment volume 97 in a predetermined manner to achieve a predetermined amount of powder material forming a substantially uniform powder layer.

[0105] 34, suction is applied to the interior of body 92 by a remote vacuum source, as indicated by the arrows associated with the word "vacuum." The vacuum source may be regulated by any device known in the art capable of providing a controllable amount of vacuum. The vacuum within body 92 results in air being drawn in through inlet end 94 which passes through porous plate 95.

[0106] Figure 34 shows the process of filling the powder intake volume 97 with powder 20 by placing the inlet end 94 into the powder hopper 91. The vacuum causes the incoming air to draw particles of powder material 20 from the reservoir 91 into the inlet end 94, where the particles are drawn into and accumulated in the powder intake volume 97. As long as the vacuum is maintained, the volume 140 of powder in the powder intake volume 97 will remain drawn by the incoming air towards the porous plate 95 when the layer deposition apparatus 90 is removed from the powder hopper 91, as shown in Figure 35, and moved into position over the recess 4, as shown in Figure 36.

[0107] 36-38 show a filling device 90 for depositing a volume 140 of powder material 20 into the space 5 of the recess 4. In the illustrated embodiment, the inlet end 94 of the body 92 is configured to be inserted into the recess 4 during powder deposition and layering. In one embodiment, as shown in FIG. 37, the inlet end 94 of the body 92 is positioned directly above the last bonded powder layer in the recess 4, here bonded powder layer 61, during powder deposition and layering. As the inlet end 94 descends towards the last bonded powder layer 61, the application of vacuum is carefully controlled and reduced to reduce the risk of the incoming airflow damaging or disturbing the powder and binder matrix of the bonded powder layer 61. After the vacuum is removed from the body 92, the amount 140 of powder 20 in the powder capture volume 97 "falls" by gravity onto the top surface of the final first bound powder layer 61, forming the second powder layer 42 as the filling device 90 is pulled upwardly, away from the recess 4, as shown in FIG.

[0108] The body 92 may be configured with thin and / or tapered walls at the inlet end 94 such that the space taken up by the walls between the deposited powder quantity 42 and the inside of the wall 9 of the recess 4 is minimized. Nevertheless, the extra thickness of the walls at the inlet end 94 may result in the lateral diameter (width) of the deposited powder layer 42 being smaller than the diameter (width) of the inner wall 9 of the recess, which may cause the peripheral walls of the deposited powder layer 42 to peel off into the gap between them, as shown in FIG.

[0109] In an alternative embodiment, the inner diameter of the powder intake volume 97 can be aligned to the same diameter as the inner wall 9 of the recess 4 at the bottom of the space 5. In this embodiment, not shown, the inlet end 94 of the body 92 is positioned far enough above the last bonded powder layer 61 in the recess 4. When the vacuum is removed from the body 92, the amount 140 of powder 20 in the powder intake volume 97 falls a short distance by gravity to the top surface of the last bonded powder layer 61, with the powder area aligned with the top surface area of ​​the last bonded powder layer 61. This embodiment avoids the gaps of the above-mentioned embodiment, but allows the powder volume to fall freely through the air space, which can create turbulence and affect the uniformity of the resulting deposited powder layer.

[0110] An alternative embodiment shown in Figures 39-41 addresses the gap problem of the previous embodiment while avoiding the problem caused by the powder volume falling freely onto the top surface of the final bound powder layer 42. In another embodiment, the porous plate 195 shown in Figure 39 is configured to have an upward annular peripheral pile, thereby creating an additional annular powder volume 197 on the periphery of the powder intake volume 97, allowing the intake of powder 240 into the powder intake volume 197 to contain an additional annular powder quantity 297 within the volume 197. As shown in Figure 40, with the inlet end 194 positioned directly above the final bound powder layer 61 in the recess 4, a vertical dashed line 198 indicating the outer diameter of the additional powder in the additional annular powder volume 197 is located inside the inner diameter of the wall 9 of the recess 4 as indicated by dashed line 199. Nonetheless, the annular powder 297 in the additional annular powder volume 197 results in sufficient filling of the annular gap between diameters 198 and 199, resulting in the deposition of a substantially uniform powder layer 42, as shown in FIG. 41.

[0111] FIG. 42 illustrates the step of applying a binding liquid to the space 5 and the first powder layer 41 (FIG. 25). In a preferred embodiment, the binding liquid is applied using 3D printing methods and techniques such as those described in U.S. Patent Nos. 6,471,992, 6,945,638, 7,300,668, 7,875,290, and 8,088,415, the disclosures of which are incorporated by reference in their entirety. In the illustrated embodiment, a first predetermined quantity of binding liquid is deposited by spraying droplets of liquid 30 from a print nozzle 32 of an inkjet print nozzle assembly 33. The droplets of binding liquid 30 bind the particles of the powder material into a cohesive powder liquid matrix to form the first wet powder layer 51 into a substantially uniform layer.

[0112] In a typical embodiment, the bonding fluid contains an amount of excess solvent in the resulting wet powder layer 51, which is preferably removed to form the completed bonded powder layer. Figure 43 shows a depression 4 located within a port or opening 16 of a support plate 15 during the solvent removal process from the wet powder layer.

[0113] A liquid removal system is provided and adapted to receive one or more blister sheets having one or more wet powder layers or finished 3DP dosage forms contained within the recesses and remove liquid therefrom. The liquid removal system may be a process area where one or more are guided. For example, the liquid removal system may remove or reduce liquid from an incrementally printed layer of a 3DP dosage form in process. Alternatively, the liquid removal system may be another process area not directly associated with the three-dimensional printing system, such as a temporary holding or storage area where the three-dimensional printed blister sheets are placed under ambient conditions to dry. In some embodiments, the liquid removal system is one or more dryers.

[0114] 43 illustrates several means of removing excess solvent liquid by heating or applying heat to the wet powder layer 51 formed in the cavity 4, generally evaporating the excess liquid solvent into a gas or vapor that is removed from the dry powder layer. The illustrated means of removing liquid solvent can include various forms of heating the excess solvent in the wet powder layer to evaporate the excess solvent liquid into a gas or vapor V. The illustrated means may be selected from one or more of: convection heat transfer using heated air 35 conveyed up and down toward the wet powder layer 51, as described, for example, in U.S. Pat. Nos. 6,990,748, 6,047,484, and 4,631,837, the disclosures of which are incorporated herein by reference in their entireties; conductive heat transfer using a heated liquid, such as a heated liquid 36 or heated air, at the underside of the recess 4 to conduct heat 38 to the sheet material of the recess 4 and to the wet powder layer 51; and radiative heating using infrared radiation 39 from a suitable infrared source conveyed into the recess and / or through the sheet material of the recess 4 to the wet powder layer 51.

[0115] In some embodiments, the drying apparatus includes multiple infrared emitting sources arranged in a pattern to emit infrared energy toward the top surface of the blister sheet 2. The blister sheet 2 with the wet powder material disposed in the recesses is passed into the housing and positioned at predetermined coordinates. In some embodiments, the pattern and coordinates of the top surface of the wet powder material are detected and mapped to form a drying profile. An infrared (IR) light source is illuminated and controlled to emit IR light exclusively onto the top surface of the wet powder material. The time and intensity of the emitted IR light is maintained to heat and evaporate the top surface, evaporating moisture and other solvents from the volume for the wet powder material. In some embodiments, the IR light emitted into the wet powder is controlled using a mask having a pattern of shaped openings that allow the IR energy to pass through. In some embodiments, the light emitted through the mask is focused using a refractive material, such as a lens. In some embodiments, the IR light source includes a high resolution IR light emitter controlled to emit a pattern of IR light.

[0116] 44 shows one embodiment of a dryer 415 suitable as a liquid removal system. The dryer includes a housing 416 in which are housed a plurality of heating elements 417 and a conveyor system 418. The housing includes an inlet 420 and an outlet 419 through which the 3DP blister sheet 422, and optionally a respective support plate, are conveyed by a conveyor. In some embodiments, the dryer includes one or more covers 421 for the inlet and / or outlet. The dryer optionally includes an exhaust system 423 for removing vapors, and / or a heated air source 424 for providing heated air to the dryer.

[0117] 45-49 show the deposition of additional predetermined amounts of powder 20 deposited or formed as substantially uniform powder layers. FIG. 45 shows a second substantially uniform powder layer 42 disposed on top of the first bonded powder layer 61 in the recess 4, and FIG. 47 shows a fifth substantially uniform powder layer 45 deposited on top of the four previously formed bonded powder layers 61, 62, 63, and 64. Droplets 30 or streams of binding liquid are deposited on top of the powder layers to form additional wet powder layers, including the second wet powder layer 52 shown in FIG. 46 and the fifth wet powder layer 55 disposed on top of the four previously formed bonded powder layers 61, 62, 63, and 64 shown in FIG.

[0118] After each successive wet powder layer is formed in the cavity, excess solvent from the binding liquid may be removed from one or more of the wet powders, as described above. Figure 49 shows the fifth, topmost bound powder layer 65 after excess solvent has been removed from the topmost wet powder layer 55. After the completed dosage form 10 is printed, it is covered with a lidding sheet 8 and sealed in the package cavity 4 to form a dosage blister 1a, which is further shown in Figure 49.

[0119] In some embodiments, some or all of the wet powder layers can be formed in sequence and a single drying step can be performed on some or all of the wet powder layers for solvent removal. In certain embodiments, excess solvent removal can be performed sequentially or in parallel during material deposition.

[0120] In FIG. 49, the completed dosage form including the bonded powder matrix 10 consisting of five bonded powder layers 61-65 has a shape and size that substantially conforms to the interior space for the cavity 4.

[0121] In one embodiment of the present invention, the inner surface of the packaging sheet 6 forming the recess 4 can include a release agent. The release agent provides a means for the outer wall 11 and bottom surface 12 of the dosage form 10 (see FIG. 1 ), which face the inner surfaces of the wall 9 and closed end 7 of the recess 4, respectively, to easily release the dosage form 10 from those inner surfaces or to avoid adhesion of the dosage form 10 to those inner surfaces. The release agent can be a compound that is added to the inner surface of the recess prior to printing of the dosages. A non-limiting example is a coating of Teflon that releases the dosage form without leaving residual compound in the recess 4. The release agent can also be a compound, an inherent property, or an applied function of the plastic material of the packaging sheet 6, such as a plastic film laminated to the inner surface of the sheet that has adhesion resistance.

[0122] In certain embodiments, the release agent can be characterized by a low surface energy compared to the surface tension of the deposition liquid, thereby limiting or controlling the degree of wetting of the inner surfaces of the recesses and inhibiting migration of the binding liquid along the periphery of the dosage form.

[0123] In some embodiments, for depositing a bonding liquid having a surface tension in the range of 40-50 mN / m, the inner surface of the cavity desirably has a surface energy of less than 40 mN / m, more particularly less than 35 mN / m. In some embodiments, for depositing a bonding liquid having a surface tension in the range of 30-40 mN / m, the inner surface of the cavity desirably has a surface energy of 29 mN / m or less, more particularly less than 25 mN / m. If a multi-layer cavity material is used, for example polyvinyl chloride / polychlorotrifluoroethylene (PVC / PCTrFE) is selected, then desirably PCTrFE flakes (30.9 mN / m) are placed on the inner surface of the cavity and PVC flakes (41.5 mN / m) are placed on the outer surface of the cavity.

[0124] In general, the surface energy of the release agent (or plastic) is desirably 1 mN / m to 5 mN / m, or 5 mN / m to 10 mN / m, or 10 mN / m or more less than the surface tension of the deposition fluid. Table 1 lists common polymers and their solid surface energy data (Source: http: / / surface-tension.de / solid-surface-energy.htm).

[0125] If a release agent is a further material added to the packaging sheet forming the recesses, when using an aqueous binding liquid, the release agent is suitable for consumption and can be selected from the group consisting of oils, waxes, or fatty acids, metal salts of fatty acids, or fatty acid esters. Suitable release agents are those listed in the USP / NF, Excipients Guide, GRAS (Generally Recognized Associated Compounds), and the like. As Safe) list of materials, or materials listed in connection with the outline of food additive regulations, etc. Exemplary release agents can include, but are not limited to, magnesium stearate, stearic acid, glyceryl dipalmitostearate, glyceryl distearate, glycerol palmitostearate, glyceryl dibehenate, mono- and diglyceride mixtures, glycerol monostearate, beeswax, carnauba wax, cetyl esters wax, or combinations thereof.

[0126] Although the formation of a single dosage form 10 in a single cavity 4 is shown, the methods and devices described herein can be used to form multiple dosage forms in each cavity of a packaging material, such as a blister sheet, as shown in Figure 1. The array of blister-type cavities can include any arrangement or pattern of cavities 4 that are well known in the art.

[0127] [Table 1]

[0128] In another embodiment, as shown in FIG. 50-FIG. 53, the print head and nozzle of the 3D printing assembly can be configured to add droplets of binding liquid 30 to any unique portion of the substantially uniform powder layer. In FIG. 50, binding liquid is added only to the side portions 48 of the second (or subsequent or optional) powder material layer 42 to form peripheral portions of the wet powder 58, leaving a central portion 71 of unwetted unbound powder. After the wet powder 58 is dried to the peripheral portion of the binding powder 68, an additional layer of powder can be added. FIG. 51 shows the addition of a third powder layer 43 over the layer in which the side portions 58 contain binding powder material, but the central powder portion 49 does not contain binding liquid. As shown in FIG. 52, droplets of binding liquid 30 are deposited on the third powder layer 43 to form the wet powder layer 53, but without adding a large amount of liquid to penetrate the central portion 49 of the unwetted unbound powder in the second powder material layer 42. In such an embodiment, of the bound powder shown in FIG. 53 , the peripheral portion 68 of the second bound powder layer 62, and / or the wet (or bound) powder layer 63 thereon and the portion of the first bound powder layer 61 therebelow, provide a resilient structure sufficient to accommodate a volume of powder alone, such as the central powder portion 49, while maintaining the structural integrity of the resulting dosage form 10.

[0129] Figures 54-59 show an alternative embodiment of a method of forming a dosage form within a cavity 4 of a blister-type package 1, the dosage form comprising a pre-formed bonded powder core 106 having a firm, resilient binder coating 120 surrounding the core 106 as shown in Figure 59.

[0130] FIG. 54 shows a first uniform layer of powder material 41 deposited in the cavity 4 on top of the bottom binder liquid coating at the closed end of the interior space 5 of the cavity 4, thereby forming a bottom wet powder layer 50 covering the inner surface of the closed end 7 and the remaining portion of the powder layer 41 thereon. Selected nozzles 132 of the 3D printing assembly 33 are configured to selectively add droplets or streams 34 of binding liquid to the periphery of the first powder layer 41, thereby wetting the powder at the periphery of the powder layer 41 and forming a wet peripheral coating 151. In the illustrated embodiment, the central portion of the powder layer 41 is not wetted by the droplets 34 of the second binding liquid. The second binding liquid may be the same or different from the binding liquid described above for wetting the uniform powder layer. Typically, the concentration of the second binding liquid added to the periphery 151 is greater than the concentration added to wet the powder layer. In one embodiment, the amount of binding liquid is sufficient to coat and cover substantially all of the particles of the powder and form a continuous wet powder of the liquid.

[0131] In one embodiment, the droplets 34 are applied using an inkjet printing system 33 in which a number of printing nozzles 132 are aligned in an array, typically in one or more linear rows of nozzles 132. The wells 4 containing the powder layer 41 and the array of nozzles 132 are moved relative to one another such that the droplets 34 of binder fluid are applied only to peripheral portions of the powder layer 41, with the wells 4 moving horizontally beneath the array of nozzles 132 while the droplets 34 are deposited in a timed, predetermined pattern. In one embodiment, the array of nozzles 132 is stationary and one or more wells 4 are moved horizontally beneath the nozzles 132. In an alternative embodiment, the wells 4 are stationary and the array of nozzles 132 is passed horizontally over the wells 4. As depression 4 passes under the array of nozzles 132, selected ones of the nozzles along array 33 are activated to present droplets 34 only as corresponding portions of powder layer 41 pass underneath, and the resulting representations of droplets 34 form an annular pattern of liquid binder 151 on the peripheral portions of powder layer 41.

[0132] In another embodiment not shown, droplets 34 are applied from a liquid spray nozzle in a fixed and uniform pattern while a cavity 4 containing a powder layer 41 is positioned under the nozzle. The cavity 4 and nozzle are typically both stationary, but in alternative embodiments, both can move simultaneously and synchronously. In a typical embodiment, the nozzle emits an annular pattern of droplets as a hollow cone.

[0133] In another embodiment, the droplets 34 are applied using a liquid stream nozzle configured to deposit a volume of the second binder liquid without the precise droplet size control of an inkjet nozzle. Typically, the droplet spray velocity of such liquid stream nozzles is significantly slower than that of inkjet spray systems. Non-limiting examples of liquid stream nozzles include ultrasonic deposition nozzles available as AccuMist™ systems from Sonotek Corporation, Milton NY. These spray nozzles result in slower droplet velocities, less disturbance of the powder material, minimal overspray, and a wide range of volumetric and central droplet sizes (diameters). Spray patterns are available in a variety of patterns, including both broad and narrow conical patterns, as well as focused linear streams.

[0134] FIG. 55 illustrates the application of a droplet 30 of a first binding liquid to a central portion of the first powder layer 41, thereby forming a first wet powder layer 51, as described above. A wet peripheral portion 151 typically surrounds and covers the central wet portion of the wet powder layer 51. In some embodiments, binding liquid is first applied to the central portion of the powder layer 41 to form a wet powder portion, followed by a wet peripheral portion 152. The order of applying the bonding liquids can be reversed by applying a second bonding liquid to the first bonding liquid to form wetted peripheral portion 151.

[0135] After drying, the wetted peripheral portion 151 is formed into a stable, hardened or resilient peripheral coating portion 161 within which the bonded powder layer portion 61 is located, as shown in FIG. 56. This cycle is repeated to deposit three additional uniform powders, each of which is wetted with a droplet or stream 34 of the second binder liquid at the periphery of the second, third, and fourth powder layers, respectively, and within the central portion of each of the powder layers to form a wetted powder layer. Each layer can be processed separately or in groups of two or more layers to remove excess binder solvent, thereby forming the second, third, and fourth bonded powder layers 62, 63, and 64, respectively, having hardened or resilient peripheral coating portions 162, 163, and 164 shown in FIG. 56. As further shown in Fig. 56, after the fifth uniform powder layer 45 is deposited, a selected nozzle 132 of the 3D printing assembly 33 is configured to add a droplet or stream 34 of the second binding solution at the periphery of the fifth, topmost powder layer 45 to wet the powder at the periphery and form a wet peripheral coating 155. In Fig. 57, the remaining portion of the topmost uniform powder layer 45 contacts the droplet 30 of the first binding solution to form a central portion of the wet powder layer 55 having a wet peripheral coating 155.

[0136] In an alternative embodiment, the wet peripheral coating 155 may be first treated to remove excess binder solvent from the wet peripheral coating 155 and form a hardened or elastic peripheral coating portion 165 before wetting the remaining non-wetted portions of the fifth uniform powder layer 45 with a binder liquid.

[0137] As shown in Figure 58, a drop or stream 34 of the second binding liquid is deposited on the top central portion of the topmost fifth powder layer 55 and contacts and overlaps the hardened or elastomeric peripheral coating portion 165 to form a wet coating 158. Figure 59 then shows the finished dosage form 110 after the wet coating 158 on the top portion of the topmost bonded powder layer 65 has been dried or cured, with the finished dosage form 110 having a top elastomeric coating 168 that completes the formation of the outer coating 120 surrounding the molded bonded dosage core 106.

[0138] In another embodiment, FIG. 60 shows a cross-sectional view of a tamper 88 having a lower surface 87 defining a cavity and a corresponding edge 89 adjusted to align with the top layer 45 of powder material in the recess 4. The cross-sectional shape of the tamper 88, and therefore the shape of the lower surface 87 of the cavity, is configured to match the shape of the desired dosage form being made. Non-limiting examples of tampers are described in International Publication WO 2017 / 034951, the disclosure of which is incorporated by reference in its entirety. In the illustrated embodiment, the cavity shape is a concave circle, but in other embodiments it can be a concave oval, square, or any other geometric shape. The edge 89 is configured to align within the inner wall 9 of the recess 4 when it strikes the top surface of the top powder layer 45 as shown by the arrow, as shown in FIG. 61, to form the top surface of the molded top powder layer 46 into a corresponding convex inverse shape, as shown in FIG. 62. The tamper 88 can be lowered (downward arrow in FIG. 61 ) onto the deposited loose powder to smooth, contour, or modify its surface. In some embodiments, the tamper 88 can be lowered once and lifted, or lowered two or more times to the same or different depths to perform one or a series of compaction steps. In some embodiments, the tamper can be lowered to contact the powder and advanced downward based on a linear (vertical) travel distance, with the magnitude of the linear travel distance affecting the degree of compaction and / or flattening of the deposited powder layer.

[0139] The level or degree of compaction results in an increase in the areal density of the powder material or wet powder material. In some embodiments, the density of the powder material can be increased by compacting the powder material by up to about 33%. In some embodiments, the increase in density caused by compacting the powder material can be up to about 30%, or up to about 25%, or up to about 20%, and can be at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%. The desired or actual density increase can be modified or selected based on the composition of the powder material and / or the portion of the dosage form that the compacted powder material forms. In some embodiments, compaction can increase the density of the deposited powder material layer from at least 0.05 grams per cubic centimeter (g / cc), including at least 1.0 g / cc, to up to about 1.5 g / cc, including at least 1.0 g / cc. In some embodiments, compaction can increase the density of the wet powder material by at least 0.03 grams per cubic centimeter (g / cc), including at least 0.05 g / cc, at least 1.0 g / cc, and up to about 1.5 g / cc, including up to about 1.0 g / cc.

[0140] In some embodiments, the tamper can be lowered to contact and advance the powder based on the detected or measured linear force or pressure on the tamper, and the magnitude of the linear force or pressure affects the degree of compaction and / or flattening of the deposited powder layer. In some embodiments, the tamper 88 is rotated in one rotational direction as the tamper is lowered, as shown in FIG. 61. Rotating the tamper 88 while lowering improves the uniformity of the powder layer depth and the uniformity of the powder surface compaction. The movement of the tamper 88 can be controlled by any control system known in the art. After the tamper 88 is lifted, the recess 4 containing the bound powder layer and the formed top powder layer 46 can be moved to the print zone, where binding liquid can be added to the convex powder material layer 46 to form the final, top bound powder layer 157, as shown in FIG. 63.

[0141] Although the underside of the tamper 88 that contacts the 3DP article in process is shown as having a concave circular shape, the underside of the tamper can be flat or have other non-flat shapes, which means that it can be shaped (or contoured) if desired.

[0142] In an alternative embodiment shown in FIG. 64 and FIG. 65, a tamper can be used to shape the top wet powder layer. After the fifth uniform powder layer 45 is deposited, a selected nozzle of the 3D printing assembly 33 is configured to add droplets 30 of binding fluid to the fifth top powder layer 45 to wet the powder and form the top wet powder layer 46, as shown in FIG. 64. In some embodiments, the top wet powder layer 46 can be shaped, compacted, or marked using a tamper. The tamper 88 can be lowered, as shown by the arrow, onto the top surface of the top wet powder layer 46 to form the top bonded powder layer 157, as shown in FIG. 65.

[0143] In some embodiments, the tamper and tamper system can be used to form one or more compacted powder layers, such as a series of compacted powder layers, or compacted wet powder layers in the recess. The one or more compacted powder layers can be uniformly or non-uniformly compacted, resulting in one or more uniformly or non-uniformly densified powder layers, or one or more uniformly or non-uniformly densified wet powder layers.

[0144] In some embodiments, one type or shape of tamper can be used on one or more powder layers or wet powder layers, and a second tamper of a different type or shape can be used on a different powder layer or layers or wet powder layers, which can provide different aesthetic or performance effects or characteristics to the resulting dosage form.

[0145] In some embodiments, the rotary compaction device can include a laterally extending cylindrical outer surface with a pattern of tampers extending radially outward from the cylindrical surface, and the position of the tampers can be moved axially to adjust the distance each tamper extends from the outer surface, allowing the tampers to extend different distances into the recesses.

[0146] An automatic compaction device can be provided to compact the dispensed layers of powder in the cavities. An example of a rotary compaction device, shown in FIG. 66, is shown in cross section across a blister sheet 2 in FIG. 67. The rotary compaction device 284 includes a rotating drum 285 having a plurality of tampers 287 disposed on an outer surface 286 of the rotating drum 285 in a number sufficient to compact each of the plurality of cavities 4 in the blister sheet 2. A blister sheet 2 having a desired number of cavities 4 is moved (horizontal arrows) under the rotary compaction device at a speed synchronous with the rotation of the rotating drum 285, with the tampers 287 aligned with the cavities 4. The tampers are of a size and shape sufficient to extend into each cavity and compact the powder material layer 41 in each cavities 4 to form a compacted powder layer 47.

[0147] Other tamper surfaces of various sizes, shapes, and contours are contemplated. The tamper surface can include raised (or possibly recessed) letters, numbers, or other symbols, and can provide imprinting in an exterior or interior incremental layer of the 3DP article that inversely mirrors the contours of the tamper surface (i.e., raised features on the tamper surface create recessed features in the incremental layer, and vice versa). The tamper surface can include a distinctive pattern or texture, with a similar goal of creating and imprinting in an interior or exterior incremental layer of the 3DP article. In certain embodiments, the pattern or texture of features on the tamper surface allows powders from two or more incremental layers to intermingle within the same horizontal slice of the 3DP article. For example, if two sequential incremental layers have different respective powders, rather than each powder remaining substantially within its own respective layer, one or both powders may move upward or downward into an adjacent incremental layer when displaced by the action of a non-smooth tamper surface with raised or recessed features. In certain embodiments, this can include a depression created in an instant incremental layer composed of a first powder, which is later filled with a second powder in a subsequent powder dispensing step, or it can include a raised area in an instant incremental layer composed of a first powder, which extends into the space allocated to the subsequent incremental layer having the second respective powder, or a combination of both.

[0148] In some embodiments, the tamper system consists of a tamper pattern aligned with a corresponding dimple pattern. In some embodiments, the tamper pattern moves vertically, perpendicular to the bottom surface of the dimples. In some embodiments, the tamper pattern moves in unison as an assembly, while in some embodiments, each tamper moves independently of the other tamper. In some embodiments, the tamper pattern is fixed in a lateral position, and alignment with the dimple pattern is provided by manipulating the dimple pattern (e.g., a blister-type packaging sheet having a pattern of dimples 4). In some embodiments, the dimple pattern is fixed in a lateral position, and alignment with the tamper pattern is provided by manipulating the tamper pattern. In some embodiments, both the tamper pattern and the dimple pattern can be independently manipulated to be aligned with the other.

[0149] Generally, a 3DP equipment assembly and / or apparatus can include various subsystems, including one or more three-dimensional printing build systems, and optionally one or more liquid removal systems. The system can include one or more three-dimensional printing build systems, one or more liquid removal (drying) systems, and optionally one or more other systems. In some embodiments, the equipment assembly includes one or more upper tamper systems, one or more control systems, and and one or more inspection systems. For example, in certain embodiments of the cavity 3DP system, it is not necessary to have a harvesting system since substantially all of the powder material that enters the cavity is incorporated into the respective dosage form within the cavity. Similarly, in certain embodiments of the cavity 3DP system, it is not necessary to eject, transport, and / or send the formed tablets into a separate package since the tablets are formed in situ within the package.

[0150] 68 shows a first non-limiting embodiment of a 3DP equipment assembly consisting of a linear equipment assembly 501. A conveyor system 511 is configured to move blister sheets, typically supported on a support plate. Non-limiting examples of conveyors are described in U.S. Patent Application Publication No. 2014 / 0065194 (Aprecia Pharmaceuticals Company), the disclosure of which is incorporated by reference in its entirety, where the build module described can include a support plate on which one or more blister sheets are supported, or a module for transporting the support plate.

[0151] Equipment assembly 501 includes powder bin 521 and rotary dosing apparatus 531 as described herein, or other embodiments disclosed herein for dispensing powder material into cavities. Equipment assembly 501 includes flattening device or apparatus 541, shown as a vibrating plate, or other embodiments of a powder flattening means, device, or apparatus described herein. Equipment assembly 501 includes a printing device or apparatus 551, such as an inkjet printing system, as described herein. Equipment assembly 501 includes a drying apparatus 561, shown as a radiant heating apparatus, or other embodiments of a drying apparatus described herein.

[0152] FIG. 69 shows a second non-limiting embodiment of a 3DP equipment assembly 502 consisting of at least two assemblies 551 and 552 arranged in series. Each of the assemblies 551 and 552 is arranged in a continuous loop on and off which the supported blister sheet 215 can be conveyed. The assembly 551 includes a powder bin 521 and a rotary dispenser 531, a flattener 541, a printing device 551, and a drying device 561. The assembly 552 includes a powder bin 522 and a rotary dispenser 532, a flattener 542, a printing device 552, and a drying device 562. In some embodiments, the supported blister sheet 215 can be passed through the first assembly 551 one or more times, or through the second assembly 552 one or more times, or through both the first assembly 551 and the second assembly 552 one or more times. In some embodiments, the powder material dispensed from powder bin 521 is different from the powder material dispensed from powder bin 522. In some embodiments, the powder dispensing devices can be different powder dispensing devices, and the dispensing device of the first assembly 551 can be different from the dispensing device of the second assembly 552. In some embodiments, the powder flattening device 541 of the first assembly 551 can be different from the powder flattening device 542 of the second assembly 552. In some embodiments, the binding liquid applied to the powder material from the printing device 551 is different from the binding liquid applied to the powder material from the printing device 552. In some embodiments, the drying device 561 is different from the drying device 562.

[0153] 70 shows a third non-limiting embodiment of a 3DP equipment assembly 503 consisting of a continuous loop 512 onto and off of which a supported blister sheet 215 can be conveyed (indicated by the green arrows). The assembly 553 includes a powder bin 521 and a rotary dosing device 531, as well as a powder flattening device 541 along a first portion of the looped conveyor 512, and includes a printing device 551 and a drying device 561 along a second portion of the looped conveyor 512. Along the first portion of the looped conveyor 512, a supported blister sheet 215 can be fed into the system 503, and the system 553 includes a printing device 551 and a drying device 561 along the second portion of the looped conveyor 512. It can be taken out from 03.

[0154] FIG. 71 shows a fourth non-limiting embodiment of a 3DP equipment assembly 504 consisting of a first continuous loop 512 and a second continuous loop 513, the two loops 512 and 513 sharing a common conveyor section 514. The assembly 504 includes a powder bin 521 and a rotary dosing device 531, as well as a printing device 551 along the common conveyor section 514. After exiting the printing device 551, the supported blister sheet 215 can be guided along the outer loop of the first continuous loop 512 or along the outer loop of the second continuous loop 513. A powder flattening device 541 is disposed along the first continuous loop 512, and a drying device 561 is disposed along the second continuous loop 513. The supported blister sheet 215 can pass along the common conveyor section 514 through the powder dispensing device (powder bin 521 and rotary dosing device 531) and the printing device 551 to form a wet powder layer in the recesses. This operation can choose to direct the supported blister sheet 215 to the flattening device 541 or the drying device 561. In some embodiments, the supported blister sheet 215 can pass through the printing device 551 without adding a binding liquid, thereby conveying the pile of powder material deposited in the powder dispensing system along the first continuous loop 512 to the flattening system 541 to flatten the powder material and pass through the printing device 551 again along the common conveyor section 514 to form a wet powder layer in the recesses.

[0155] FIG. 72 shows a fifth non-limiting embodiment of a 3DP equipment assembly 505 consisting of a first continuous loop 512 and a second continuous loop 513, the two loops 512 and 513 sharing a common conveyor portion 514. The assembly 505 includes a powder dispensing device (powder bin 521 and rotary dosing device 531) and a flattening device 541 along the outer portion of the looped conveyor 512, and a printing device 551 and a pair of drying devices consisting of a first drying device 561 and a second drying device 562 along the outer portion of the looped conveyor 513. The first continuous loop 512 provides for dispensing and flattening the powder material into the recesses of the supported blister sheet 215, and the second continuous loop 513 provides for dispensing a binding liquid into the powder layer and drying the residual binding liquid (or solvent therein) from the formed tablets. The first drying device 561 and the second drying device 562 can be independently selected from any of the embodiments of the drying device described herein. The first drying device 561 can be different from the second drying device 562.

[0156] The powder can include one or more materials suitable for pharmaceutical or non-pharmaceutical applications. In some embodiments, the powder includes one or more pharmaceutical excipients, one or more pharmaceutical active agents, or combinations thereof. In some embodiments, the three-dimensional printed article is a pharmaceutical dosage form, a medical device, a medical implant, or other such article as described. Exemplary types of pharmaceutical excipients that can be included in the three-dimensional printed article include, by way of example and not limitation, chelating agents, preservatives, adsorbents, acidifying agents, alkalizing agents, antifoaming agents, buffering agents, colorants, electrolytes, flavoring agents, abrasives, salts, stabilizers, sweeteners, tonicity adjusting agents, anti-adhesive agents, binders, diluents, disintegrants, glidants, lubricants, opacifying agents, abrasives, plasticizers, other pharmaceutical excipients, or combinations thereof.

[0157] The bound powder matrix may include one or more binders. The binder may be included in the powder material or in the binding liquid. The binder is selected independently for each case. The adhesion of the particles to and / or by the binder occurs when the binder is contacted by the binding liquid from the print head or is present (i.e., soluble) in the binding liquid. The binder is preferably soluble in water, soluble in an aqueous fluid, partially soluble in water, or partially soluble in an aqueous fluid. In some embodiments, the printing fluid comprises 1-20%, 5-15%, or 8-12% by weight of the binder. In some embodiments, the binder is soluble in water, soluble in an aqueous fluid, partially soluble in water, or partially soluble in an aqueous fluid. In some embodiments, the printing fluid comprises 1-20%, 5-15%, or 8-12% by weight of the binder. In some embodiments, the bulk powder comprises 0.1-10%, 5-15%, 0-15%, 8-14%, or more than 9-11% by weight of the binder. In some embodiments, the print matrix comprises 1-20%, 5-14%, or 8-12% by weight of the binder. In some embodiments, the binder is not present in the print fluid or in the bulk material. Suitable binders include water-soluble synthetic polymers, polyvinylpyrrolidone (povidone), sorbitol, mannitol, xylitol, lactitol, erythritol, pregelatinized starch, modified starch, hydroxypropyl methylcellulose, and the like. Preferred binders include polyvinylpyrrolidone, such as PVP K30, modified starch (e.g., starch sodium octenyl succinate), mannitol, or combinations thereof. PVPs having K values ​​different from 30 can also be used, including, but not limited to, PVP K25 and PVP K90.

[0158] In some embodiments, the powder material in each of the one or more powder layers is the same powder material in composition. In some embodiments, the powder material in one or more powder layers is different from the powder material in another powder layer. In such embodiments, the powder materials of different compositions can include different active pharmaceutical ingredients (APIs) or API placebos, or can include no API ingredients.

[0159] Pharmaceutically active agents generally include physiologically or pharmacologically active substances that produce one or more systemic or localized effects in animals, cells, tissues, organs, non-humans, and humans.

[0160] Whenever described, and unless otherwise specified, the term "active agent" includes all forms of the active agent, including neutral, ionic, salt, base, acidic, natural, synthetic, diastereomeric, isomeric, enantiomerically pure, racemic, hydrate, solvate, chelate, derivative, analog, optically active, optically enhanced, free base, free acid, positional isomer, amorphous, anhydrous, and / or crystalline forms.

[0161] In some embodiments, the powder material composition within a powder layer can be the same, hi some embodiments, one region of the powder layer can contain a powder material that is compositionally different from the powder contained in another region of the powder layer.

[0162] The three-dimensional printed dosage form may include one, two, or more different active agents. Particular combinations of active agents may be provided. Some combinations of active agents include: 1) a first drug from a first therapeutic class and a different second drug from the same therapeutic class; 2) a first drug from a first therapeutic class and a different second drug from a different therapeutic class; 3) a first drug with a first type of bioactivity and a different second drug with approximately the same bioactivity; 4) a first drug with a first type of bioactivity and a different second drug with a different second type of bioactivity. Exemplary combinations of active agents are described herein.

[0163] The active agent may be independently selected in each case from active agents such as antibiotics, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, antivirals, local anesthetics, antifungals, antiamoebic agents, antitrichomonas agents, analgesics, antiarthritic agents, antiasthmatic agents, anticoagulants, anticonvulsants, antidepressants, antidiabetic agents, antitumor agents, antipsychotic agents, neuroleptic agents, antihypertensive agents, hypnotics, sedatives, anxiolytic agents, antiparkinsonian agents, muscle relaxants, antimalarials, hormonal agents, contraceptive agents, sympathomimetics, hypoglycemic agents, antilipidemic agents, ophthalmic agents, electrolyte agents, diagnostic agents, prokinetic agents, gastric acid suppressants, antiulcer agents, intestinal agents, antiincontinence agents, cardiovascular agents, or combinations thereof. A description of these and other classes of useful drugs, as well as a listing of species within each class, can be found in Martindale, et al., The Journal of Clinical Chemistry, 1999, 144:131-135, the disclosure of which is incorporated herein by reference in its entirety. 37th Edition (2017), The Extra Pharmacopoeia, 31ST Ed (The Pharmaceutical Press, London 1996).

[0164] Exemplary types of non-pharmaceutical excipients that can be included in the powder material can include, by way of example and without limitation, ash, clay, ceramic, metal, polymer, biological material, plastic, inorganic material, salt, other such material, or combinations thereof.

[0165] In some embodiments, the powder includes one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or multiple components, each component being independently selected in each case. In some embodiments, the equipment assembly includes one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or multiple powder (or solid component) supply reservoirs.

[0166] The binding liquid added to the powder can be a solution or a suspension. The liquid can include an aqueous carrier, a non-aqueous carrier, an organic carrier, or a combination thereof. The aqueous carrier can be water or an aqueous buffer, or a combination of water and one or more alcohols. The non-aqueous carrier can be an organic solvent, a low molecular weight polymer, an oil, a silicone, other suitable materials, alcohol, ethanol, methanol, propanol, isopropanol, poly(ethylene glycol), glycol, other such materials, or a combination thereof. The terms liquid, binding liquid, printing fluid, binding fluid, and liquid can be used interchangeably to refer to the liquid delivered as part of 3DP.

[0167] In some embodiments, the device assembly includes one or more, two or more, three or more, four or more, or multiple liquid reservoirs. The liquid may be colored or uncolored. The liquid may include pigments, paints, dyes, colorants, inks, or combinations thereof. The liquid may include one or more solutes dissolved therein. The powder and / or liquid may include one or more binders. In one embodiment, the binder liquid may also include a binder. In some embodiments, the liquid may include an active ingredient.

[0168] In some embodiments, the binding liquid can be deposited in a pattern on the top surface of the powder layer or on the entire surface. In some embodiments, the pattern has a shape selected from the group consisting of an annulus, a circle, a polygon, or any other desired shape. In some embodiments, the concentration (mass per unit area) of the binding liquid added in the pattern to the top surface of the powder layer is uniform, while in other embodiments, the concentration of the binding liquid added to one or more portions of the pattern is higher or lower than the concentration of the binding liquid added to other portions. In some embodiments, the powder layer has a thickness distribution across the surface area, and a higher concentration of binding liquid can be added to portions of the powder layer that have a positive thickness distribution (thicker than the weight average thickness) and a lower concentration of binding liquid can be added to portions of the powder layer that have a negative thickness distribution (thinner than the weight average thickness). Any one of the embodiments in this paragraph can be combined with any other embodiment described herein.

[0169] Non-limiting examples of powder materials and binding liquids are described in U.S. Patent Nos. 9,339,489, 9,492,380, and 9,314,429, the disclosures of which are incorporated herein by reference. All of the embodiments described herein may be used with water (distilled water and / or A binder liquid may be used that includes an alcohol, which may be selected from any lower linear or branched alcohol having 1 to 3 carbon atoms (which may include deionized water), a soluble binder, an antioxidant, glycerin, and a surfactant or emulsifier. The printing fluid may comprise 1 to 25% by weight, 5 to 20% by weight, or 10 to 15% by weight of at least one organic solvent, preferably an alcohol. Suitable alcohols may include ethanol, methanol, n-propanol, and isopropanol, or combinations thereof.

[0170] In some embodiments, the content of glycerin in the binding liquid ranges from at least about 0.1% by weight, including at least 0.5%, at least 1.0%, and at least 1.5%, up to about 10%, including up to about 20% by weight and up to about 5% by weight. In some embodiments, the content of glycerin in the dosage form based on the final weight of the dosage form ranges from at least about 0.05% by weight, including at least 0.1% and at least 0.5%, up to about 5%, including up to about 3%, up to about 2%, and up to about 1.0% by weight.

[0171] The above is a detailed description of a specific embodiment of the present invention. Although specific embodiments of the present invention have been described herein for illustrative purposes, it will be understood that various modifications can be made without departing from the spirit and scope of the present invention. Accordingly, the present invention is not limited except as by the appended claims, and any amendment to the claims incorporating any element or configuration of the embodiments described herein will be recognized by those skilled in the art as of the filing date as being directly and unambiguously derived from the description of the present specification. All of the embodiments disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.

Claims

1. 1. A method of forming a dosage form into a dosage portion of a package, comprising: 1) providing a dosage portion of a package including at least one cavity, the cavity including a side wall; 2) depositing a quantity of powder material including particles into at least one depression into a substantially uniform powder layer, the sidewall having a depression depth, and the substantially uniform powder layer having a thickness that is at least 5% and up to 50% of the depression depth; 3) depositing a binding liquid in a pattern onto the powder layer in the at least one recess to bind at least a portion of the particles of the powder layer to form an incrementally wetted layer; 4) repeating steps 2) and 3) in sequence at least one or more times; thereby forming a dosage form within the dosage portion of the packaging.

2. The method of claim 1 , wherein the at least one cavity has a fixed shape and volume.

3. 3. The method of claim 1 or 2, wherein the package comprises a sheet including a plurality of recesses formed therein, the side walls within the recesses extending from the sheet to the closed end.

4. The method according to any one of claims 1 to 3, wherein step 4) is repeated at least three times.

5. The method according to any one of claims 1 to 4, wherein the powder material comprises particles of a binding material and the binding liquid binds the particles of the binding material together.

6. The method of any one of claims 1 to 5, further comprising, prior to step 2), depositing a quantity of bonding liquid at least on the closed end of the recess.

7. The method of any one of claims 1 to 6, wherein at least one recess includes an interior surface that includes a release agent.

8. The method according to any one of claims 1 to 7, wherein the bonding liquid comprises a volatile solvent.

9. 9. The method of claim 8, further comprising, after step 3), removing a portion of the volatile solvent from the incremental wetting layer by evaporation to form an incremental bonding layer.

10. 9. The method of claim 8, further comprising the step of removing a portion of the volatile solvent from the at least two or more incrementally wetted layers by evaporation after step 4).

11. 10. The method of claim 1, wherein the dosage form is formed from multiple layers of powder deposited within the cavity and formed into multiple incrementally bonded powder layers.

12. The method of any one of claims 1 to 11, wherein the pattern of deposited binding liquid comprises a peripheral pattern of binding liquid applied to the powder layer on the inner surface of the depression.

13. The method of any one of claims 1 to 12, further comprising the step of adding a lidding layer over the dosage form and the at least one recess to form a sealed package for the dosage form.

14. The method of any one of claims 1 to 13, wherein the binding liquid is deposited by inkjet printing to form the dosage form.

15. Step 2) depositing a predetermined amount of powder material including particles into the at least one depression into a substantially uniform powder layer includes: 1) depositing a quantity of powder material including particles into at least one cavity; 2) forming the deposited quantity of powder material into a substantially uniform powder layer within the at least one depression.

16. The method of any one of claims 1 to 15, wherein the forming step comprises compacting the final deposited quantity of powder material into a final formed powder layer having a top surface.

17. 17. The method of claim 16, wherein the compacting step utilizes a stamp and the upper surface is convex.

18. A package having one or more recesses, the one or more recesses containing a preformed bonded powder dosage form formed in the one or more recesses by the method of any one of claims 1 to 17, the package comprising a film material and a peelable or removable cover sheet adhered to the film material so as to enclose the bonded powder form in the one or more recesses.

19. 20. The package of claim 18, wherein a peripheral portion of the bonded powder article facing the inner surface of the one or more recesses includes an additional amount of bonding liquid.

20. 20. The package of claim 18 or 19, wherein the combined powder article comprises a 3D printed fast dispersing dosage form.

21. 21. The package of any one of claims 18 to 20, wherein the bonded powder article is formed in the one or more cavities by bonding the powder deposited in the one or more cavities with a binding liquid.

22. 22. The package of any one of claims 18 to 21, wherein a bonded powder article is formed in the one or more recesses by bonding the powder deposited in the one or more recesses with a binding liquid.

23. The package of any one of claims 18 to 22, wherein the bonded powder article comprises an API.

Images