Precision pharmaceutical 3D printing device

Abstract

Providing systems and devices for additive manufacturing, and methods of using such devices SOLUTION: Provided herein are devices and systems for depositing materials or manufacturing products, such as pharmaceutical dosage forms, by additive manufacturing. Further provided are methods of using the devices and systems, and methods of manufacturing products, such as pharmaceutical dosage forms, by additive manufacturing. In certain embodiments, a device includes a material feed system (102) configured to melt and pressurize a material, a pressure sensor (214) configured to detect a pressure of the material in the device, and a control switch (216) including a sealing needle (218) operable in an open position and a closed position.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. patent application Ser. No. 16 / 233,831, filed December 27, 2018, which is a divisional application of and claims priority to U.S. patent application Ser. No. 15 / 937,528, filed March 27, 2018, which claims priority under 35 U.S.C. § 365(a) to International Application No. PCT / CN2018 / 071965, entitled "PRECISION PHARMACEUTICAL 3D PRINTING DEVICE," filed January 9, 2018, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] The present invention relates to systems and devices for additive manufacturing and methods of using such devices. The present invention further includes methods of making products, such as pharmaceutical dosage forms, by additive manufacturing. [Background technology]

[0003] Additive manufacturing, also known as three-dimensional printing, enables the creation of products by extruding molten material into computer-modeled shapes. A computer system operates the three-dimensional printer, controlling the flow of material and the movement of the print nozzle until the desired shape is formed. In the fused filament manufacturing process (also known as fused deposition modeling), material in the form of a filament is fed through a heated head, which melts the material onto a surface. The surface or heated head can be moved according to instructions from the computer system to extrude the molten material into a set shape. Other additive manufacturing methods utilize non-fibrous materials that are melted and pressurized before being extruded through a print nozzle, but such methods often result in undesirable leakage from the print nozzle, especially when the molten material is viscous.

[0004] Recent developments in additive manufacturing have enabled the use of many different three-dimensional printing processes and many different materials. For example, biologically inert materials can be used in additive manufacturing processes for the production of implantable medical devices or custom laboratory consumables. See, for example, Poh et al., "Polylactides in Additive Biomanufacturing," Advanced Drug Delivery Reviews, vol. 107, pp. 228-246 (2016). Advances have also been made in the development of additive manufacturing techniques for the production of pharmaceutical products. See Goyanes et al., "3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics," Molecular Pharmaceutics, vol. 12, no. 11, pp. 4077-4084 (2015).

[0005] However, current additive manufacturing technologies are limited by the precision with which 3D printers extrude materials. Pharmaceuticals require careful control to ensure the manufactured product is uniformly shaped and contains a precise and accurate dose of drug. There is a continuing need to develop precision systems for additive manufacturing processes, including for the production of pharmaceutical products.

[0006] The disclosures of all publications, patents, patent applications, and published patent applications referenced herein are hereby incorporated by reference in their entirety. Summary of the Invention [Means for solving the problem]

[0007] Described herein is a device for depositing material by additive manufacturing, the device comprising: a material supply system configured to melt and pressurize material, the material supply system including a supply channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect the pressure of the material in the nozzle or in the supply channel proximate to the nozzle; and a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the supply channel and including a tapered end, wherein when the sealing needle is in the closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent flow of material through the nozzle.

[0008] In some embodiments, the material is non-fibrous. In some embodiments, the material has a viscosity of about 100 Pa·s or greater when extruded from the device. In some embodiments, the material has a viscosity of about 400 Pa·s or greater when extruded from the device. In some embodiments, the material melts at about 50°C to about 400°C. In some embodiments, the material is extruded from the nozzle at a temperature of about 50°C to about 400°C. In some embodiments, the material is extruded from the nozzle at a temperature of about 90°C to about 300°C.

[0009] In some embodiments, any portion of the sealing needle that contacts the material does not include a protrusion.

[0010] In some embodiments, the pressure sensor is connected to a computer system that operates the material supply system to pressurize the material to a desired pressure in response to the pressure reported by the pressure sensor. In some embodiments, the material pressure is within about 0.05 MPa of the desired pressure. In some embodiments, the material supply system includes a piston and a barrel connected to the supply channel, the piston operated to control the pressure of the material in the barrel. In some embodiments, the piston is operated using a stepper motor. In some embodiments, the pressure sensor is positioned proximal to the nozzle.

[0011] In some embodiments, the tapered end of the seal needle comprises a sharp tip. In some embodiments, the tapered end of the seal needle is frustoconical. In some embodiments, the tapered inner surface of the nozzle has a first taper angle and the tapered end of the seal needle has a second taper angle, the second taper angle being less than or equal to the first taper angle. In some embodiments, the second taper angle is less than or equal to about 60°. In some embodiments, the second taper angle is less than or equal to about 45°. In some embodiments, the ratio of the first taper angle to the second taper angle is between about 1:1 and about 4:1.

[0012] In some embodiments, the extrusion port has a diameter of about 0.1 mm to about 1 mm. In some embodiments, the tapered end has a maximum diameter of about 0.2 mm to about 3.0 mm. In some embodiments, the extrusion port has a diameter, the tapered end has a maximum diameter, and the ratio of the maximum diameter of the tapered end to the diameter of the extrusion port is about 1:0.8 to about 1:0.1.

[0013] In some embodiments, the control switch includes an actuator that positions the sealing needle in an open or closed position. In some embodiments, the actuator is a pneumatic actuator. In some embodiments, the actuator is a mechanical actuator. In some embodiments, the actuator is an electric motor actuator. In some embodiments, the electric motor actuator is a linear stepper motor actuator.

[0014] In some embodiments, the sealing needle passes through a gasket that is fixed in position relative to the nozzle, the gasket sealing the delivery channel.

[0015] In some embodiments, the material delivery system includes one or more heaters configured to melt the material. In some embodiments, the material delivery system includes one or more temperature sensors configured to detect the temperature of the melted material. In some embodiments, the one or more temperature sensors are connected to a computer system that operates the one or more heaters in response to temperatures reported by the one or more temperature sensors.

[0016] In some embodiments, the tapered end of the sealing needle or the tapered inner surface of the nozzle comprises a flexible pad or liner.

[0017] In some embodiments, the device further comprises a computer system including one or more processors and a computer-readable memory, the computer system configured to operate the device. In some embodiments, the computer-readable memory comprises instructions for printing a product using the device. In some embodiments, the computer-readable memory comprises instructions for controlling a pressure of the material in response to a pressure detected by a pressure sensor. In some embodiments, the computer-readable memory comprises instructions for controlling a temperature of the material in response to a temperature detected by a temperature sensor. In some embodiments, the computer-readable memory comprises instructions for positioning a sealing needle based on the instructions for printing the product. In some embodiments, the instructions for positioning the sealing needle comprise instructions for selecting an opening distance of the sealing needle based on a desired flow rate of the material from the extrusion port.

[0018] In some embodiments, an additive manufacturing system is provided that includes a plurality of the above-described devices, each material supply system configured with a control switch. In some embodiments, the system includes a first device from the plurality of devices filled with a first material and a second device from the plurality of devices filled with a second material, wherein the first material and the second material are different. In some embodiments, the control switch for each device from the plurality of devices is different. In some embodiments, the control switch for each device from the plurality of devices is the same. In some embodiments, the system includes a computer system including one or more processors and a computer-readable memory, the computer system configured to operate the system. In some embodiments, the computer-readable memory includes instructions for printing a product using the system. In some embodiments, the computer-readable memory includes instructions for controlling a pressure of material in each material supply system in response to a pressure detected by a pressure sensor in the corresponding material supply system. In some embodiments, the computer-readable memory includes instructions for controlling a temperature of material in each material supply system in response to a temperature detected by a temperature sensor in the corresponding material supply system. In some embodiments, the computer-readable memory includes instructions for positioning a sealing needle based on the instructions for printing the product. In some embodiments, the instructions for positioning the sealing needle include instructions for selecting an opening distance of the sealing needle based on a desired flow rate of material from the extrusion port.In some embodiments, at least two devices from the plurality of devices include: a material supply system configured to melt and pressurize material, the material supply system including a feed channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect the pressure of the material in the nozzle or in the feed channel proximate to the nozzle; and a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the feed channel and including a tapered end, wherein when the sealing needle is in the closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent flow of material through the nozzle. In some embodiments, the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle. In some embodiments, the pressure sensor is positioned proximal to the nozzle.

[0019] In another aspect, a method of manufacturing a product by additive manufacturing is provided, the method including melting and pressurizing a material, flowing the material through an extrusion port of a nozzle including a tapered inner surface, monitoring the pressure of the material in or proximate the nozzle, engaging the tapered end of a sealing needle with the tapered inner surface of the nozzle to thereby seal the extrusion port and stop the flow of molten material, and withdrawing the tapered end of the sealing needle to thereby resume the flow of material through the extrusion port. In some embodiments, the method includes receiving instructions to manufacture the product.

[0020] In another aspect, a method of producing a pharmaceutical dosage form by additive manufacturing is provided, the method comprising melting and pressurizing a pharmaceutically acceptable material; monitoring the pressure of the material in or proximate a nozzle; flowing the material through an extrusion port of the nozzle including a tapered inner surface; engaging the tapered end of a sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of molten material; and withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port. In some embodiments, the pharmaceutically acceptable material comprises a drug. In some embodiments, the pharmaceutical dosage form has a desired drug release profile. In some embodiments, the method comprises receiving instructions to manufacture the pharmaceutical dosage form.

[0021] In some embodiments of the above method, the pressure of the material in the nozzle remains approximately constant. In some embodiments, the method includes controlling the pressure of the material using a feedback system based on the monitored pressure.

[0022] In some embodiments of the above method, the material is non-fibrous. In some embodiments, the material has a viscosity of about 100 Pa·s or greater.

[0023] In some embodiments of the above method, any portion of the sealing needle that contacts the material does not include a protrusion.

[0024] In some embodiments of the above method, the temperature of the material in the nozzle remains approximately constant. In some embodiments, the method includes monitoring the temperature of the material. In some embodiments, the method includes controlling the temperature of the material using a feedback system based on the monitored temperature.

[0025] Some embodiments of the above method include withdrawing the tapered end of the sealing needle to a selected opening distance.

[0026] In some embodiments of the above method, the tapered end of the sealing needle includes a sharp tip. In some embodiments, the tapered end of the sealing needle is frustoconical. In some embodiments, the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle. In some embodiments, the second taper angle is less than or equal to about 60°. In some embodiments, the second taper angle is less than or equal to about 45°. In some embodiments, the ratio of the first taper angle to the second taper angle is between about 1:1 and about 4:1. In some embodiments, the extrusion port has a diameter of between about 0.1 mm and 1 mm. In some embodiments, the tapered end has a maximum diameter of between about 0.2 mm and about 3.0 mm. In some embodiments, the extrusion port has a diameter, the tapered end has a maximum diameter, and the ratio of the maximum diameter of the tapered end to the diameter of the extrusion port is from about 1:0.8 to about 1:0.1.

[0027] In another aspect, there is a method of manufacturing a product by additive manufacturing, the method including melting and pressurizing a first material, flowing the first material through a first extrusion port of a first nozzle including a tapered inner surface, engaging the tapered end of a first sealing needle with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and stopping the flow of the molten first material, melting and pressurizing a second material, and withdrawing the tapered end of a second sealing needle from the tapered inner surface of the second nozzle, thereby commencing the flow of the second material through the second extrusion port. In some embodiments, the method includes receiving instructions to manufacture the product.

[0028] In another aspect, there is a method of producing a pharmaceutical dosage form by additive manufacturing, the method comprising: melting and pressurizing a first pharmaceutically acceptable material; flowing the first pharmaceutically acceptable material through a first extrusion port of a first nozzle including a tapered inner surface; engaging the tapered end of a first seal needle with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and stopping the flow of the molten first pharmaceutically acceptable material; melting and pressurizing a second pharmaceutically acceptable material; and withdrawing the tapered end of the second seal needle from the tapered inner surface of the second nozzle, thereby starting the flow of the second pharmaceutically acceptable material through the second extrusion port. In some embodiments, the first pharmaceutically acceptable material or the second pharmaceutically acceptable material is an erodible material. In some embodiments, the first pharmaceutically acceptable material or the second pharmaceutically acceptable material comprises a drug. In some embodiments, the pharmaceutical dosage form has a desired drug release profile. In some embodiments, the method further comprises receiving instructions to manufacture the pharmaceutical dosage form.

[0029] In some embodiments of the above method, the method further includes monitoring the pressure of the first material in or proximate the first nozzle or monitoring the pressure of the second material in or proximate the second nozzle. In some embodiments, the pressure of the first material in the first nozzle or the pressure of the second material in the second nozzle remains substantially constant. In some embodiments, the method includes controlling the pressure of the first material or the second material using a feedback system based on the monitored pressure.

[0030] In some embodiments of the above method, the first material or the second material is non-fibrous.

[0031] In some embodiments of the above method, any portion of the first seal needle that contacts the first material or any portion of the second seal needle that contacts the second material does not include a protrusion.

[0032] In some embodiments of the above method, the temperature of the first material in the first nozzle or the temperature of the second material in the second nozzle remains substantially constant. In some embodiments, the method includes monitoring the temperature of the first material or the temperature of the second material. In some embodiments, the method includes controlling the temperature of the first material using a feedback system based on the monitored temperature of the first material or controlling the temperature of the second material using a feedback system based on the monitored temperature of the second material.

[0033] Some embodiments of the above method include withdrawing the tapered end of the second sealing needle to a selected opening distance.

[0034] In some embodiments of the above method, the tapered end of the first seal needle or the tapered end of the second seal needle comprises a pointed tip. In some embodiments of the above method, the tapered end of the first seal needle or the tapered end of the second seal needle is frustoconical.

[0035] In some embodiments of the above method, the tapered inner surface of the first nozzle has a first taper angle, and the tapered end of the first sealing needle has a second taper angle, where the second taper angle is equal to or less than the first taper angle; or the tapered inner surface of the second nozzle has a third taper angle, and the tapered end of the second sealing needle has a fourth taper angle, where the fourth taper angle is equal to or less than the third taper angle. In some embodiments, the fourth taper angle is equal to or less than about 60°. In some embodiments of the above method, the second taper angle or the fourth taper angle is equal to or less than about 45°. In some embodiments of the above method, the ratio of the first taper angle to the second taper angle, or the ratio of the third taper angle to the fourth taper angle, is between about 1:1 and about 4:1. In some embodiments of the above method, the first extrusion port or the second extrusion port has a diameter of between about 0.1 mm and about 1 mm. In some embodiments of the above method, the tapered end of the first seal needle or the tapered end of the second seal needle has a maximum diameter of about 0.2 to about 3.0 mm.

[0036] In some embodiments of the above method, the first material or the second material has a viscosity of about 100 Pa·s or greater.

[0037] In some embodiments of the above methods, the product or pharmaceutical dosage form is manufactured in a batch mode. In some embodiments of the above methods, the product or pharmaceutical dosage form is manufactured in a continuous mode.

[0038] Also provided herein is a product or pharmaceutical dosage form made according to any one of the above methods. The present specification also provides, for example, the following items: (Item 1) 1. A device for depositing material by additive manufacturing, comprising: a material supply system configured to melt and pressurize the material, the material supply system including a supply channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect a pressure of the material within the nozzle or within the delivery channel proximate the nozzle; a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the delivery channel and including a tapered end; When the sealing needle is in the closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent material from flowing through the nozzle. 2. The device of claim 1, wherein the material is non-fibrous. (Item 3) 3. The device of claim 1 or 2, wherein any portion of the sealing needle that contacts the material does not include a protrusion. (Item 4) 4. The device of any one of items 1 to 3, wherein the pressure sensor is connected to a computer system that operates the material supply system to pressurize the material to a desired pressure in response to the pressure reported by the pressure sensor. (Item 5) 5. The device of any one of items 1 to 4, wherein the material supply system includes a piston and a barrel connected to the supply channel, the piston being operated to control the pressure of the material in the barrel. (Item 6) 6. The device of any one of items 1 to 5, wherein the tapered end of the sealing needle comprises a sharp tip. (Item 7) 7. The device of any one of items 1 to 6, wherein the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle. (Item 8) 8. The device of any one of items 1 to 7, wherein the material has a viscosity of about 100 Pa·s or greater when extruded from the device. (Item 9) 9. The device according to any one of items 1 to 8, wherein the material melts at about 50°C to about 400°C. (Item 10) 10. The device of any one of items 1 to 9, wherein the material is extruded from the nozzle at a temperature of about 50°C to about 400°C. (Item 11) 11. The device of any one of items 1 to 10, wherein the control switch includes an actuator that positions the sealing needle in the open position or the closed position. (Item 12) Item 12. The device according to item 11, wherein the actuator is a pneumatic actuator or a mechanical actuator. (Item 13) Item 12. The device of item 11, wherein the actuator is an electric motor actuator. (Item 14) 14. The device of any one of items 11 to 13, wherein the sealing needle passes through a gasket fixed in position relative to the nozzle, the gasket sealing the delivery channel. (Item 15) 15. The device of any one of items 1 to 14, wherein the material supply system includes one or more heaters configured to melt the material. (Item 16) Item 16. The device of item 15, wherein the material supply system includes one or more temperature sensors configured to detect the temperature of the molten material. (Item 17) Item 17. The device of item 16, wherein the one or more temperature sensors are connected to a computer system that operates the one or more heaters in response to temperatures reported by the one or more temperature sensors. (Item 18) 18. The device of any one of items 1 to 17, wherein the tapered end of the sealing needle or the tapered inner surface of the nozzle comprises a flexible pad or liner. (Item 19) 19. The device of any one of items 1 to 18, further comprising a computer system including one or more processors and computer-readable memory, the computer system configured to operate the device. (Item 20) 20. The device of claim 19, wherein the computer-readable memory includes instructions for using the device to print a product. (Item 21) 21. The device of claim 19 or 20, wherein the computer-readable memory includes instructions for controlling the pressure of the material in response to the pressure detected by the pressure sensor. (Item 22) 22. The device of any one of items 19 to 21, wherein the computer-readable memory includes instructions for controlling the temperature of the material in response to a temperature detected by the temperature sensor. (Item 23) 23. The device of any one of items 20 to 22, wherein the computer-readable memory includes instructions for positioning the sealing needle based on the instructions for printing the product. (Item 24) 24. The device of any one of items 1 to 23, wherein the pressure sensor is positioned proximal to the nozzle. (Item 25) 19. An additive manufacturing system comprising a plurality of devices according to any one of items 1 to 18, wherein each material supply system is configured with a control switch. (Item 26) Item 26. The system of item 25, comprising a first device filled with a first material and a second device filled with a second material, wherein the first material and the second material are different. (Item 27) 27. The system of claim 25 or 26, further comprising a computer system including one or more processors and computer-readable memory, the computer system configured to operate the system. (Item 28) 28. The system of claim 27, wherein the computer-readable memory includes instructions for printing a product using the system. (Item 29) 29. The system of claim 27 or 28, wherein the computer-readable memory includes instructions for controlling the pressure of the material in each material supply system in response to the pressure detected by the pressure sensor in the corresponding material supply system. (Item 30) 30. The system of any one of items 27-29, wherein the computer-readable memory includes instructions for controlling the temperature of the material in each material supply system in response to the temperature detected by the temperature sensor in the corresponding material supply system. (Item 31) 31. The system of any one of items 28 to 30, wherein the computer-readable memory includes instructions for positioning the sealing needle based on the instructions for printing the product. (Item 32) At least two of the devices from the plurality of devices a material supply system configured to melt and pressurize the material, the material supply system including a supply channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect a pressure of the material within the nozzle or within the delivery channel proximate the nozzle; a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the delivery channel and including a tapered end; 32. The system of claim 25, wherein when the sealing needle is in the closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent flow of material through the nozzle. (Item 33) Item 33. The system of item 32, wherein the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle. (Item 34) 34. The system of any one of items 25 to 33, wherein the pressure sensor is positioned proximal to the nozzle. (Item 35) 1. A method of manufacturing a product by additive manufacturing, comprising: Melting and pressurizing the material; flowing the material through an extrusion port of a nozzle including a tapered inner surface; monitoring the pressure of the material in or proximate to the nozzle; engaging a tapered end of a sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of the molten material; and withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port. (Item 36) Item 36. The method of item 35, comprising receiving an instruction to manufacture the product. (Item 37) 1. A method of producing a pharmaceutical dosage form by additive manufacturing, comprising: Melting and compressing pharmaceutically acceptable materials; monitoring the pressure of the material in or proximate to the nozzle; flowing the material through an extrusion port of a nozzle including a tapered inner surface; engaging a tapered end of a sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of the molten material; and withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port. (Item 38) 38. The method of claim 37, wherein the pharmaceutically acceptable material comprises a drug. (Item 39) 39. The method of claim 38, wherein the pharmaceutical dosage form has a desired drug release profile. (Item 40) 40. The method of any one of items 37 to 39, comprising receiving an order to manufacture the pharmaceutical dosage form. (Item 41) 41. The method of any one of items 35 to 40, comprising controlling the pressure of the material using a feedback system based on the monitored pressure. (Item 42) 42. The method according to any one of items 35 to 41, wherein any part of the sealing needle that contacts the material does not include a protrusion. (Item 43) 43. The method of claim 42, comprising controlling the temperature of the material using a feedback system based on monitored temperature. (Item 44) 44. The method of any one of items 35 to 43, comprising withdrawing the tapered end of the sealing needle to a selected opening distance. (Item 45) 45. The method according to any one of items 35 to 44, wherein the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being equal to or less than the first taper angle. (Item 46) 1. A method of manufacturing a product by additive manufacturing, comprising: Melting and pressurizing a first material; flowing the first material through a first extrusion port of a first nozzle including a tapered inner surface; engaging a tapered end of a first sealing needle with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and stopping the flow of the molten first material; Melting and pressurizing a second material; and withdrawing the tapered end of the second sealing needle from the tapered inner surface of the second nozzle, thereby initiating flow of the second material through the second extrusion port. (Item 47) Item 47. The method of item 46, comprising receiving an instruction to manufacture the product. (Item 48) 1. A method of producing a pharmaceutical dosage form by additive manufacturing, comprising: Melting and compressing a first pharmaceutically acceptable material; flowing the first pharmaceutically acceptable material through a first extrusion port of a first nozzle including a tapered inner surface; engaging a tapered end of a first sealing needle with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and stopping the flow of the molten first material; melting and compressing a second pharmaceutically acceptable material; and withdrawing the tapered end of the second sealing needle from the tapered inner surface of the second nozzle, thereby initiating flow of the second pharmaceutically acceptable material through the second extrusion port. (Item 49) Item 49. The method of item 48, wherein the first pharmaceutically acceptable material or the second pharmaceutically acceptable material is an erodible material. (Item 50) 50. The method of claim 48 or 49, wherein the first pharmaceutically acceptable material or the second pharmaceutically acceptable material comprises a drug. (Item 51) 51. The method of claim 50, wherein the pharmaceutical dosage form has a desired drug release profile. (Item 52) 52. The method of any one of items 46 to 51, comprising receiving an order to manufacture the pharmaceutical dosage form. (Item 53) 53. The method of any one of items 46 to 52, comprising controlling the pressure of the first material or the second material using a feedback system based on monitored pressure. (Item 54) 54. The method according to any one of items 46 to 53, wherein any portion of the first seal needle contacting the first material or any portion of the second seal needle contacting the second material does not include a protrusion. (Item 55) 55. The method of any one of items 46 to 54, comprising controlling the temperature of the first material using a feedback system based on a monitored temperature of the first material, or controlling the temperature of the second material using a feedback system based on a monitored temperature of the second material. (Item 56) 56. The method of any one of items 46 to 55, comprising withdrawing the tapered end of the second sealing needle to a selected opening distance. (Item 57) the tapered inner surface of the first nozzle has a first taper angle and the tapered end of the first sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle; or 57. The method according to any one of items 46 to 56, wherein the tapered inner surface of the second nozzle has a third taper angle and the tapered end of the second sealing needle has a fourth taper angle, and the fourth taper angle is equal to or less than the third taper angle. (Item 58) 58. The method according to any one of items 46 to 57, wherein the product or the pharmaceutical dosage form is manufactured in batch mode. (Item 59) 58. The method according to any one of items 46 to 57, wherein the product or the pharmaceutical dosage form is manufactured in a continuous mode. (Item 60) 60. A product or pharmaceutical dosage form made according to the method of any one of items 35 to 59. [Brief explanation of the drawings]

[0039] [Figure 1] 1 illustrates an exemplary embodiment of a device for depositing material by additive manufacturing, according to the present invention.

[0040] [Figure 2A] 1 illustrates a cross-sectional view of an exemplary device for depositing material by additive manufacturing, in accordance with the present invention. [Figure 2B] 2B shows a close-up view of the print head of the device shown in FIG. 2A, with the sealing needle in a closed position and engaging the inner surface of the nozzle. While FIG. 2A shows a pneumatic actuator, an electric motor actuator (e.g., a linear stepper motor actuator) may also be used. The electric motor actuator can position the sealing needle in an open position between the closed position and the maximum open position, such as a position having a selected opening distance.

[0041] [Figure 3A] 1 shows the tapered end of a sealing needle with a sharp tip. [Figure 3B] 1 shows the tapered end of a sealing needle with a frusto-conical tip. [Figure 3C] 1 shows the taper of the inner surface of the nozzle.

[0042] [Figure 4] 1 shows an exploded view of the components of a pneumatic actuator connected to the sealing needle for controlling the sealing needle.

[0043] [Figure 5A] 1 shows a longitudinal cross section of an exemplary device. [Figure 5B] 1 shows a cross-sectional view of an exemplary device in plane "AA." [Figure 5C] 5A-5C show side views of an exemplary device. While Figures 5A-5C show a pneumatic actuator, an electric motor actuator (e.g., a linear stepper motor actuator) may also be used. The electric motor actuator can position the sealing needle at an open position between the closed position and the maximum open position, such as a position having a selected opening distance.

[0044] [Figure 6] 1 illustrates another exemplary embodiment of a device described herein.

[0045] [Figure 7] 1 shows a portion of an exemplary device that includes three material supply systems, each with a separate print head. DETAILED DESCRIPTION OF THE INVENTION

[0046] The present application relates to a device for depositing material by additive manufacturing. The device includes a material supply system that melts and pressurizes a material, the material optionally including a drug. In certain embodiments, the material is a non-fibrous material. The material supply system includes a feed channel connected to a nozzle. The material can be pressurized and / or melted within or upstream of the feed channel, flows through the feed channel, and is dispensed through the nozzle. Further provided herein are systems for manufacturing products by additive manufacturing, these systems including two or more devices, each of which includes a material supply system and a control switch. Also described herein are methods of using such devices, as well as methods for manufacturing products by additive manufacturing and methods for manufacturing pharmaceutical dosage forms by additive manufacturing.

[0047] When manufacturing products, particularly pharmaceutical products, it is desirable to carefully control the amount of material dispensed by a nozzle. A major problem with conventional additive manufacturing devices is unintentional leakage of material through the nozzle, which can result in more than the desired amount of material being dispensed. The problem becomes even more complex when using two or more nozzles that can dispense different materials and need to be alternately switched on or off. For example, if a first nozzle is leaking a first material while a second nozzle is dispensing a second material, this can result in production defects or material waste. The devices and systems described herein are well-suited for manufacturing pharmaceutical dosage forms with complex geometries and compositions because they can handle a variety of pharmaceutical materials with high precision and accuracy of material deposition. The devices, systems, and methods described herein also facilitate personalized medicine, including personalized doses and / or personalized release profiles. Personalized medicine refers to the stratification of patient populations based on biomarkers to aid in therapeutic decisions and personalized dosage form design. Personalized drug dosage forms allow for the adjustment of the amount of drug delivered, including its release profile, based on the patient's weight and metabolism. Pharmaceutical dosage forms manufactured using the devices described herein can ensure accurate dosing in growing children and enable personalized dosing of highly potent medications. Personalized dosage forms can consolidate all of a patient's medications into a single daily dose, thus improving patient adherence and treatment compliance. Modifying a digital design is easier than modifying a physical device. Automated, small-scale three-dimensional printing can also have negligible operating costs. Thus, additive manufacturing using the devices described herein makes multiple small, individualized batches economically feasible and enables personalized dosage forms designed to improve adherence.

[0048] In certain embodiments, a customized pharmaceutical drug dosage form design having a desired release profile is received by a computer system, which is configured to operate a device or system described herein. The computer system can send instructions to the system or device for manufacturing a pharmaceutical dosage form having the desired release profile, which then manufactures the customized product. In some embodiments, the computer-readable memory includes instructions for controlling a control switch. In some embodiments, the control switch includes an electric motor actuator that positions a sealing needle, and the computer-readable memory includes instructions for controlling the electric motor actuator to position the sealing needle in an open position (including open positions with various distances between the end of the sealing needle and the extrusion port of the nozzle, up to a maximum open position) and a closed position.

[0049] The present invention provides a more precise system for depositing material or manufacturing products (such as pharmaceutical dosage forms) by carefully controlling the pressure within the nozzle or within a feed channel proximal to the nozzle and utilizing a control switch with a sealing needle that prevents material from flowing through the nozzle when the sealing needle is in a closed position. For example, a pneumatic actuator within the control switch may adjust the sealing needle between an open position (such as a maximum open position or a position with any distance between the end of the sealing needle and the nozzle's extrusion port that allows material to flow from the nozzle's extrusion port) and a closed position. When the control switch utilizes an actuator (such as a linear stepper motor actuator) that allows for a variety of open positions (compared to a maximum open / closed dual-position switch), the amount and / or rate of material extrusion can be adjusted by adjusting the distance between the position of the tapered end of the sealing needle when it is in the open position (e.g., the tip of the tapered end) and the position of the tapered end when it is in a closed position that completely seals the nozzle's extrusion port. This distance can be referred to as the "opening distance." By controlling the amount and / or rate of material extrusion, the system can better synchronize printing speeds. For example, for finer portions of the tablet, the printing speed may be slowed down and the material extrusion rate may be reduced, while for portions of the tablet that do not require excessive precision, both the printing speed and the material extrusion rate may be increased. This may be achieved by increasing the opening distance of the sealing needle valve, switching to a nozzle with a larger diameter, or by irrigation. The nozzle includes a tapered inner surface, and the sealing needle includes a tapered end that engages with the tapered inner surface of the nozzle to limit leakage of the material. The sealing needle is preferably sharp and thin, and has no protrusions that could extrude the material from the nozzle when positioned in the closed position. The pressure of the material is preferably kept approximately constant within the device, which can be controlled by monitoring the pressure and applying pressure to the material using a feedback system. This allows the material to be extruded at a constant rate as soon as the sealing needle is positioned in the open position without increasing the pressure. This further enables precise dispensing of the material, resulting in accurate and precise production of drug dosage units such as pharmaceutical tablets.

[0050] In some embodiments, a device for depositing material or producing a product (such as a pharmaceutical dosage form) by additive manufacturing is provided, the device comprising: a material supply system configured to melt and pressurize material, the material supply system including a feed channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect the pressure of the material in the print head or in the feed channel proximate to the print head; and a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the feed channel and including a tapered end, wherein when the sealing needle is in the closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent flow of material through the nozzle. The open position can have an opening distance selected from the extrusion port.

[0051] FIG. 1 illustrates an exemplary embodiment of a device for depositing material or producing a product by additive manufacturing, according to the present invention. The device includes a material supply system 102 operative to melt and pressurize material. The molten and pressurized material flows through a supply channel connected to a nozzle 104. A pressure sensor 106 is positioned proximal to the nozzle and an end of the supply channel and can detect the pressure of the material in the supply channel. Optionally, the pressure sensor 106 can be configured to detect the pressure of the material directly within the nozzle 104. A control switch 108 includes a linear actuator and a sealing needle and can operate the sealing needle between open and closed positions. The linear actuator can be, for example, a mechanical actuator (which may include, for example, a screw), a hydraulic actuator, a pneumatic actuator (which may include a pneumatic valve), or a solenoid actuator (which may include a solenoid valve). In some embodiments, the actuator includes a pin cylinder, such as a pneumatic pin cylinder. In some embodiments, the actuator includes a spring-loaded pneumatic cylinder. In some embodiments, the spring-loaded pneumatic cylinder includes a spring that assists in extending the sealing needle (i.e., positioning the sealing needle from an open position (e.g., a maximum open position) to a closed position). In some embodiments, the spring-loaded pneumatic cylinder includes a spring that assists in retracting the sealing needle (i.e., positioning the sealing needle from a closed position to an open position (e.g., a maximum open position)). When the sealing needle is in the open position, pressurized molten material can flow through the feed channel and through the extrusion port of the nozzle 104. The amount and / or rate of material flow through the extrusion port can be adjusted by adjusting the opening distance of the sealing needle valve. For example, when a signal is given to the control switch 108 from instructions in a computer-readable memory, the control switch 108 lowers the sealing needle to a closed position, and the tip of the sealing needle engages the inner surface of the nozzle 104.

[0052] In some embodiments, the material is a non-fibrous material such as a powder, granules, gel, or paste. The non-fibrous material is melted and pressurized so that it can be extruded through the extrusion port of the nozzle. As further described herein, the pressure, particularly for viscous materials, is carefully controlled to ensure precise and accurate deposition of the material. The material can be melted within the material supply system using one or more heaters located within the material supply system, such as within or around the barrel, feed channel, and / or print head containing the material. In some embodiments, the melting temperature of the material is about 50°C or higher, such as about 60°C or higher, about 70°C or higher, about 80°C or higher, about 100°C or higher, about 120°C or higher, about 150°C or higher, about 200°C or higher, or about 250°C or higher. In some embodiments, the melting temperature of the material is about 400°C or less, such as about 350°C or less, about 300°C or less, about 260°C or less, about 200°C or less, about 150°C or less, about 100°C or less, or about 80°C or less. The material extruded from the nozzle can be extruded at a temperature above the melting temperature of the material. In some embodiments, the material is extruded at a temperature of about 50°C or greater, such as about 60°C or greater, about 70°C or greater, about 80°C or greater, about 100°C or greater, about 120°C or greater, about 150°C or greater, about 200°C or greater, or about 250°C or greater. In some embodiments, the material is extruded at a temperature of about 400°C or less, such as about 350°C or less, about 300°C or less, about 260°C or less, about 200°C or less, about 150°C or less, about 100°C or less, or about 80°C or less.

[0053] The devices described herein are useful for accurately and precisely extruding viscous materials. In some embodiments, the material, when extruded from the device, has a viscosity of about 100 Pa·s or greater, such as about 200 Pa·s or greater, about 300 Pa·s or greater, about 400 Pa·s or greater, about 500 Pa·s or greater, about 750 Pa·s or greater, or about 1000 Pa·s or greater. In some embodiments, the material has a viscosity of about 2000 Pa·s or less, such as about 1000 Pa·s or less, about 750 Pa·s or less, about 500 Pa·s or less, about 400 Pa·s or less, about 300 Pa·s or less, or about 200 Pa·s or less.

[0054] In some embodiments, the material is a pharmaceutically acceptable material. In some embodiments, the material is inert or biologically inert. In some embodiments, the material is an erodible or bioerodible material. In some embodiments, the material is a non-erodible or non-bioerodible material. In some embodiments, the material is a pharmaceutically acceptable material. In some embodiments, the material comprises one or more thermoplastic materials, one or more non-thermoplastic materials, or a combination of one or more thermoplastic materials and one or more non-thermoplastic materials. In some embodiments, the material is a polymer or copolymer.

[0055] In some embodiments, the material comprises a thermoplastic material. In some embodiments, the material is a thermoplastic material. In some embodiments, the material comprises an erodible thermoplastic material. In some embodiments, the thermoplastic material is edible (i.e., suitable for consumption by an individual). In some embodiments, the thermoplastic material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erodible polymers (such as soluble polymers), pH-sensitive polymers, natural polymers, wax-like materials, and combinations thereof. In some embodiments, the thermoplastic material is selected from the group consisting of cellulose ethers, cellulose esters, acrylic resins, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, C 12 ~C 30 Mono- or diglycerides of fatty acids, C 12 ~C 30Fatty alcohols, waxes, poly(meth)acrylic acid, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate copolymer (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, vinyl pyrrolidone-vinyl acetate copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer 25 / 75, kollicoatIR-polyvinyl alcohol 60 / 40, polyvinyl alcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, poly(dimethylaminoethyl methacrylate-co-methacrylic acid ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, poly( methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramide, hydroxypropyl methylcellulose phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or hypromellose (HMPC), hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL), hydroxylpropyl cellulose (HPC), polyoxyl 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil, hydrogenated soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB), polyvinyl acetate phthalate (PVAP), wax, beeswax, hydrogel, gelatin, hydrogenated vegetable oil, polyvinyl acetal diethylaminolactate (AEA), paraffin, shellac, sodium alginate, cellulose acetate phthalate (CAP), gum arabic, xanthan gum, glyceryl monostearate, octadecanoic acid, thermoplastic starch, derivatives thereof (such as salts, amides, or esters thereof), or combinations thereof.

[0056] In some embodiments, the erodible material comprises a non-thermoplastic material. In some embodiments, the erodible material is a non-thermoplastic material. In some embodiments, the non-thermoplastic material is non-thermoplastic starch, sodium starch glycolate (CMS-Na), sucrose, dextrin, lactose, microcrystalline cellulose (MCC), mannitol, magnesium stearate (MS), powdered silica gel, titanium dioxide, glycerin, syrup, lecithin, soybean oil, black tea oil, ethanol, propylene glycol, glycerol, Tween, animal fat, silicone oil, cocoa butter, fatty acid glycerides, petrolatum, chitosan, cetyl alcohol, stearyl alcohol, polymethacrylate, non-toxic polyvinyl chloride, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, or a combination thereof.

[0057] Exemplary materials that may be used with the devices or methods described herein include, but are not limited to, poly(meth)acrylate copolymers (such as copolymers sold under the trade name Eudragit® RSPO, including copolymers comprising one or more of aminoalkyl methacrylate, methacrylic acid, methacrylic acid esters, and / or ammonioalkyl methacrylate), and hydroxylpropyl cellulose (HPC).

[0058] In some embodiments, the material comprises a drug. In some embodiments, the material is mixed with a drug.

[0059] The material can be pressurized in the material control system using a pressure controller. The material is loaded into a barrel, and the pressure controller can apply pressure to the material contained in the barrel. The pressure controller can be a motor (such as a stepper motor), a valve, or any other suitable control device that can apply force to the material contained in the barrel, for example, operating a piston, a pressure screw, or compressed air (i.e., a pneumatic controller). The barrel includes one or more heaters that can melt the material loaded into the heater. In some embodiments, the heater is located within the barrel. In some embodiments, the heater is located on the side of the barrel or surrounding the barrel. In some embodiments, the heater is an electric radiant heater, for example, an electric heating tube or coil. The barrel heater is preferably a powerful heater with high voltage and high power output. In some embodiments, the barrel heater has a voltage rating of 110V to 600V. In some embodiments, the barrel heater has a voltage rating of 210V to 240V. In some embodiments, the barrel heater is a 220V heater. In some embodiments, the barrel heater has a wattage output of about 30 W to about 100 W, such as 40 W to 80 W, or about 60 W. In some embodiments, the heater is an electric heating coil that surrounds the outside of the barrel. Preferably, the barrel is made of a heat-resistant material, such as stainless steel (e.g., 316L stainless steel).

[0060] The material supply system includes a feed channel connecting the barrel to the nozzles in the print head. Material melted or softened in the barrel flows through the feed channel to the print head. In some embodiments, one or more heaters are positioned within, around, or adjacent to the feed channel or a portion of the feed channel (e.g., a lateral portion of the feed channel). The one or more heaters are configured to heat the material in the feed channel. In some embodiments, the heater is an electric radiant heater, such as an electric heating tube or coil. For example, in some embodiments, an electric heating tube is positioned along the length of the feed channel or along at least a portion of the length of the feed channel. The heater is preferably a powerful heater having a high voltage and high power output. In some embodiments, the feed channel heater has a voltage rating of 110V to 600V. In some embodiments, the feed channel heater has a voltage rating of 210V to 240V. In some embodiments, the feed channel heater is a 220V heater. In some embodiments, the feed channel heater has a wattage output of about 30 W to about 100 W, such as 40 W to 80 W, or about 60 W. In some embodiments, the device includes one or more temperature sensors positioned adjacent to or within the feed channel, the temperature sensors configured to measure the temperature of the material within the feed channel. The feed channel is relatively wide compared to the extrusion port of the nozzle. In some embodiments, the feed channel has a diameter of about 1 mm to about 15 mm, such as about 1 mm to about 5 mm, about 5 mm to about 10 mm, or about 10 mm to about 15 mm. In an exemplary embodiment, the feed channel has a diameter of about 8 mm.

[0061] The print head of the device includes a nozzle, which includes an extrusion port through which molten material is extruded. The extrusion port is located at the distal end of the nozzle relative to the feed channel. When the sealing needle is in an open position (including open positions with various opening distances, e.g., a maximum open position), the molten material flows from the feed channel through the nozzle and out the extrusion port. The nozzle includes a tapered inner surface, and the extrusion port is located proximal to the apex of the tapered inner surface. In some embodiments, the inner surface of the nozzle includes a pad or liner. The pad or liner may be made of polytetrafluoroethylene (PTFE) or any other suitable material. In some embodiments, the print head includes one or more heaters, which may be positioned within, around, or adjacent to the nozzle of the print head. The one or more heaters are configured to heat the material in the nozzle, which may be at the same or a different temperature than the material in the barrel or feed channel. In some embodiments, the nozzle heater is an electric radiant heater, such as an electric heating tube or coil. This heater may be a lower voltage and / or lower wattage heater than the barrel heater or the feed channel heater. In some embodiments, the nozzle heater has a voltage rating of 6 V to 60 V. In some embodiments, the nozzle heater is a 12 V heater. In some embodiments, the nozzle heater has a wattage output of about 10 W to about 60 W, such as 20 W to 45 W, or about 30 W. In some embodiments, the print head includes one or more temperature sensors positioned adjacent to or within the nozzles, the temperature sensors configured to measure the temperature of the material in the nozzles.

[0062] The device includes a pressure sensor configured to detect the pressure of material in the print head or in a feed channel proximal to the print head. In some embodiments, the pressure sensor is connected to a computer system that operates the material feed system to pressurize the material to a desired pressure in response to the pressure reported by the pressure sensor. For example, the computer system can operate a pressure controller to adjust the amount of pressure applied to the material in the barrel. In some embodiments, the system operates as a closed-loop feedback system to maintain a substantially constant pressure in the device. In some embodiments, the feedback system operates using a proportional-integral-derivative (PID) controller, a bang-bang controller, a predictive controller, a fuzzy control system, an expert system controller, or any other suitable algorithm. In some embodiments, the pressure sensor is accurate to within 0.005 MPa, within 0.008 MPa, within 0.05 MPa, within 0.1 MPa, within 0.2 MPa, within 0.5 MPa, or within 1 MPa. In some embodiments, the sample rate of the pressure sensor is about 20 ms or less, such as about 10 ms or less, about 5 ms or less, or about 2 ms or less. In some embodiments, the material pressure is within about 0.005 MPa, about 0.008 MPa, about 0.05 MPa, about 0.1 MPa, about 0.2 MPa, about 0.5 MPa, or about 1 MPa of the desired pressure.

[0063] In some embodiments, the device includes one or more temperature sensors. In some embodiments, the device includes a temperature sensor positioned in or adjacent to the barrel, or configured to detect the temperature in the barrel. In some embodiments, the device includes a temperature sensor positioned in or adjacent to the feed channel, or configured to detect the temperature in the feed channel. In some embodiments, the device includes a temperature sensor positioned in or adjacent to the print head, or configured to detect the temperature in the nozzle. In some embodiments, the one or more temperature sensors are connected to a computer system that operates one or more heaters in response to temperatures reported by the one or more temperature sensors. For example, the computer system may operate one or more heaters to adjust the temperature of material in the barrel, feed channel, and / or nozzle. In some embodiments, the system operates as a closed-loop feedback system to maintain a substantially constant temperature in the device, or in a component of the device (i.e., the barrel, nozzle, or feed channel). The temperatures of material in different components of the device may be the same or different. In some embodiments, the feedback system operates using a proportional-integral-derivative (PID) controller, a bang-bang controller, a predictive controller, a fuzzy control system, an expert system controller, or any other suitable algorithm.

[0064] The devices described herein include a control switch that can be operated to prevent or allow molten material to flow from the extrusion port of the device. The control switch includes a sealing needle operable in an open position (including open positions with various opening distances, e.g., a maximum open position) and a closed position, and material flow through the nozzle is prevented with the sealing needle in the closed position. The sealing needle extends through at least a portion of the feed channel and includes a tapered end. When the sealing needle is in the closed position, the tapered end of the sealing needle engages a tapered inner surface of the nozzle (e.g., at the extrusion port of the nozzle).

[0065] The "opening distance" of the sealing needle valve described herein is the distance from the opening of the sealing needle to the open position (hereinafter, position d x The position of the tapered end (for example, the tip of the tapered end) when the sealing needle is in the closed position (hereinafter referred to as position d) where the sealing needle completely seals the extrusion port of the nozzle. o The distance (D open ), i.e., D open =d x -d0, refers to the movement or distance D of the sealing needle open can be controlled via an actuator within the control switch, such as an electric motor actuator (e.g., a linear stepper motor actuator), to adjust the amount and / or rate of material extrusion from the nozzle. The amount of material extrusion from the nozzle (e.g., average amount of material extrusion, mg) and the corresponding distance D open By measuring the material extrusion rate (e.g., mm), a plot of the sealing needle valve opening distance (x-axis) versus the material extrusion rate (y-axis) can be obtained. In some embodiments, when the pressure of the material in the print head or in a supply channel proximal to the print head is constant, the material extrusion rate (e.g., average rate) increases with increasing sealing needle valve opening distance. Once the maximum material extrusion rate (e.g., average rate) is reached, the material extrusion rate (e.g., average rate) continues to remain at a substantially stable value even with further increases in sealing needle valve opening distance. In some embodiments, when the material pressure in the print head or in a supply channel proximal to the print head is approximately 0.4 MPa, the maximum material extrusion rate (e.g., average rate) is reached when the sealing needle valve opening distance is greater than approximately 0.8 mm. In some embodiments, the relationship between the maximum material extrusion rate (e.g., average rate) and the sealing needle valve opening distance can be affected by factors such as the printing material, printing temperature, nozzle and / or sealing needle diameter, nozzle and / or sealing needle shape, nozzle and / or sealing needle material, material pressure, and sealing needle movement speed.

[0066] In some embodiments, the sealing needle can be positioned in an open position having an opening distance of up to about 5 mm, such as up to about 4 mm, up to about 3 mm, up to about 2 mm, up to about 1.5 mm, up to about 1.4 mm, up to about 1.3 mm, up to about 1.2 mm, up to about 1.1 mm, up to about 1.0 mm, up to about 0.9 mm, up to about 0.8 mm, up to about 0.7 mm, up to about 0.6 mm, up to about 0.5 mm, up to about 0.4 mm, up to about 0.3 mm, up to about 0.2 mm, or up to about 0.1 mm. In some embodiments, the sealing needle has a diameter of about 0.1 mm to about 2.0 mm, about 0.2 mm to about 1.6 mm, about 0.4 mm to about 1.2 mm, about 0.4 mm to about 1.0 mm, about 0.4 mm to about 0.9 mm, about 0.4 mm to about 0.8 mm, about 0.4 mm to about 0.7 mm, about 0.4 mm to about 0.6 mm, about 0.7 mm to about 1.1 mm, about 0.7 mm to about 1.0 mm, about 0.7 mm to about 0.9 mm, about 0.5 mm, or about 0.6 mm. m, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.1 mm, about 1.2 mm, about 0.89 mm, about 0.88 mm, about 0.87 mm, about 0.86 mm, about 0.85 mm, about 0.84 mm, about 0.83 mm, about 0.82 mm, about 0.81 mm, about 0.79 mm, about 0.78 mm, about 0.77 mm, about 0.76 mm, or about 0.75 mm.

[0067] In some embodiments, any portion of the seal needle that contacts the material does not include a protrusion. A protrusion may be any portion of the seal needle that has a larger diameter than the seal needle shaft or any member of the seal needle that extends further outward than the seal needle shaft. A protrusion on the seal needle may, and preferably does not, push molten material through the extrusion port when the seal needle is positioned in the closed position. In some embodiments, the entire seal needle (whether or not the seal needle contacts the material) does not include a protrusion. In some embodiments, portions of the seal needle that do not contact the material include one or more protrusions, which can, for example, engage components of an actuator or function as a depth break to prevent the seal needle from being overdriven within the feed chamber.

[0068] The portion of the sealing needle that contacts the material (i.e., the portion positioned within the feed channel when the sealing needle is in an open position (including open positions with various opening distances, e.g., a maximum open position) or a closed position) is relatively thin compared to the feed channel, which allows the molten material to flow around the sealing needle rather than being forced down and out the extrusion port. In some embodiments, the portion of the sealing needle that contacts the material has a maximum diameter of about 0.2 mm to about 3.0 mm, such as about 0.2 mm to about 0.5 mm, about 0.5 mm to about 1.0 mm, about 1.0 mm to about 1.5 mm, about 1.5 mm to about 2.0 mm, about 2.0 mm to about 2.5 mm, or about 2.5 mm to about 3.0 mm. In some embodiments, the sealing needle (including the portion of the sealing needle that contacts the material and the portion of the sealing needle that does not contact the material) has a maximum diameter of about 0.2 mm to about 3.0 mm, such as about 0.2 mm to about 0.5 mm, about 0.5 mm to about 1.0 mm, about 1.0 mm to about 1.5 mm, about 1.5 mm to about 2.0 mm, about 2.0 mm to about 2.5 mm, or about 2.5 mm to about 3.0 mm.

[0069] In some embodiments, the seal needle includes a pointed tip at a tapered end, as shown in FIG. 3A. In some embodiments, the tapered end of the tip is frustoconical, as shown in FIG. 3B. Both the nozzle and seal needle include tapered surfaces such that the tapered end of the seal needle leads into the tapered inner surface of the nozzle. As used herein, "taper angle" refers to the angle of the apex of the mating surface. In the case of a frustoconical tapered tip, "taper angle" refers to the apex of the extrapolated mating surface. The taper angle of the tapered end of the seal needle is indicated by α in FIGS. 3A and 3B, and the taper angle of the nozzle is indicated by β in the nozzle shown in FIG. 3C. In some embodiments, the taper angle of the tapered end of the seal needle is about 60° or less, such as about 50° or less, 45° or less, 40° or less, 35° or less, 30° or less, 25° or less, 20° or less, or 15° or less. In some embodiments, the taper angle (α) of the sealing needle is less than or equal to the taper angle (β) of the inner surface of the nozzle. In some embodiments, the ratio of the taper angle (β) of the inner surface of the nozzle to the taper angle (α) of the sealing needle is about 1:1 to about 4:1, or about 1:1 to about 3:1, or about 1:1 to about 2:1.

[0070] The sealing needle is positioned in a closed position by lowering the sealing needle toward the extrusion port, aligning the extrusion port with the sealing needle. When the sealing needle is in an open position (including various open positions, e.g., a maximum open position), pressurized, molten material can flow through the extrusion port; however, when the sealing needle is in a closed position, the sealing needle engages the inner surface of the nozzle, preventing material flow. If the taper angle (β) of the inner surface of the nozzle is wider than the taper angle (α) of the sealing needle, the tapered end of the sealing needle engages the inner surface of the nozzle at the tip of the extrusion port. In some embodiments, the extrusion port has a diameter of about 0.1 mm or greater, such as about 0.15 mm or greater, about 0.25 mm or greater, about 0.5 mm or greater, or about 0.75 mm or greater. In some embodiments, the extrusion port has a diameter of about 1 mm or less, such as about 0.75 mm or less, about 0.5 mm or less, about 0.25 mm or less, or about 0.15 mm or less. The sealing needle, including the base of the tapered end of the sealing needle, is preferably narrow to limit the molten material being forced through the extrusion port when the sealing needle is positioned in the closed position. In some embodiments, the ratio of the maximum diameter of the tapered end of the sealing needle (i.e., the base of the taper) to the diameter of the extrusion port is about 1:0.8 to about 1:0.1, such as about 1:0.8 to about 1:0.7, about 1:0.7 to about 1:0.6, about 1:0.6 to about 1:0.5, about 1:0.5 to about 1:0.4, about 1:0.4 to about 1:0.3, about 1:0.3 to about 1:0.2, or about 1:0.2 to about 1:0.1.

[0071] The sealing needle preferably comprises a sturdy yet flexible material. Exemplary materials include, but are not limited to, stainless steel, polytetrafluoroethylene (PTFE), and carbon fiber. In some embodiments, the inner surface of the nozzle comprises a flexible pad or liner, which can limit damage to the needle or nozzle when the sealing needle is repeatedly repositioned between open and closed positions. In some embodiments, the pad or liner is made of polytetrafluoroethylene (PTFE).

[0072] The sealing needle of the control switch is operated using an actuator that can position the sealing needle in an open position (including open positions having various opening distances, e.g., a maximum open position) (i.e., raising the sealing needle so that the tapered end of the sealing needle no longer engages the inner surface of the nozzle) or a closed position (i.e., lowering the sealing needle so that the tapered end of the sealing needle engages the inner surface of the nozzle). In some embodiments, the actuator is a linear actuator. In some embodiments, the actuator is a pneumatic actuator, which can be controlled using air pressure within the actuator. In some embodiments, the actuator is a mechanical actuator, which can raise or lower the sealing needle using one or more gears and a motor. In some embodiments, the actuator is a hydraulic actuator. In some embodiments, the actuator is an electric motor actuator, such as a linear stepper motor actuator or a torque actuator. In some embodiments, the actuator includes a solenoid valve or an electrostrictive polymer.

[0073] FIG. 2A shows a cross-sectional view of an exemplary device for depositing material by additive manufacturing, according to the present invention. Material can be loaded into a barrel 202 of a material supply system, and a piston 204 applies pressure to the material by being pushed into the barrel 202. The piston 204 is connected to a pressure controller via a guide arm 206. The piston 204 can be lowered by a motor, such as a stepper motor, to increase the pressure of the material in the barrel 202, or raised to decrease the pressure of the material. The material in the barrel 202 can be heated above the material's melting temperature using a heater inside or surrounding the barrel. The molten material from the barrel 202 flows through a feed channel 208, which is joined to a print head 210 that includes a nozzle 212. A pressure sensor 214 is positioned at the end of the feed channel 208 proximal to the print head 210 and configured to detect the pressure of the material proximal to the print head. In some embodiments, the pressure sensor 214 is positioned to detect the pressure of the material in the print head 210. The pressure sensor 214 can transmit the detected pressure to a computer system, which can operate a pressure controller (or a motor of the pressure controller) to reposition the piston 204 and control the pressure of the material in the barrel 202. This can operate in a feedback system, where a change in pressure is detected by the pressure sensor 214, which in turn causes the computer system to operate the pressure controller.

[0074] The device includes a control switch 216, which includes a seal needle 218 and a linear actuator 220. The seal needle 218 includes an upper end 222 that engages the actuator 220 and a tapered lower end 224. The seal needle 218 extends through the feed channel 208 into the print head 210. The actuator 220 operates the seal needle 218 between an open position (raised) and a closed position (lowered). When the seal needle 218 is positioned in the closed position, the tapered end 224 of the seal needle 218 engages the tapered inner surface of the nozzle 212 to prevent the flow of molten material through the nozzle. To open the nozzle 212 and allow molten material to flow through the extrusion port, the actuator 220 operates the sealing needle 218 to position the sealing needle 218 in an open position by raising the sealing needle 218, thereby disengaging the tapered lower end 224 from the inner surface of the nozzle 212. FIG. 2B shows an enlarged view of the print head 210 with the sealing needle 218 in a closed position and engaged with the nozzle 212. In the closed position, the tapered end 224 of the sealing needle 218 blocks the extrusion port 226 by engaging the tapered inner surface of the nozzle 212. Thus, molten material in the feed channel 208 is prevented from flowing through the extrusion port 226 by the tapered end 224 of the sealing needle. The pressure of the material within or proximal to the print head 210 is detected by a pressure sensor 214, and a pressure controller can operate to prevent excessive pressure buildup within the device when the sealing needle 218 is in the closed position.

[0075] A sealing needle 218 extends through the feed channel 208 into the print head 210. When the sealing needle 218 is positioned from an open to a closed position, careful design prevents molten material in the feed channel 208 from being extruded by the sealing needle 218 out of the extrusion port 226. The tapered end 224 of the sealing needle 218 allows the sealing needle 218 to pierce the molten material, allowing the molten material to flow over and around the closing sealing needle 218 instead of being forced down.

[0076] Pneumatic actuator 220 includes a solenoid valve used to control the flow of gas into air chamber 226, which can drive a central rod 228 attached to the upper end 222 of sealing needle 218 up and down. High-pressure gas entering air chamber 226 from below diaphragm 230 or the removal of gas from above diaphragm 230 moves diaphragm 230 upward, thereby positioning sealing needle 218 in an open position. Removing gas from below diaphragm 230 or applying high-pressure gas above diaphragm 230 moves diaphragm 230 downward, thereby positioning sealing needle 218 in a closed position.

[0077] While the device in FIG. 2A includes a pneumatic actuator, other linear actuators may be used. For example, the actuator may be an electric motor actuator, such as a linear stepper motor actuator. Similarly, the linear stepper motor actuator may move a central rod 228 attached to the upper end 222 of the sealing needle 218 upward (to position the sealing needle 218 in an open position (including open positions with various opening distances, e.g., a maximum open position)) or downward (to position the sealing needle 218 in a closed position). Furthermore, the linear stepper motor actuator may provide more precise control of the opening distance of the sealing needle valve to adjust the amount and flow rate of material extrusion from the nozzle.

[0078] FIG. 4 shows an exploded view of the components of a pneumatic actuator connected to a sealing needle to control it. A diaphragm 402 is positioned within the air chamber of the pneumatic actuator and is connected to a central rod 404, e.g., via a threaded fitting. The central rod 404 is connected to an adapter 406, e.g., via a threaded fitting. The adapter 406 is attached to the sealing needle 408, e.g., via a threaded fitting or via a pressure fit. For example, the bottom of the adapter 406 can include an opening, and the upper portion of the sealing needle 408 can fit snugly into the opening by jamming the sealing needle 408 into the opening of the adapter 406. The sealing needle 408 passes through a gasket 410, which is held in place by a locking nut 412. The locking nut 412 is attached to the rest of the device via a manifold block, which holds the locking nut 412 and the gasket in place. Referring to FIG. 2A , the manifold block 232 is positioned above the feed channels 208 and aligned with the nozzles 212 of the print head 210. Manifold block channels 234 extend through the manifold block 232 and connect to the feed channels. A gasket 236 fits into an opening toward the top of the manifold block 232, which is wider than the channels 234, preventing the gasket 236 from moving toward the print head 210. The gasket 236 can be made of an inert, flexible material such as plastic or synthetic rubber and seals the feed channels 208 to prevent leakage of molten material flowing from the feed channels 208. In some embodiments, the gasket comprises polytetrafluoroethylene (PTFE). A locking nut 238 is secured to the manifold block 232, for example, by a threaded fit, securing the position of the gasket 236. Thus, the gasket 236 is in a fixed position relative to the print head 210 and nozzles 212. The sealing needle 218 passes through a hole in the locking nut 238 and the gasket 236 to reach the supply channel 208 .The hole is sized to allow the needle to pass through and move as controlled by the actuator 220, but not so large as to allow leakage of molten material.

[0079] The material supply system includes one or more heaters that melt the material contained therein. The heaters can be positioned around or within the barrel, feed channel, and / or print head of the device that contains the material. FIG. 5A shows a longitudinal cross-sectional view of a portion of an exemplary device, FIG. 5B shows a cross-sectional view along the plane "AA," and FIG. 5C shows a non-cross-sectional view of the device. In this exemplary device, a pneumatic actuator is used. In some embodiments, the device includes a heater 502 that surrounds the barrel 504 of the device and can heat and melt the material contained within the barrel 504. The heater 502 can be, for example, a coil heater that surrounds the outside of the barrel 504. In some embodiments, the heater is disposed within the barrel. The material disposed within the barrel is first melted within the barrel by the heater, and pressure is applied to the material by a piston 506. The molten material then flows from the barrel 504 to the feed channel 508. In some embodiments, one or more heaters can be positioned adjacent to or within the feed channel 508 to ensure that the material in the feed channel 508 remains molten at a desired temperature. FIGS. 5B and 5C show two heaters 510a and 510b, one positioned adjacent to the feed channel 508 on opposite sides of the feed channel 508. In some embodiments, the heaters 510a and / or 510b span the length of the feed channel 508 or the length of a lateral portion of the feed channel 508. In some embodiments, the one or more heaters adjacent to or within the feed channel 508 are heating rods. In some embodiments, the one or more heaters adjacent to or within the feed channel 508 are coils surrounding the feed channel 508. The one or more heaters that heat the material in the feed channel 508 ensure that the material remains molten and has the correct viscosity for predictable flow for a given applied pressure. In some embodiments, the print head 512 of the device includes one or more heaters 514 that ensure that the material remains molten and of the correct viscosity within the nozzle 516 .

[0080] In some embodiments, the device includes one or more temperature sensors, which may be positioned at one or more locations within the device, capable of detecting the temperature of material within the device, such as within the barrel, feed channel, or print head. The embodiment illustrated by FIGS. 5A-5C includes a first temperature sensor 518 adjacent the feed channel 508 and a second temperature sensor 520 adjacent the print head 512. Although the temperature sensor 518 adjacent the feed channel 508 is illustrated at the beginning of a lateral portion of the feed channel 508, the temperature sensor 518 can optionally be positioned anywhere along the length of the feed channel 508. The temperature sensor 518 and one or more heaters (e.g., 510a and 510b) positioned to heat and / or melt the material within the feed channel 508 can be operated in a closed-loop feedback system, which can ensure a substantially constant temperature of material within the feed channel. For example, the temperature sensor 518 can transmit the measured temperature to a computer system, which can operate one or more heaters 510a and 510b to ensure a substantially constant temperature. A temperature sensor 520 in the device's print head 512 can operate in conjunction with one or more heaters 514 in the print head in a closed-loop feedback system to ensure a substantially constant temperature of material in the print head. The feedback system can operate using a proportional-integral-derivative (PID) controller, a bang-bang controller, a predictive controller, a fuzzy control system, an expert system controller, or any other suitable algorithm. In some embodiments, one or more heaters in the device heat the material in the system to a temperature above the melting temperature of the material. In some embodiments, the one or more heaters heat the material to a temperature of about 60°C or above, such as about 70°C or above, 80°C or above, 100°C or above, 120°C or above, 150°C or above, 200°C or above, or 250°C or above. In some embodiments, the one or more heaters heat the material to a temperature of about 300°C or less, such as about 260°C or less, 200°C or less, 150°C or less, 100°C or less, or 80°C or less.In some embodiments, one or more heaters heat the material to different temperatures in different locations of the device. For example, in some embodiments, the material is heated to a first temperature in the barrel, a second temperature in the feed channel, and a third temperature in the print head, which may be the same or different temperatures. As an example, the material may be heated to 140°C in the barrel and feed channel, while being heated to 160°C in the print head. A feedback control system allows for high temperature precision. In some embodiments, the temperature is controlled to within 0.1°C of the target temperature, within 0.2°C of the target temperature, within 0.5°C of the target temperature, or within 1°C of the target temperature.

[0081] The device includes one or more pressure sensors that can detect the pressure of the material within the device. In some embodiments, the pressure sensor is configured to detect the pressure of the material within the print head or within a feed channel proximal to the print head. In some embodiments, the pressure sensor is positioned within the print head or adjacent to the feed channel and proximal to the print head. The pressure sensor can operate with a pressure controller in a closed-loop feedback system to provide a substantially constant pressure for the material within the device. For example, if the pressure sensor detects a decrease in pressure, the feedback system can send a signal to the pressure controller to increase the pressure of the material (e.g., by lowering the piston, increasing the air pressure in the barrel, rotating the pressure screw, etc.). Similarly, if the pressure sensor detects an increase in pressure, the feedback system can send a signal to the pressure controller to decrease the pressure of the material (e.g., by raising the piston, decreasing the air pressure in the barrel, rotating the pressure screw, etc.). The constant pressure ensures that the molten material within the device is extruded at a constant rate through the extrusion port of the nozzle when the sealing needle is in an open position (including open positions with various opening distances, e.g., a maximum open position). However, when the sealing needle is in the closed position, a constant pressure increase (e.g., by lowering the piston, increasing the air pressure in the barrel, rotating the pressure screw, etc.) can cause leakage of molten material through the nozzle. In addition, a feedback system including a pressure sensor and a pressure controller maintains a nearly constant pressure in the system when the sealing needle is repositioned from an open position (including open positions with various opening distances, e.g., the maximum open position) to a closed position, or from a closed position to an open position (including open positions with various opening distances, e.g., the maximum open position). This minimizes the "ramp" in extrusion rate because there is no need to increase the pressure of the material in the system when the sealing needle is repositioned from an open position (including open positions with various opening distances, e.g., the maximum open position) to a closed position.In some embodiments, the pressure sensor detects pressure changes within the print head while the opening distance of the sealing needle valve is changing and sends a signal to a device to control the open position of the sealing needle via a closed-loop feedback system in sync with the print speed (e.g., by the product print command). The feedback system can operate using a proportional-integral-derivative (PID) controller, a bang-bang controller, a predictive controller, a fuzzy control system, an expert system controller, or any other suitable algorithm. In some embodiments, the sample rate of the pressure sensor is about 20 ms or less, such as about 10 ms or less, about 5 ms or less, or about 2 ms or less. In some embodiments, the pressure is controlled to within 0.05 MPa of the target pressure, within 0.1 MPa of the target pressure, within 0.2 MPa of the target pressure, within 0.5 MPa of the target pressure, or within 1 MPa of the target pressure.

[0082] FIG. 6 shows another embodiment of a device described herein. Material is loaded into a barrel 602 of a material supply system, and a pressure screw 604 (i.e., a screw piston) can apply pressure to the material in the barrel 602. To increase the pressure on the material, a pressure controller 608 (e.g., a stepper motor) rotates a first gear 610, which rotates a second gear 612 connected to the pressure screw 604. The material in the barrel 602 can be heated by a heater 614 surrounding the barrel. Molten material from within the barrel 602 flows through a feed channel 616 to a print head 618, which includes a nozzle 620. The device can include a pressure sensor 630 configured to detect the pressure of the material in the barrel 602, the feed channel 616, and / or the print head 618. The pressure sensor 630 can transmit the detected pressure to a computer system, which can operate the pressure controller 608 to reposition the pressure screw 604 and control the pressure of the material in the barrel 602. This can operate in a feedback system, where a change in pressure is detected by the pressure sensor 630, which in turn operates the pressure controller. The exemplary device shown in FIG. 6 includes a control switch that includes a sealing needle 622 aligned along the same axis as the barrel 602 and an actuator 624. The sealing needle 622 includes an upper end that interfaces with the actuator 624 and a tapered lower end (not shown). The actuator 624 operates the sealing needle 622 between an open position (raised, including open positions with various opening distances, e.g., a maximum open position) and a closed position (lowered). When the sealing needle 622 is positioned in the closed position, the tapered end of the sealing needle 622 engages the tapered inner surface of the nozzle 620 to prevent the flow of molten material through the nozzle. The print head 618 may also include one or more heaters 626 and temperature sensors 628, which may operate in a feedback system.

[0083] In certain embodiments, there is an additive manufacturing system that includes a plurality (e.g., two or more, three or more, four or more, five or more, or six or more) of devices as described herein, the devices including a material supply system configured with a control switch (including a sealing needle having a tapered end operable in an open position (including open positions with various opening distances, e.g., a maximum open position) and a closed position, and an actuator). In some embodiments, at least two devices from the plurality of devices include: a material supply system configured to melt and pressurize material, the material supply system including a feed channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect a pressure of the material in the nozzle or in the feed channel proximate to the nozzle; and a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the feed channel and including a tapered end, wherein when the sealing needle is in the closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent flow of material through the nozzle. In some embodiments, the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle. In some embodiments, the control switches of each device in the system are different. In some embodiments, the control switches of some devices are the same but different from the control switches of other devices in the system. For example, in some embodiments, the actuators (such as linear actuators, e.g., pneumatic actuators, linear stepper motor actuators) of each control switch are the same but the configured sealing needles are different (e.g., different diameters). In some embodiments, the actuators (such as linear actuators) of each control switch are different (e.g., one device includes a pneumatic actuator and the other device includes an electric motor actuator), but the sealing needles are the same. In some embodiments, the actuators (such as linear actuators) and configured sealing needles are all different between different devices in the system.In some embodiments, the control switch for all devices in the system is the same (e.g., the same electric motor actuator configured with the same sealing needle). The materials in each of the separate devices may be the same or different. For example, in some embodiments, the system includes two devices and two different materials (i.e., a first material and a second material). In some embodiments, the system includes three devices and three different materials (i.e., a first material, a second material, and a third material). In some embodiments, the system includes four devices and four different materials (i.e., a first material, a second material, a third material, and a fourth material). In some embodiments, the system includes five devices and five different materials (i.e., a first material, a second material, a third material, a fourth material, and a fifth material). In some embodiments, the system includes six devices and six different materials (i.e., a first material, a second material, a third material, a fourth material, a fifth material, and a sixth material). In some embodiments, an additive manufacturing system includes a first device filled with a first material and a second device filled with a second material, where the first material and the second material are different. Different material supply systems within the additive manufacturing system can extrude different materials to form a multi-component printed product, such as a multi-component pharmaceutical dosage form (such as a tablet). When one of the material supply systems is active (i.e., the sealing needle is in an open position (including open positions with various opening distances, e.g., a maximum open position)), the other material supply systems within the device are inactive (i.e., the sealing needle is in a closed position). The device can quickly transition between active material supply systems by adjusting the position of the sealing needle to either an open position (including open positions with various opening distances, e.g., a maximum open position) or a closed position. Figure 7 shows a portion of an exemplary system including three material supply systems, each having a separate print head 702, 704, and 706.The print table 708 is movable in the x, y, and z dimensions to position the resulting product under the correct print head, which can extrude material to produce the product 710 (such as a pharmaceutical tablet).

[0084] In some embodiments, a device (or a system including multiple devices) described herein is connected to a computer system, which can operate any one or more of the various components of the device. For example, in some embodiments, the computer system operates one or more heaters, pressure controllers, and / or control switches. In some embodiments, the computer system operates one or more heaters in response to temperatures detected by one or more temperature sensors (i.e., with feedback control). In some embodiments, the computer system operates a pressure controller in response to pressure detected by one or more pressure sensors. In some embodiments, the computer system operates a control switch in response to instructions to print a product to switch a sealing needle between an open position (including open positions with various opening distances, e.g., a maximum open position) and a closed position, and further controls the opening distance of the sealing needle valve. In some embodiments, the computer system coordinates the transition between active material supply systems among multiple devices in response to instructions to print a product. The computer system includes one or more processors and computer-readable memory, and the computer-readable memory can include instructions for operating a device (or a system including multiple devices), such as instructions for controlling the actuators (such as linear actuators, e.g., pneumatic actuators, linear stepper motor actuators) of each device to control the open positions (including open positions with various opening distances, e.g., a maximum open position) and closed positions of each sealing needle in each device and / or the opening distance of the sealing needle valve of each device. In some embodiments, the computer system is a desktop computer, a laptop computer, a mobile device (such as a cell phone or tablet), a programmable logic controller (PLC), or a microcontroller. The computer system may include, for example, a processor, memory, storage, and input / output devices (e.g., a monitor, a keyboard, a disk drive, an internet connection, etc.).However, a computing system may also include circuitry or other specialized hardware for performing some or all aspects of the methods described herein and / or for operating the devices and systems described herein. In some operational settings, a computing system may be configured as a system including one or more units, each configured to perform some aspects of a process either in software, hardware, or some combination thereof. The main system of an exemplary computer system may include a motherboard having an input / output ("I / O") section, one or more central processing units ("CPUs"), and a memory section, which may have a flash memory card associated therewith. The I / O section may be connected to a display, a keyboard, a disk storage unit, a media drive unit, and / or one of the devices or systems described herein. The media drive unit may read / write computer-readable media, which may contain programs (i.e., instructions) and / or data. At least some values ​​based on the results of the above-described processes may be stored for subsequent use. Additionally, a non-transitory computer-readable medium can be used to store (e.g., tangibly embody) one or more computer programs for performing any one of the above-described processes by a computer. The computer programs may be written, for example, in a general-purpose programming language (e.g., Pascal, C, C++, Java, Python, JSON, etc.) or some specialized application-specific language.

[0085] In some embodiments, a computer system comprises one or more processors and a computer-readable memory including instructions for printing a product (such as a pharmaceutical dosage form, e.g., a tablet) by additive manufacturing. In some embodiments, the computer system operates a control switch in response to the instructions for printing the product. In some embodiments, the instructions for printing the product include instructions for printing the product using a layer-by-layer extrusion method. In some embodiments, the computer-readable memory includes instructions for controlling an actuator (such as a linear actuator, e.g., a pneumatic actuator, a linear stepper motor actuator) of the device (or each device in the system) to control an open position (an open position with various opening positions, e.g., a maximum open position) and a closed position of each sealing needle in the device (or each device in the system) and / or an opening distance of a sealing needle valve of the device (or each device in the system). In some embodiments, the computer-readable memory includes instructions for positioning the sealing needle based on the instructions for printing the product. In some embodiments, the instructions for positioning the sealing needle include instructions for selecting an opening distance of the sealing needle based on a desired flow rate of material from the extrusion port. In some embodiments, the instructions for positioning the sealing needle are based on a signal transmitted from a pressure sensor in the print head. For example, if the pressure in the print head is too high and / or the instructions for printing the product require a slower print speed, the computer readable memory may instruct the sealing needle valve to decrease its opening distance, and if the pressure in the print head is too low and / or the instructions for printing the product require a higher print speed, the computer readable memory may instruct the sealing needle valve to increase its opening distance.

[0086] Instructions for printing products such as pharmaceutical dosage forms can be generated using any one or more of a variety of methods, including direct encoding, derivation from a solid CAD model, or other means specific to the 3D printer's computer interface and application software. These instructions can include information regarding the number and spatial arrangement of droplets, as well as general printing parameters such as drop spacing in each linear dimension (X, Y, Z) and fluid volume or mass per droplet. For a given material set, these parameters can be adjusted to improve the quality of the fabricated structures. The overall resolution of the fabricated structures is a function of powder particle size, fluid droplet size, printing parameters, and material properties.

[0087] A method for depositing material or producing a product by additive manufacturing can include melting and pressurizing a material, flowing the material through an extrusion port of a nozzle including a tapered inner surface, monitoring the pressure of the material in or proximate the nozzle, engaging the tapered end of a sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of molten material, and withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port. In some embodiments, the method includes withdrawing the tapered end of the sealing needle to a selected opening distance (e.g., a maximum open position). In some embodiments, the method is performed using a device described herein. In some embodiments, the device includes multiple material supply systems, each material supply system configured with a control switch. In some embodiments, the control switch configured for each material supply system is the same. In some embodiments, the control switch configured for each material supply system is different (e.g., by using a different actuator or a sealing needle with a different diameter). The method can include dispensing a first material from a first material supply system and dispensing a second material from a second material supply system, wherein a sealing needle of the first material supply system is in a closed position when the second material is dispensed from the second material supply system and a sealing needle of the second supply system is in a closed position when the first material is dispensed from the first material supply system. In some embodiments, the method is performed in a batch mode of operation. In some embodiments, the device or system operates in a batch mode. The term "batch mode" refers to a mode of operation in which a predetermined number of products (such as pharmaceutical dosage forms) are manufactured. In some embodiments, the method is performed in a continuous mode of operation. In some embodiments, the device or system operates in a continuous mode. The term "continuous mode" refers to a mode of operation in which the device or system operates for a predetermined period of time or until a predetermined amount of material is used.

[0088] In some embodiments, a method for producing a product by additive manufacturing includes melting and pressurizing a first material, flowing the first material through a first extrusion port of a first nozzle including a tapered inner surface, engaging the tapered end of a first sealing needle with the tapered inner surface of the first nozzle to seal the first extrusion port and stop the flow of the molten first material, melting and pressurizing a second material, and withdrawing the tapered end of a second sealing needle from the tapered inner surface of the second nozzle to initiate the flow of the second material through the second extrusion port. In some embodiments, the method includes withdrawing the tapered end of the second sealing needle to a selected opening distance (e.g., a maximum open position), which may adjust the amount and / or rate of material flow through the extrusion port. In some embodiments, the method includes receiving instructions to manufacture the product, for example, from a computer system.

[0089] In some embodiments, a method of producing a pharmaceutical dosage form (such as a tablet) by additive manufacturing includes melting and pressurizing a pharmaceutically acceptable material; monitoring the pressure of the material in or proximate a nozzle; flowing the material through an extrusion port of the nozzle, the extrusion port including a tapered inner surface; engaging the tapered end of a sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of the molten material; and withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port. In some embodiments, the method includes withdrawing the tapered end of the sealing needle to a selected opening distance (e.g., a maximum open position). In some embodiments, the pharmaceutically acceptable material comprises a drug. In some embodiments, the method is performed using a device described herein. In some embodiments, the device includes multiple material supply systems, each material supply system configured with a control switch. In some embodiments, the control switch configured for each material supply system is the same. In some embodiments, the control switch configured for each material supply system is different (e.g., by using different actuators or sealing needles with different diameters). The method can include dispensing a first material from a first material supply system and dispensing a second material from a second material supply system, wherein a sealing needle of the first material supply system is in a closed position when the second material is dispensed from the second material supply system and a sealing needle of the second supply system is in a closed position when the first material is dispensed from the first material supply system. In some embodiments, the method further includes monitoring a pressure of the first material in or proximate the first nozzle and / or monitoring a pressure of the second material in or proximate the second nozzle. In some embodiments, the method includes retracting a tapered end of a second sealing needle configured on the second material supply system to a selected opening distance (e.g., a maximum open position), thereby adjusting the amount and / or rate of flow of the second material through the second extrusion port.

[0090] In some embodiments, a method of producing a pharmaceutical dosage form by additive manufacturing includes melting and pressurizing a first pharmaceutically acceptable material, flowing the first pharmaceutically acceptable material through a first extrusion port of a first nozzle including a tapered inner surface, engaging the tapered end of a first seal needle with the tapered inner surface of the first nozzle to seal the first extrusion port and stop the flow of the molten first material, melting and pressurizing a second pharmaceutically acceptable material, and withdrawing the tapered end of the second seal needle from the tapered inner surface of the second nozzle to initiate the flow of the second pharmaceutically acceptable material through the second extrusion port. In some embodiments, the method includes withdrawing the tapered end of the second seal needle to a selected opening distance (e.g., a maximum open position), thereby adjusting the amount and / or rate of flow of the second pharmaceutically acceptable material through the second extrusion port. In some embodiments, the first pharmaceutically acceptable material or the second pharmaceutically acceptable material is an erodible material. In some embodiments, the first pharmaceutically acceptable material or the second pharmaceutically acceptable material comprises a drug. In some embodiments, the method further includes receiving instructions, for example, from a computer system, for manufacturing the pharmaceutical dosage form. In some embodiments, the method further includes monitoring the pressure of the first material in or proximate the first nozzle and / or monitoring the pressure of the second material in or proximate the second nozzle.

[0091] In some embodiments, pharmaceutical dosage forms manufactured according to the methods described herein or using the devices or systems described herein comprise a multilayer structure including multiple layers of a first erodible material mixed with a drug, wherein the erosion of the first erodible material mixed with the drug correlates with the release rate of the drug from the pharmaceutical dosage form. Pharmaceutical dosage forms, such as oral drug dosage forms, can provide any desired drug release profile based on controlling various parameters, such as the thickness of the layer of the first erodible material mixed with the drug, the surface area of ​​the layer of the first erodible material, and the drug mass fraction of the layer of the first erodible material. Pharmaceutical dosage forms with desired drug release profiles for a drug or multiple drugs can be easily designed and printed using the devices or systems for additive manufacturing described herein.

[0092] Pharmaceutical dosage forms manufactured according to the methods described herein or using the devices or systems described herein can be designed to provide a desired drug release profile. In some embodiments, the pharmaceutical dosage form is custom-designed to provide a desired drug release profile, for example, for use in personalized medicine. In some embodiments, the pharmaceutical dosage form includes one or more layers comprising a first erodible material mixed with a drug, where the first erodible material is embedded in a second material that is not mixed with the drug. A pharmaceutical dosage form with a desired drug release profile can be designed, for example, by (a) selecting a first erodible material and a second material to form the pharmaceutical dosage form, (b) determining the erosion rate of the first erodible material, and (c) determining the thickness, surface area, and / or drug mass fraction of each layer based on the release rate of the drug and the desired drug release profile. In some embodiments, the pharmaceutical dosage form further includes one or more additional layers of a third erodible material mixed with a second drug.

[0093] In some embodiments, the pharmaceutical dosage form comprises two or more drugs, such as any of about 5 or more, about 10 or more, about 20 or more, about 30 or more, or about 50 or more, each drug having a desired drug release profile. In some embodiments, the oral drug dosage form comprises two or more drugs, and at least two of the drugs have different desired drug release profiles.

[0094] The desired release profile of a drug can be tailored depending on the materials and design used to manufacture the pharmaceutical dosage form. In some embodiments, the pharmaceutical dosage form is manufactured from two or more different materials, which may be deposited in one or more layers using the devices described herein, and the one or more layers may be the same or different. In some embodiments, the pharmaceutical dosage form comprises a first layer having a first material in which the drug is mixed and a second layer having a second material that does not contain the drug. In some embodiments, the pharmaceutical dosage form comprises a multilayer structure comprising one or more layers of a first erodible material mixed with the drug, the first erodible material being embedded in a second material that is not mixed with the drug. The erosion of the first erodible material mixed with the drug can be correlated with the release rate of the drug from the drug dosage form.

[0095] In some embodiments, the desired drug release profile comprises the rate or percentage of the total (i.e., cumulative) amount of drug to be released from the oral drug dosage form by a time point after administration of the oral drug dosage form (e.g., an enteric-coated oral drug dosage form) or after the initiation of subsequent drug release from the oral drug dosage form. In some embodiments, the desired drug release profile is predetermined.

[0096] In some embodiments, the drug begins to be released from the oral drug dosage form when the first erodible material layer containing the drug is exposed to a solution, such as oral fluid or gastrointestinal (GI) fluid. In some embodiments, the desired drug release profile of the oral drug dosage form spans the period from oral administration to complete release of the drug contained in the oral drug dosage form. In some embodiments, the desired drug release profile includes an initial lag period prior to the desired drug release period, which is patient-specific or an estimated period resulting from, for example, use of the enteric-coated oral dosage form.

[0097] In some embodiments, the desired drug release profile of the oral drug dosage form comprises a zero order release profile, a first order release profile, a delayed release profile, a pulsatile release profile, a repeated pulsatile release profile, an immediate release profile, a sustained release profile, or a combination thereof.

[0098] In some embodiments, the total time period for the desired drug release profile of the oral drug dosage form is from about 1 hour to about 72 hours, such as from about 1 hour to about 6 hours, from about 1 hour to about 12 hours, from about 1 hour to about 18 hours, from about 1 hour to about 24 hours, from about 1 hour to about 30 hours, from about 1 hour to about 36 hours, from about 1 hour to about 42 hours, from about 1 hour to about 48 hours, from about 1 hour to about 54 hours, from about 1 hour to about 60 hours, or from about 1 hour to about 66 hours. In some embodiments, the total time period for the desired drug release profile of the oral drug dosage form is any of about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, about 28 hours, about 30 hours, about 32 hours, about 34 hours, about 36 hours, about 40 hours, about 42 hours, about 44 hours, about 46 hours, about 48 hours, about 50 hours, about 52 hours, about 54 hours, about 56 hours, about 58 hours, about 60 hours, about 62 hours, about 64 hours, about 66 hours, about 68 hours, about 70 hours, or about 72 hours. In some embodiments, the total time period for the desired drug release profile of the oral drug dosage form is about 6 hours or more, about 12 hours or more, about 18 hours or more, about 24 hours or more, about 30 hours or more, about 36 hours or more, about 42 hours or more, about 48 hours or more, about 54 hours or more, about 60 hours or more, about 66 hours or more, or about 72 hours or more. In some embodiments, the total time period for the desired drug release profile of the oral drug dosage form is about 6 hours or less, about 12 hours or less, about 18 hours or less, about 24 hours or less, about 30 hours or less, about 36 hours or less, about 42 hours or less, about 48 hours or less, about 54 hours or less, about 60 hours or less, about 66 hours or less, or about 72 hours or less.

[0099] In some embodiments, one or more of the erodible materials are suitable for mixing with a drug. In some embodiments, the erodible materials mixed with the drug do not chemically react with the drug. In some embodiments, the erodible materials are selected based on their compatibility for mixing with the drug. In some embodiments, the erodible materials are selected based on their chemical non-reactivity with the drug.

[0100] In some embodiments, the material mixed with the drug is a material that substantially erodes (e.g., substantially completely erodes or substantially completely dissolves) during the time the oral drug dosage form is in an individual. In some embodiments, substantially all of the erodible material mixed with the drug in the oral drug dosage form erodes during the time the oral drug dosage form is in an individual. In some embodiments, substantially all of the first erodible material mixed with the drug in the oral drug dosage form erodes during a desired time frame while the oral drug dosage form is in an individual. In some embodiments, substantially all of the first erodible material mixed with the drug in the oral drug dosage form erodes in less than about 72 hours, such as less than any of about 48 hours, about 36 hours, about 24 hours, about 18 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, or about 1 hour.

[0101] In some embodiments, the erosion rate of the first erodible material mixed with the drug is between about 0.1 mm / hr and about 4 mm / hr. In some embodiments, the erosion rate of the first erodible material mixed with the drug is greater than about 0.1 mm / hr, such as greater than any of about 0.2 mm / hr, about 0.4 mm / hr, about 0.6 mm / hr, about 0.8 mm / hr, about 1.0 mm / hr, about 1.5 mm / hr, about 2.0 mm / hr, about 2.5 mm / hr, about 3.0 mm / hr, about 3.5 mm / hr, or about 4.0 mm / hr. In some embodiments, the erosion rate of the first erodible material mixed with the drug is less than about 0.1 mm / hour, such as less than any of about 0.2 mm / hour, about 0.4 mm / hour, about 0.6 mm / hour, about 0.8 mm / hour, about 1.0 mm / hour, about 1.5 mm / hour, about 2.0 mm / hour, about 2.5 mm / hour, about 3.0 mm / hour, about 3.5 mm / hour, or about 4.0 mm / hour.

[0102] The thickness of the deposited material (either drug-mixed or drug-free) can significantly change the release profile of the manufactured pharmaceutical dosage form. The devices and systems described herein allow for improved control over product thickness, as the device pressure is carefully controlled and control switches regulate the amount and / or flow rate of material extrusion as well as limiting leakage of the extruded material. In addition, the devices described herein limit the "rise" of the extrusion rate of the extruded material, thereby allowing for better control of the material thickness.

[0103] In some embodiments, a method for producing a pharmaceutical dosage form (e.g., a tablet) configured to provide a desired drug release profile by additive manufacturing includes melting and pressurizing a first material including a drug; flowing the material through a first extrusion port of a first nozzle including a tapered inner surface; engaging the tapered end of a first sealing needle with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and stopping the flow of the first molten material; melting and pressurizing a second material; and withdrawing the tapered end of a second sealing needle from the tapered inner surface of the second nozzle, thereby flowing the second material through the second extrusion port. In some embodiments, the method includes monitoring the pressure of the first material in or proximate the first nozzle. In some embodiments, the method includes monitoring the pressure of the second material in or proximate the second nozzle. In some embodiments, the method is performed using a device or system described herein. Illustrative Embodiments

[0104] Embodiment 1. A device for depositing material by additive manufacturing, comprising: a material supply system configured to melt and pressurize a material, the material supply system including a supply channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect a pressure of the material within the nozzle or within a feed channel proximate to the nozzle; a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the delivery channel and including a tapered end; A device in which, when the sealing needle is in a closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent the flow of material through the nozzle.

[0105] Embodiment 2. The device of embodiment 1, wherein the material is non-fibrous.

[0106] Embodiment 3. A device according to embodiment 1 or 2, wherein any portion of the sealing needle that contacts the material does not include a protrusion.

[0107] Embodiment 4. A device as described in any one of embodiments 1 to 3, wherein the pressure sensor is connected to a computer system that operates the material supply system to pressurize the material to a desired pressure in response to the pressure reported by the pressure sensor.

[0108] Embodiment 5. A device according to any one of embodiments 1 to 4, wherein the pressure of the material is within about 0.05 MPa of the desired pressure.

[0109] Embodiment 6. A device described in any one of embodiments 1 to 5, wherein the material supply system includes a piston and a barrel connected to the supply channel, and the piston is operated to control the pressure of the material in the barrel.

[0110] Embodiment 7. The device of embodiment 6, wherein the piston is operated using a stepper motor.

[0111] Embodiment 8. A device described in any one of embodiments 1 to 7, wherein the tapered end of the sealing needle comprises a pointed tip.

[0112] Embodiment 9. A device according to any one of embodiments 1 to 7, wherein the tapered end of the sealing needle is frustoconical.

[0113] Embodiment 10. A device described in any one of embodiments 1 to 8, wherein the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle.

[0114] Embodiment 11. The device of embodiment 10, wherein the second taper angle is less than or equal to about 60°.

[0115] Embodiment 12. A device according to embodiment 10 or 11, wherein the second taper angle is less than or equal to about 45°.

[0116] Embodiment 13. A device described in any one of embodiments 10 to 12, wherein the ratio of the first taper angle to the second taper angle is from about 1:1 to about 4:1.

[0117] Embodiment 14. A device described in any one of embodiments 1 to 13, wherein the extrusion port has a diameter of about 0.1 mm to about 1 mm.

[0118] Embodiment 15. A device described in any one of embodiments 1 to 14, wherein the tapered end has a maximum diameter of about 0.2 mm to about 3.0 mm.

[0119] Embodiment 16. A device described in any one of embodiments 1 to 15, wherein the extrusion port has a diameter, the tapered end has a maximum diameter, and the ratio of the maximum diameter of the tapered end to the diameter of the extrusion port is from about 1:0.8 to about 1:0.1.

[0120] Embodiment 17. A device described in any one of embodiments 1 to 16, wherein the material has a viscosity of about 100 Pa·s or greater when extruded from the device.

[0121] Embodiment 18. A device according to any one of embodiments 1 to 17, wherein the material has a viscosity of about 400 Pa·s or greater when extruded from the device.

[0122] Embodiment 19. A device according to any one of embodiments 1 to 18, wherein the material melts at about 50°C to about 400°C.

[0123] Embodiment 20. A device according to any one of embodiments 1 to 19, wherein the material is extruded from the nozzle at a temperature of from about 50°C to about 400°C.

[0124] Embodiment 21. A device according to any one of embodiments 1 to 19, wherein the material is extruded from the nozzle at a temperature of about 90°C to about 300°C.

[0125] Embodiment 22. A device described in any one of embodiments 1 to 21, wherein the control switch includes an actuator that positions the sealing needle in an open or closed position.

[0126] Embodiment 23. A device according to embodiment 22, wherein the actuator is a pneumatic actuator.

[0127] Embodiment 24. A device according to embodiment 22, wherein the actuator is a mechanical actuator.

[0128] Embodiment 25. A device as described in embodiment 22, wherein the actuator is an electric motor actuator.

[0129] Embodiment 26. A device as described in embodiment 25, wherein the electric motor actuator is a linear stepper motor actuator.

[0130] Embodiment 27. A device described in any one of embodiments 22 to 26, wherein the sealing needle passes through a gasket fixed in position relative to the nozzle, and the gasket seals the supply channel.

[0131] Embodiment 28. A device described in any one of embodiments 1 to 27, wherein the material supply system includes one or more heaters configured to melt the material.

[0132] Embodiment 29. A device as described in embodiment 28, wherein the material supply system includes one or more temperature sensors configured to detect the temperature of the molten material.

[0133] Embodiment 30. A device as described in embodiment 29, wherein the one or more temperature sensors are connected to a computer system that operates the one or more heaters in response to temperatures reported by the one or more temperature sensors.

[0134] Embodiment 31. A device described in any one of embodiments 1 to 30, wherein the tapered end of the sealing needle or the tapered inner surface of the nozzle comprises a flexible pad or liner.

[0135] Embodiment 32. A device described in any one of embodiments 1 to 31, further comprising a computer system including one or more processors and a computer-readable memory, the computer system being configured to operate the device.

[0136] Embodiment 33. A device as described in embodiment 32, wherein the computer-readable memory contains instructions for using the device to print a product.

[0137] Embodiment 34. A device as described in embodiment 32 or 33, wherein the computer-readable memory includes instructions for controlling the pressure of the material in response to the pressure detected by the pressure sensor.

[0138] Embodiment 35. A device described in any one of embodiments 32 to 34, wherein the computer-readable memory includes instructions for controlling the temperature of the material in response to the temperature detected by the temperature sensor.

[0139] Embodiment 36. A device described in any one of embodiments 33 to 35, wherein the computer-readable memory includes instructions for positioning the sealing needle based on instructions for printing the product.

[0140] Embodiment 37. The device of embodiment 36, wherein the instructions for positioning the sealing needle include instructions for selecting an opening distance of the sealing needle based on a desired flow rate of material from the extrusion port.

[0141] Embodiment 38. A device described in any one of embodiments 1 to 37, wherein the pressure sensor is positioned proximal to the nozzle.

[0142] Embodiment 39: An additive manufacturing system comprising a plurality of devices described in any one of embodiments 1 to 31, wherein each material supply system is configured with a control switch.

[0143] Embodiment 40. The system of embodiment 39, comprising a first device filled with a first material and a second device filled with a second material, wherein the first material and the second material are different.

[0144] Embodiment 41. A system described in embodiment 39 or 40, wherein the control switches of each device from the plurality of devices are different.

[0145] Embodiment 42. A system described in embodiment 39 or 40, wherein the control switch of each device from the plurality of devices is the same.

[0146] Embodiment 43. A system described in any one of embodiments 39 to 42, further comprising a computer system including one or more processors and computer-readable memory, the computer system being configured to operate the system.

[0147] Embodiment 44. The system of embodiment 43, wherein the computer-readable memory includes instructions for printing a product using the system.

[0148] Embodiment 45. A system as described in embodiment 43 or 44, wherein the computer-readable memory includes instructions for controlling the pressure of the material in each material supply system in response to the pressure detected by the pressure sensor in the corresponding material supply system.

[0149] Embodiment 46. A system described in any one of embodiments 39 to 45, wherein the computer-readable memory includes instructions for controlling the temperature of the material in each material supply system in response to the temperature detected by a temperature sensor in the corresponding material supply system.

[0150] Embodiment 47. A system described in any one of embodiments 44 to 46, wherein the computer-readable memory includes instructions for positioning a sealing needle based on instructions for printing a product.

[0151] Embodiment 48. The system of embodiment 47, wherein the instructions for positioning the sealing needle include instructions for selecting an opening distance of the sealing needle based on a desired flow rate of material from the extrusion port.

[0152] Embodiment 49. At least two devices from the plurality of devices: a material supply system configured to melt and pressurize a material, the material supply system including a supply channel connected to a print head including a nozzle, the nozzle including a tapered inner surface and an extrusion port configured to dispense the material; a pressure sensor configured to detect a pressure of the material within the nozzle or within a feed channel proximate to the nozzle; a control switch including a sealing needle operable in an open position and a closed position, the sealing needle extending through a portion of the delivery channel and including a tapered end; 49. A system according to any one of embodiments 39 to 48, wherein when the sealing needle is in the closed position, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent the flow of material through the nozzle.

[0153] Embodiment 50. The system described in embodiment 49, wherein the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle.

[0154] Embodiment 51. A system described in any one of embodiments 39 to 50, wherein the pressure sensor is positioned proximal to the nozzle.

[0155] Embodiment 52. A method for producing a product by additive manufacturing, comprising: Melting and pressurizing the material; flowing the material through an extrusion port of a nozzle including a tapered inner surface; monitoring the pressure of the material in or proximate the nozzle; engaging the tapered end of the sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of molten material; and withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port.

[0156] Embodiment 53. The method of embodiment 52, comprising receiving an instruction to manufacture the product.

[0157] Embodiment 54. A method for producing a pharmaceutical dosage form by additive manufacturing, comprising: Melting and compressing pharmaceutically acceptable materials; monitoring the pressure of the material in or proximate the nozzle; flowing the material through an extrusion port of a nozzle including a tapered inner surface; engaging the tapered end of the sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of molten material; and withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port.

[0158] Embodiment 55. The method of embodiment 54, wherein the pharmaceutically acceptable material comprises a drug.

[0159] Embodiment 56. The method of embodiment 55, wherein the pharmaceutical dosage form has a desired drug release profile.

[0160] Embodiment 57. The method of any one of embodiments 54-56, comprising receiving an instruction to manufacture a pharmaceutical dosage form.

[0161] Embodiment 58. The method of any one of embodiments 52 to 57, wherein the pressure of the material in the nozzle remains approximately constant.

[0162] Embodiment 59. The method of any one of embodiments 52-58, comprising controlling the pressure of the material using a feedback system based on the monitored pressure.

[0163] Embodiment 60. The method of any one of embodiments 52 to 59, wherein the material is non-fibrous.

[0164] Embodiment 61. The method of any one of embodiments 52 to 60, wherein any portion of the sealing needle that contacts the material does not include a protrusion.

[0165] Embodiment 62. The method of any one of embodiments 52 to 61, wherein the temperature of the material in the nozzle remains approximately constant.

[0166] Embodiment 63. The method of any one of embodiments 52-62, comprising monitoring the temperature of the material.

[0167] Embodiment 64. The method of embodiment 63, comprising controlling the temperature of the material using a feedback system based on the monitored temperature.

[0168] Embodiment 65. The method of any one of embodiments 52 to 64, comprising withdrawing the tapered end of the sealing needle to a selected opening distance.

[0169] Embodiment 66. The method of any one of embodiments 52 to 65, wherein the tapered end of the sealing needle comprises a sharp tip.

[0170] Embodiment 67. The method of any one of embodiments 52 to 65, wherein the tapered end of the sealing needle is frustoconical.

[0171] Embodiment 68. The method of any one of embodiments 52 to 67, wherein the tapered inner surface of the nozzle has a first taper angle and the tapered end of the sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle.

[0172] Embodiment 69. The method of embodiment 68, wherein the second taper angle is less than or equal to about 60°.

[0173] Embodiment 70. The method of embodiment 68 or 69, wherein the second taper angle is less than or equal to about 45°.

[0174] Embodiment 71. The method of any one of embodiments 68 to 70, wherein the ratio of the first taper angle to the second taper angle is from about 1:1 to about 4:1.

[0175] Embodiment 72. The method of any one of embodiments 52 to 71, wherein the extrusion port has a diameter of about 0.1 mm to about 1 mm.

[0176] Embodiment 73. The method of any one of embodiments 52 to 72, wherein the tapered end has a maximum diameter of about 0.2 to about 3.0 mm.

[0177] Embodiment 74. The method of any one of embodiments 52 to 73, wherein the extrusion port has a diameter, the tapered end has a maximum diameter, and the ratio of the maximum diameter of the tapered end to the diameter of the extrusion port is from about 1:0.8 to about 1:0.1.

[0178] Embodiment 75. The method of any one of embodiments 52 to 74, wherein the material has a viscosity of about 100 Pa·s or greater.

[0179] Embodiment 76. A method for producing a product by additive manufacturing, comprising: Melting and pressurizing a first material; flowing a first material through a first extrusion port of a first nozzle including a tapered inner surface; engaging the tapered end of the first sealing needle with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and stopping the flow of the molten first material; Melting and pressurizing a second material; and withdrawing the tapered end of the second sealing needle from the tapered inner surface of the second nozzle, thereby initiating flow of the second material through the second extrusion port.

[0180] Embodiment 77. The method of embodiment 76, comprising receiving an instruction to manufacture the product.

[0181] Embodiment 78. A method for producing a pharmaceutical dosage form by additive manufacturing, comprising: Melting and compressing a first pharmaceutically acceptable material; flowing a first pharmaceutically acceptable material through a first extrusion port of a first nozzle including a tapered inner surface; engaging the tapered end of the first sealing needle with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and stopping the flow of the molten first material; 1. A method comprising: melting and pressurizing a second pharmaceutically acceptable material; and withdrawing the tapered end of the second sealing needle from the tapered inner surface of the second nozzle, thereby initiating flow of the second pharmaceutically acceptable material through the second extrusion port.

[0182] Embodiment 79. The method of embodiment 78, wherein the first pharmaceutically acceptable material or the second pharmaceutically acceptable material is an erodible material.

[0183] Embodiment 80. The method of embodiment 78 or 79, wherein the first pharmaceutically acceptable material or the second pharmaceutically acceptable material comprises a drug.

[0184] Embodiment 81. The method of embodiment 80, wherein the pharmaceutical dosage form has a desired drug release profile.

[0185] Embodiment 82. The method of any one of embodiments 78-81, comprising receiving an instruction to manufacture a pharmaceutical dosage form.

[0186] Embodiment 83. The method of any one of embodiments 76 to 82, comprising monitoring the pressure of the first material in or near the first nozzle, or monitoring the pressure of the second material in or near the second nozzle.

[0187] Embodiment 84. The method of any one of embodiments 76 to 83, wherein the pressure of the first material in the first nozzle or the pressure of the second material in the second nozzle remains approximately constant.

[0188] Embodiment 85. The method of any one of embodiments 76 to 84, comprising controlling the pressure of the first material or the second material using a feedback system based on the monitored pressure.

[0189] Embodiment 86. The method of any one of embodiments 76 to 85, wherein the first material or the second material is non-fibrous.

[0190] Embodiment 87. The method of any one of embodiments 76 to 86, wherein any portion of the first sealing needle that contacts the first material or any portion of the second sealing needle that contacts the second material does not include a protrusion.

[0191] Embodiment 88. The method of any one of embodiments 76 to 87, wherein the temperature of the first material in the first nozzle or the temperature of the second material in the second nozzle remains approximately constant.

[0192] Embodiment 89. The method of any one of embodiments 76 to 88, comprising monitoring the temperature of the first material or the temperature of the second material.

[0193] Embodiment 90. The method of embodiment 89, comprising controlling the temperature of the first material using a feedback system based on the monitored temperature of the first material, or controlling the temperature of the second material using a feedback system based on the monitored temperature of the second material.

[0194] Embodiment 91. The method of any one of embodiments 76 to 90, comprising withdrawing the tapered end of the second sealing needle to a selected opening distance.

[0195] Embodiment 92. The method of any one of embodiments 76 to 91, wherein the tapered end of the first seal needle or the tapered end of the second seal needle comprises a sharp tip.

[0196] Embodiment 93. The method of any one of embodiments 76 to 91, wherein the tapered end of the first sealing needle or the tapered end of the second sealing needle is frustoconical.

[0197] 94. the tapered inner surface of the first nozzle has a first taper angle and the tapered end of the first sealing needle has a second taper angle, the second taper angle being less than or equal to the first taper angle; or 94. The method of any one of embodiments 76-93, wherein the tapered inner surface of the second nozzle has a third taper angle and the tapered end of the second sealing needle has a fourth taper angle, the fourth taper angle being less than or equal to the third taper angle.

[0198] Embodiment 95. The method of embodiment 94, wherein the second taper angle or the fourth taper angle is less than or equal to about 60°.

[0199] Embodiment 96. The method of embodiment 94 or 95, wherein the second taper angle or the fourth taper angle is less than or equal to about 45°.

[0200] Embodiment 97. The method of any one of embodiments 94 to 96, wherein the ratio of the first taper angle to the second taper angle, or the ratio of the third taper angle to the fourth taper angle, is from about 1:1 to about 4:1.

[0201] Embodiment 98. The method of any one of embodiments 76 to 97, wherein the first extrusion port or the second extrusion port has a diameter of about 0.1 mm to about 1 mm.

[0202] Embodiment 99. The method of any one of embodiments 76 to 98, wherein the tapered end of the first sealing needle or the tapered end of the second sealing needle has a maximum diameter of about 0.2 to about 3.0 mm.

[0203] Embodiment 100. The method of any one of embodiments 76 to 99, wherein the first material or the second material has a viscosity of about 100 Pa·s or greater.

[0204] Embodiment 101. The method of any one of embodiments 52 to 100, wherein the product or pharmaceutical dosage form is manufactured in batch mode.

[0205] Embodiment 102. The method of any one of embodiments 52 to 100, wherein the product or pharmaceutical dosage form is manufactured in a continuous mode.

[0206] Embodiment 103. A product or pharmaceutical dosage form made according to the method of any one of embodiments 52 to 102. Example Example 1

[0207] The precision of a device substantially as described herein and shown in Figures 2A-2B and 5A-5C was measured using a material containing 80.75% Kollidon® VA64, 14.25% triethyl citrate (TEC), and 5% drug loaded into the barrel of the device. The material was heated to 110°C in the barrel, 110°C in the feed channel, and 135°C in the print head. The print head included a stainless steel nozzle with a 0.4 mm extrusion port. The material was pressurized to the desired pressure of 0.5 MPa (±0.02 MPa) using a piston inserted into the barrel, controlled by a pressure controller in response to the pressure detected by a pressure sensor. The sealing needle was positioned in the open position for 2.50 seconds, 3.33 seconds, or 5 seconds, and the mass of material extruded through the extrusion port was measured. The results are shown in Table 1. [Table 1] Example 2

[0208] The precision of a device substantially as described herein and shown in Figures 2A-2B and 5A-5C was measured using a material containing 79.68% HPC, 19.92% triethyl citrate (TEC), and 0.4% drug loaded into the barrel of the device. The material was heated to 90°C in the barrel, 110°C in the feed channel, and 120°C in the print head. The print head included a stainless steel nozzle with a 0.3 mm extrusion port. The material was pressurized to the desired pressure of 1.2 MPa (±0.05 MPa) using a piston inserted into the barrel, controlled by a pressure controller in response to the pressure detected by the pressure sensor. The sealing needle was positioned in the open position for 1.25 seconds, 2.5 seconds, or 5 seconds, and the mass of material extruded through the extrusion port was measured. The results are shown in Table 2. [Table 2] Example 3

[0209] The precision of a device substantially as described herein and shown in FIGS. 2A-2B and 5A-5C was measured using a material containing 100% Eudragit® RSPO loaded into the barrel of the device. The material was heated to 140°C in the barrel, 140°C in the feed channel, and 165°C in the print head. The print head included a stainless steel nozzle with a 0.3 mm extrusion port. The material was pressurized to the desired pressure of 1.2 MPa (±0.05 MPa) using a piston inserted into the barrel, controlled by a pressure controller in response to the pressure detected by a pressure sensor. The sealing needle was positioned in the open position for 1.67 seconds, 4 seconds, or 7 seconds, and the mass of material extruded through the extrusion port was measured. The results are shown in Table 3. [Table 3]

[0210] Although the embodiments of the present disclosure have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will be apparent to those skilled in the art, and such changes and modifications are to be understood as being included within the scope of the embodiments of the present disclosure, as defined by the appended claims.

Claims

1. A method for producing a pharmaceutical product by additive manufacturing, comprising: Melting and pressurizing the material; flowing the material through an extrusion port of a nozzle including a tapered inner surface; engaging a tapered end of a sealing needle with the tapered inner surface of the nozzle, thereby sealing the extrusion port and stopping the flow of the molten material; withdrawing the tapered end of the sealing needle, thereby resuming the flow of material through the extrusion port; heating the material in a print head including the nozzle using one or more heaters, wherein a material supply system includes a barrel and a supply channel connecting the barrel to the print head; heating the material in the barrel, the material being heated in the print head to a temperature greater than the temperature of the material heated in the barrel; A method comprising:

2. The method of claim 1, comprising receiving instructions to manufacture the pharmaceutical product.

3. The method of claim 1, wherein the pharmaceutical product is a pharmaceutical dosage form and the material is a pharmaceutically acceptable material.

4. The method of claim 3, wherein the pharmaceutically acceptable material comprises a drug.

5. The method of claim 4, wherein the pharmaceutical dosage form has a desired drug release profile.

6. The method of claim 3, comprising receiving instructions to manufacture the pharmaceutical dosage form.

7. The method of claim 3, wherein the tapered end of the sealing needle is withdrawn to a selected opening distance between a maximum open position and a closed position.

8. The method of claim 3, wherein the tapered end of the sealing needle includes a truncated conical tip.

9. The method of claim 3, wherein the tapered end of the sealing needle includes a pointed tip.

10. The method described in claim 3, wherein the material has a viscosity of 100 Pa·s or more when extruded from the extrusion port.

11. The method of claim 3, wherein the sealing needle is operable in an open position between a maximum open position and a closed position.

12. A method for producing a pharmaceutical product by additive manufacturing, comprising: Melting and pressurizing a first material; flowing the first material through a first extrusion port of a first nozzle including a tapered inner surface; engaging a tapered end of a first sealing needle, thereby sealing the first extrusion port and stopping the flow of the molten first material; Melting and pressurizing a second material; withdrawing the tapered end of the second sealing needle, thereby initiating flow of said second material through the second extrusion port; A method comprising:

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