A precise pharmaceutical three-dimensional printing device

Abstract

Apparatuses and systems for depositing materials or manufacturing products, such as pharmaceutical dosage forms, by additive manufacturing are provided. Methods of using the apparatuses and systems, as well as methods of manufacturing products, such as pharmaceutical dosage forms, by additive manufacturing are also provided. In certain embodiments, the apparatuses include a material supply system (102) configured to melt and pressurize a material, a pressure sensor (214) configured to detect a pressure of the material within the apparatus, and a control switch (216) including a sealing needle (218) operable between an open position and a closed position. The sealing needle (218) extends through a feed channel (208) containing the material and includes a tapered end (224), wherein the tapered end (224) of the sealing needle (218) engages a tapered inner surface of a nozzle (212) to prevent the material from flowing through the nozzle (212) when the sealing needle (218) is in the closed position.

Description

[0001] This application is a divisional application of the invention patent application filed on January 7, 2019, with application number 201980007693.8 and invention title "A Precision Drug 3D Printing Device".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Patent Application No. 16 / 233,831, filed December 27, 2018; is a divisional application of U.S. Patent Application No. 15 / 937,528, filed March 27, 2018, and claims priority thereto; and the entire contents of PCT / CN2018 / 071965, filed January 9, 2018, entitled “PRECISION PHARMACEUTICAL 3DPRINTING DEVICE,” filed under section 365(a) of 35 U.S.SC International PCT, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0004] This invention relates to a system and apparatus for additive manufacturing, and a method of using such an apparatus. In particular, it relates to a method of producing products (e.g., pharmaceutical dosage forms) via additive manufacturing. Background Technology

[0005] Additive manufacturing, also known as 3D printing, allows computer models to be shaped by extruding molten material. A computer system controls the 3D printer and the flow of material and the movement of the print nozzles until the desired shape is formed. In filament deposition modeling (also known as fused deposition modeling), material is extruded in filament form into a heated head that melts and shapes the material onto a surface. The surface or the heated head can be moved to extrude the molten material into a shape set by the computer system. Other additive manufacturing methods use non-linear materials, which are melted and pressurized, and then extruded through a print nozzle; however, these methods often result in undesirable leakage from the print nozzle, especially when the molten material is viscous.

[0006] Recent developments in additive manufacturing have allowed for the use of a wide variety of 3D printing processes and materials. For example, bio-inert materials can be used in additive manufacturing processes to produce 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 developing additive manufacturing technologies for pharmaceutical manufacturing. 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).

[0007] However, current additive manufacturing technologies are limited by the precision of material extrusion in 3D printers. Pharmaceuticals require careful control to ensure consistent product shape and precise drug dosage. The development of precise systems for additive manufacturing processes, including those for pharmaceuticals, remains necessary.

[0008] All publicly available publications, patents, patent applications, and published patent applications are incorporated herein by reference. Summary of the Invention

[0009] The present invention provides an apparatus for depositing material by additive manufacturing, comprising: a feed module for melting and applying pressure, the feed module including a feed channel connected to a printhead, the printhead including a nozzle including a tapered inner surface and an extrusion orifice for printing material; a pressure sensor for detecting pressure of material within or near the nozzle in the feed channel; and a control switch including a sealing pin switchable between an open position and a closed position, the sealing pin extending through a portion of the feed channel and including a tapered end; wherein the tapered end of the sealing pin engages with the tapered inner surface of the nozzle to prevent material from flowing through the nozzle when the sealing pin is in the closed position.

[0010] In some embodiments, the material is non-wire. In some embodiments, the material has a viscosity of about 100 Pa·s or higher when extruded from the apparatus. In some embodiments, the material has a viscosity of about 400 Pa·s or higher when extruded from the apparatus. In some embodiments, the material melts at a temperature of about 50°C to 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 300°C.

[0011] In some embodiments, no portion of the sealing needle in contact with the material has a protrusion.

[0012] In some embodiments, a pressure sensor is connected to a computer system controlling the feeding module to respond to pressure reported by the pressure sensor and to pressurize the material to the desired pressure. In some embodiments, the material pressure is within 0.05 MPa of the desired pressure. In some embodiments, the feeding module includes a piston and a cylinder connected to the feed channel, wherein the piston is driven to control the pressure of the material within the cylinder. In some embodiments, a stepper motor is used to drive the piston. In some embodiments, the pressure sensor is located near the nozzle.

[0013] In some embodiments, the tapered end of the sealing needle includes a pointed tip. In some embodiments, the tapered end of the sealing needle is a truncated cone. In some embodiments, the inner tapered surface of the nozzle has a first cone angle and the tapered end of the sealing needle has a second cone angle; and the second cone angle is the same as or smaller than the first cone angle. In some embodiments, the second cone angle is about 60° or less. In some embodiments, the second cone angle is about 45° or less. In some embodiments, the ratio of the first cone angle to the second cone angle is about 1:1 to 4:1.

[0014] In some embodiments, the extrusion orifice has a diameter of about 0.1 mm to 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 orifice 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 orifice is about 1:0.8 to about 1:0.1.

[0015] In some embodiments, the control switch includes an actuator that can position the sealing pin 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 actuator. In some embodiments, the electric actuator is a linear stepper electric actuator.

[0016] In some embodiments, a sealing needle passes through a gasket fixed at a position relative to the nozzle, wherein the gasket closes the feed channel.

[0017] In some embodiments, the feeding module includes one or more heaters for melting material. In some embodiments, the feeding module includes one or more temperature sensors for detecting the temperature of the molten material. In some embodiments, the one or more temperature sensors are connected to a computer system that controls one or more heaters based on the temperature monitored by the one or more temperature sensors.

[0018] In some embodiments, the tapered end of the sealing needle or the tapered inner surface of the nozzle includes a flexible pad or bushing.

[0019] In some embodiments, the apparatus further includes a computer system comprising one or more processors and a computer-readable storage device, wherein the computer system is used to control the apparatus. In some embodiments, the computer-readable storage device stores instructions for controlling the apparatus to print products. In some embodiments, the computer-readable storage device stores instructions for controlling material pressure in response to pressure detected by a pressure sensor. In some embodiments, the computer-readable storage device stores instructions for controlling material temperature in response to temperature detected by a temperature sensor. In some embodiments, the computer-readable storage device includes instructions for positioning a sealing needle based on instructions for printing products. 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 the extruded material.

[0020] In some embodiments, the additive manufacturing system includes a plurality of the aforementioned devices, wherein each feed module is configured with a control switch. In some embodiments, the system includes a first device among the plurality of devices loaded with a first material and a second device among the plurality of devices loaded with a second material, wherein the first material and the second material are different. In some embodiments, the control switch of each of the plurality of devices is different. In some embodiments, the control switch of each of 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 storage device, wherein the computer system is used to control the system. In some embodiments, the computer-readable storage device stores instructions for printing a product using the system. In some embodiments, the computer-readable storage device stores instructions for controlling the pressure of the material in each feed module in response to pressure detected by a pressure sensor in the respective feed module. In some embodiments, the computer-readable storage device stores instructions for controlling the temperature of the material in each feed module in response to temperature detected by a temperature sensor in the respective feed module. In some embodiments, the computer-readable storage device includes instructions for positioning a sealing needle based on instructions for printing a 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 the extruded material. In some embodiments, at least two of the plurality of devices include: a material supply system configured to melt and pressurize material, comprising a feed channel connected to a nozzle printhead including a tapered inner surface and an extrusion orifice configured to dispense material; a pressure sensor configured to detect material pressure within or near the nozzle in the feed channel; and a control switch including a sealing pin switchable to an open position and a closed position, the sealing pin extending through a portion of the feed channel and including a tapered end. The tapered end of the sealing pin engages with the tapered inner surface of the nozzle to prevent material from flowing through the nozzle when the sealing pin is in the closed position. In some embodiments, the tapered inner surface of the nozzle has a first cone angle, and the tapered end of the sealing pin has a second cone angle. The second cone angle is equal to or less than the first cone angle. In some embodiments, the pressure sensor is located near the nozzle.

[0021] On the other hand, the present invention provides a method for producing a product using additive manufacturing, comprising: melting a material and pressurizing the material; flowing the material through an extrusion nozzle, the nozzle including a conical inner surface; monitoring the pressure of the material at or near the nozzle; engaging a conical end of a sealing needle with the conical inner surface of the nozzle to close the extrusion orifice and prevent the flow of molten material; and retracting the conical end of the sealing needle to restore the flow of material through the extrusion orifice. In some embodiments, the method includes receiving instructions for manufacturing the product.

[0022] On the other hand, the present invention provides a method for producing a pharmaceutical dosage form by additive manufacturing, comprising: melting and pressurizing a pharmaceutical material; monitoring the pressure of the material in or near a nozzle; allowing the material to flow through an extrusion orifice of the nozzle, the nozzle including a conical inner surface; engaging a conical end of a sealing needle with the conical inner surface of the nozzle to close the extrusion orifice and prevent the flow of molten material; and retracting the conical end of the sealing needle to restore the flow of material through the extrusion orifice. In some embodiments, the pharmaceutically acceptable material comprises a drug. In some embodiments, the pharmaceutical dosage form has a target release profile of the drug. In some embodiments, the method includes receiving instructions for manufacturing the pharmaceutical dosage form.

[0023] In some embodiments of the method described above, the pressure of the material within the nozzle remains approximately constant. In some embodiments, the method uses a feedback system to control the pressure of the material based on the monitored pressure.

[0024] In some embodiments of the above method, the material is non-wire. In some embodiments, the material has a viscosity of about 100 Pa·s or higher.

[0025] In some embodiments of the above method, no part of the sealing needle in contact with the material has a protrusion.

[0026] In some embodiments of the above method, the temperature of the material within the nozzle is kept approximately constant. In some embodiments, the method includes monitoring the temperature of the material. In some embodiments, the method includes using a feedback system to control the temperature of the material based on the monitored temperature.

[0027] In some embodiments of the above method, the conical end of the sealing needle is retracted to a set opening distance.

[0028] 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 a truncated cone. In some embodiments, the inner tapered surface of the nozzle has a first cone angle and the tapered end of the sealing needle has a second cone angle; wherein the second cone angle is equal to or less than the first cone angle. In some embodiments, the second cone angle is about 60° or less. In some embodiments, the second cone angle is about 45° or less. In some embodiments, the ratio of the first cone angle to the second cone angle is about 1:1 to 4:1. In some embodiments, the extrusion orifice has a diameter of about 0.1 mm to 1 mm. In some embodiments, the tapered end has a maximum diameter of about 0.2 to about 3.0 mm. In some embodiments, the extrusion orifice has a diameter and the tapered end has a maximum diameter, and the ratio of the maximum diameter of the tapered end to the diameter of the extrusion orifice is about 1:0.8 to about 1:0.1.

[0029] On the other hand, a method for manufacturing a product by additive manufacturing is provided, comprising: melting and pressurizing a first material; causing the first material to flow 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 to close the first extrusion port and prevent the flow of the molten first material; melting and pressurizing a second material; and withdrawing a tapered end of a second sealing needle from the tapered inner surface of a second nozzle to initiate the flow of the second material through a second extrusion port. In some embodiments, the method includes receiving instructions for manufacturing the product.

[0030] On the other hand, a method for producing a pharmaceutical dosage form by additive manufacturing is provided, comprising: melting and pressurizing a first pharmaceutical material; flowing the first pharmaceutical material through a first extrusion port of a first nozzle including a conical inner surface; engaging a conical end of a first sealing needle with the conical inner surface of the first nozzle to seal the first extrusion port and prevent the flow of the molten first pharmaceutical material; melting and pressurizing a second pharmaceutical material; and withdrawing a conical end of a second sealing needle from the conical inner surface of a second nozzle to allow the second pharmaceutical material to flow through a second extrusion port. In some embodiments, the first pharmaceutical material or the second pharmaceutical material is a soluble material. In some embodiments, the first pharmaceutical material or the second pharmaceutical material contains a drug. In some embodiments, the pharmaceutical dosage form has a specified drug release profile. In some embodiments, the method further includes receiving control instructions for manufacturing the pharmaceutical dosage form.

[0031] In some embodiments of the above method, the method further includes monitoring the pressure of a first material in or near a first nozzle; or monitoring the pressure of a second material in or near a 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 approximately constant. In some embodiments, the method includes using a feedback system to control the pressure of the first material or the second material based on the monitored pressure.

[0032] In some embodiments of the above method, the first material or the second material is a non-wire material.

[0033] In some embodiments of the above method, no part of the first sealing needle that contacts the first material or any part of the second sealing needle that contacts the second material has a protrusion.

[0034] 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 approximately 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 using a feedback system to control the temperature of the first material based on the monitored temperature, or using a feedback system to control the temperature of the second material based on the monitored temperature.

[0035] In some embodiments of the above method, the conical end of the second sealing needle is retracted to a set opening distance.

[0036] In some embodiments of the above method, the tapered end of the first sealing needle or the tapered end of the second sealing needle includes a pointed tip. In some embodiments of the above method, the tapered end of the first sealing needle or the tapered end of the second sealing needle is a truncated cone shape.

[0037] In some embodiments of the above method, the conical inner surface of the first nozzle has a first cone angle and the conical end of the first sealing needle has a second cone angle; wherein the second cone angle is equal to or less than the first cone angle; or the conical inner surface of the second nozzle has a third cone angle and the conical end of the second sealing needle has a fourth cone angle; wherein the fourth cone angle is equal to or less than the third cone angle. In some embodiments, the fourth cone angle is about 60° or less. In some embodiments of the above method, the second cone angle or the fourth cone angle is about 45° or less. In some embodiments of the above method, the ratio of the first cone angle to the second cone angle or the ratio of the third cone angle to the fourth cone angle is about 1:1 to about 4:1. In some embodiments of the above method, the first extrusion port or the second extrusion port has a diameter of about 0.1 mm to about 1 mm. In some embodiments of the above method, the conical end of the first sealing needle or the conical end of the second sealing needle has a maximum diameter of about 0.2 mm to about 3.0 mm.

[0038] In some embodiments of the above method, the first or second material has a viscosity of about 100 Pa·s or higher.

[0039] In some embodiments of the above methods, the product or drug dosage form is manufactured in a batch mode. In some embodiments of the above methods, the product or drug dosage form is manufactured in a continuous mode.

[0040] The present invention also provides products or pharmaceutical dosage forms prepared according to any of the above methods. Attached Figure Description

[0041] Figure 1 An exemplary embodiment of the apparatus of the present invention for printing materials by additive manufacturing is shown.

[0042] Figure 2A A cross-sectional view of an exemplary apparatus for additive manufacturing of printed materials according to the present invention is shown. Figure 2B It shows Figure 1 An enlarged view of the printhead of the device shown. Figure 2A As shown, the sealing needle is in the closed position and engages with the inner surface of the nozzle. Although Figure 2AA pneumatic actuator is shown, but an electric actuator (e.g., a linear stepper motor actuator) can also be used. An electric actuator can position the sealing pin in an open position between a closed position and a maximum open position, such as a position with a selected opening distance.

[0043] Figure 3A The tapered end of the sealing needle with a pointed tip is shown. Figure 3B The tapered end of a sealing needle with a truncated conical tip is shown. Figure 3C The cone shape of the inner surface of the nozzle is shown.

[0044] Figure 4 An exploded view of the sealing needle and the components of the pneumatic actuator connected to the sealing needle to drive it is shown.

[0045] Figure 5A A longitudinal cross-sectional view of an exemplary device is shown. Figure 5B A cross-sectional view of an exemplary device at plane “AA” is shown. Figure 5C A side view of an exemplary device is shown. Although Figures 5A-5C A pneumatic actuator is shown, but an electric actuator (e.g., a linear stepper motor actuator) can be used. The electric actuator can position the sealing pin in an open position between a closed position and a maximum open position, such as a position with a selected opening distance.

[0046] Figure 6 Another exemplary embodiment of the device described in this invention is shown.

[0047] Figure 7 A portion of an exemplary apparatus is shown, comprising three feeding modules, each with a different printhead. Detailed Implementation

[0048] This application relates to an apparatus for depositing materials via additive manufacturing. The apparatus includes a feed module for melting and pressurizing materials, which may selectively contain a drug. In some embodiments, the material is a non-linear material. The feed module includes a feed channel connected to a nozzle. The material may be pressurized and / or melted in or upstream of the feed channel, the molten material flowing through the feed channel and being printed through the nozzle. The invention further provides a system for manufacturing products via additive manufacturing, comprising two or more devices, each device including a feed module and a control switch. The invention also describes methods for using such an apparatus, methods for producing products via additive manufacturing, and methods for producing drug dosage forms via additive manufacturing.

[0049] When manufacturing products, especially pharmaceutical products, precise control of the amount of material printed by the nozzle is desirable. A significant problem with existing additive manufacturing apparatuses is the unintended leakage of material through the nozzle, which can result in printing more material than required. This problem becomes more complex when using two or more nozzles, which may print different materials, requiring alternating on / off switching. For example, if the first nozzle leaks the first material while the second nozzle is printing the second material, manufacturing defects or material waste can occur. Because the apparatus and systems described in this invention can handle a range of pharmaceutical materials with high accuracy and precision material deposition, they are well-suited for manufacturing pharmaceutical dosage forms with complex geometries and compositions. The apparatus, systems, and methods described in this invention also facilitate personalized medicine, including personalized dosing and / or personalized release profiling. Personalized medicine refers to the stratification of patient populations based on biomarkers to aid in treatment decisions and personalized dosage form design. Personalized drug formulations allow for adjustments to drug dosages and release profiles based on a patient's physiology and metabolism. Pharmaceutical dosage forms manufactured using the apparatus described in this invention can ensure accurate dosing for children's growth and allow for personalized dosing of highly effective drugs. Personalized dosage forms can also combine medications for all patients into a single daily dose, thereby improving patient adherence to medication and treatment. Modifying digital designs is easier than modifying physical equipment. Furthermore, automated, small-scale 3D printing may have negligible operating costs. Therefore, the additive manufacturing apparatus described in this invention makes multiple small, personalized batches economically feasible and enables personalized dosage forms designed to improve adherence.

[0050] In some embodiments, a custom drug dosage form design with a specific release profile is received by a computer system that controls the apparatus or system described herein. The computer system can transmit instructions for manufacturing a drug dosage form with a specific release profile to the system or device, which then manufactures the custom product. In some embodiments, the computer-readable storage includes instructions for controlling a control switch. In some embodiments, the control switch includes an electric actuator for positioning a sealing needle, and the computer-readable storage includes instructions for controlling the electric actuator to position the sealing needle in an open position (including a plurality of open positions with different distances between the tip of the sealing needle and the nozzle outlet, up to a maximum open position) and a closed position.

[0051] This invention provides a more precise system for additive manufacturing of materials or products (e.g., pharmaceutical dosage forms) by precisely controlling the pressure in a nozzle or feed channel near 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 the closed position. For example, the pneumatic actuator of the control switch can adjust the sealing needle between an open position (e.g., the maximum open position or any position between the end of the sealing needle and the nozzle extrusion port, allowing material to flow from the nozzle extrusion port) and a closed position. When the control switch uses an actuator (e.g., a linear stepper motor actuator) that allows a variety of open positions (compared to a maximum open / close dual-position switch), the amount and / or speed of material extrusion can be adjusted by regulating the distance between the position of the tapered end of the sealing needle (e.g., the tip of the tapered end) in the open position and when the sealing needle is in the closed position, completely sealing the nozzle outlet; this distance can be referred to as the "open distance". By controlling the amount and / or speed of material extrusion, the system can better synchronize printing speeds. For example, for detailed portions of a tablet, the printing speed can be slowed down and the amount of material extruded can be reduced. For tablet portions that don't require high precision, both printing speed and material extrusion rate can be increased. This can be achieved by increasing the opening distance of the sealing needle, switching to a larger diameter nozzle, or using a filling system. 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 material leakage. The sealing needle is preferably sharp, thin, and without protrusions that could push material out of the nozzle when in the closed position. The material pressure is preferably kept approximately constant within the device, and this pressure can be controlled by monitoring the pressure and applying pressure to the material using a feedback system. This allows material to be extruded immediately at a constant rate once the sealing needle is positioned in the open position without needing to increase the pressure. This further enables precise printing of the material, allowing for accurate and precise manufacture of drug dosage units, such as tablets.

[0052] In some embodiments, the present invention provides an apparatus for depositing materials or manufacturing products (e.g., pharmaceutical dosage forms) by additive manufacturing, comprising: a feed module for melting and pressurizing materials, the feed module including a feed channel and a printhead, the feed channel being connected to the printhead, the printhead including a nozzle having a tapered inner surface and an extrusion orifice for printing the material; a pressure sensor for detecting pressure of the material within the feed channel or near the printhead; and a control switch including a sealing pin switchable between an open position and a closed position, the sealing pin extending through a portion of the feed channel and including a tapered end; wherein the tapered end of the sealing pin engages with the tapered inner surface of the nozzle to prevent material from flowing through the nozzle when the sealing pin is in the closed position. The open position may have a selected opening distance from the extrusion orifice.

[0053] Figure 1 An exemplary embodiment of an apparatus for depositing materials or manufacturing products by additive manufacturing, provided by the present invention, is shown. The apparatus includes a feed module 102 for melting and pressurizing materials. The molten and pressurized materials flow through a feed channel connected to a nozzle 104. A pressure sensor 106 is located near the end of the nozzle and the feed channel and can detect the pressure of the material within the feed channel. Optionally, the pressure sensor 106 may be designed to directly detect the pressure of the material within the nozzle 104. A control switch 108 includes a linear actuator and a sealing needle, which can control the sealing needle to switch between an open position and a closed position. The linear actuator may be a mechanical actuator (which may include a lead screw), a hydraulic actuator, a pneumatic actuator (which may include a pneumatic valve), or an electromagnetic actuator (which may include a solenoid valve). In some embodiments, the actuator includes a syringe, such as a pneumatic syringe. In some embodiments, the actuator includes a spring-assisted cylinder. In some embodiments, the spring-assisted cylinder includes a spring that assists in the actuation of the sealing needle (i.e., pulls the sealing needle from an open position (e.g., a fully open position) to a closed position). In some embodiments, the spring-assisted cylinder includes a spring that assists in retracting the sealing pin (i.e., pulling the sealing pin from a closed position to an open position (e.g., the maximum open position)). When the sealing pin is in the open position, pressurized molten material can flow through the feed channel and through the extrusion orifice of nozzle 104. The flow rate and / or velocity of the material through the extrusion orifice can be adjusted by adjusting the opening distance of the sealing pin. When a signal is given to control switch 108, for example, according to a computer-readable stored instruction, control switch 108 lowers the sealing pin to the closed position, and the end of the sealing pin engages with the inner surface of nozzle 104.

[0054] In some embodiments, the material is a nonlinear material, such as a powder, granules, gel, or paste. The nonlinear material is melted and pressurized so that it can be extruded through the extrusion orifice of a nozzle. Further described herein, the pressure of particularly viscous materials is precisely controlled to ensure that the material can be deposited accurately and precisely. The material can be heated and melted within the feed module using one or more heaters arranged within the feed module (e.g., inside or around the barrel, feed channel, and / or printhead). 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 lower, such as about 350°C or lower, about 300°C or lower, about 260°C or lower, about 200°C or lower, about 150°C or lower, about 100°C or lower, or about 80°C or lower. Material extruded from the nozzle may be extruded at a temperature equal to or higher than the material's melting temperature. In some embodiments, the material is extruded at a temperature of 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 material is extruded at a temperature of about 400°C or lower, such as about 350°C or lower, about 300°C or lower, about 260°C or lower, about 200°C or lower, about 150°C or lower, about 100°C or lower, or about 80°C or lower.

[0055] The apparatus described in this invention can be used to accurately and precisely extrude viscous materials. In some embodiments, when extruded from the apparatus, the material viscosity has about 100 Pa·s or greater, for example, 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 viscosity has about 2000 Pa·s or less, for example, 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.

[0056] In some embodiments, the material is a pharmaceutical material. In some embodiments, the material is inert or bio-inert. In some embodiments, the material is a soluble or biosoluble material. In some embodiments, the material is an insoluble or non-biosoluble material. In some embodiments, the material is a pharmaceutical 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.

[0057] In some embodiments, the material comprises a thermoplastic material. In some embodiments, the material is a thermoplastic material. In some embodiments, the material is or comprises a soluble thermoplastic material. In some embodiments, the thermoplastic material is edible (i.e., suitable for individual digestion and absorption). In some embodiments, the thermoplastic material is selected from hydrophilic polymers, hydrophobic polymers, swelling polymers, non-swelling polymers, porous polymers, non-porous polymers, soluble polymers (e.g., soluble polymers), pH-sensitive polymers, natural polymers, waxy materials, and combinations thereof.In some embodiments, the thermoplastic material is a cellulose ether, cellulose ester, acrylic resin, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, monoglycerides or diglycerides of C12-C30 fatty acids, C12-C30 fatty alcohols, waxes, poly(meth)acrylic acid, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, vinylpyrrolidone-vinyl acetate copolymer (PVP-VA), vinylpyrrolidone-vinyl acetate copolymer (PVP-VA) 60 / 40, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80 / 20, vinylpyrrolidone-vinyl acetate copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer 25 / 75, kollicoat IR-Polyvinyl alcohol 60 / 40, Polyvinyl alcohol (PVA or PV-OH), Poly(vinyl acetate) (PVAc), Butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer 1:2:1, Dimethylaminoethyl methacrylate-methyl methacrylate copolymer, Ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymer, Methyl methacrylate-methyl methacrylate-methyl methacrylate copolymer 7:3:1, Methacrylate-methyl methacrylate copolymer 1:2, Methacrylate-ethyl acrylate copolymer 1:1, Polyethylene oxide (PEO), Polyethylene glycol (PEG), Hyperbranched polyesteramide, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methylcellulose or hydroxypropyl methylcellulose (HMPC), Hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose succinate (HPMCAS) Plylide-glycolic acid copolymer (PLGA), carbomer, ethylene-vinyl acetate copolymer, polyethylene (PE) and polycaprolactone (PCL), hydroxypropyl cellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil, hydrogenated soybean oil, glyceryl palmitate stearate, 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 aminolactic acid ester (AEA), paraffin wax, shellac, sodium alginate, cellulose acetate phthalate (CAP), gum arabic, xanthan gum, glyceryl monostearate, octadecanoic acid, thermoplastic starch, and one or a combination thereof (e.g., its salts, amides or esters).

[0058] In some embodiments, the soluble material comprises a non-thermoplastic material. In some embodiments, the soluble material is a non-thermoplastic material. In some embodiments, the non-thermoplastic material is non-thermoplastic starch, sodium glycolate starch (CMS-Na), sucrose, dextrin, lactose, microcrystalline cellulose (MCC), mannitol, magnesium stearate (MS), powdered silica gel, glycerin, syrup, lecithin, soybean oil, tea oil, ethanol, propylene glycol, glycerin, Tween, animal fat, silicone oil, cocoa butter, fatty acid glycerides, petrolatum, chitosan, cetyl alcohol, stearyl alcohol, polymethyl methacrylate, non-toxic polyvinyl chloride, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, or combinations thereof.

[0059] Exemplary materials that can be used with the apparatus or methods described herein include, but are not limited to, poly(meth)acrylate copolymers (e.g., containing one or more aminoalkyl methacrylates, methacrylates, methacrylates and / or ammonium alkyl methacrylates, for example, under a trademark). RSPO sells copolymers and hydroxypropyl cellulose (HPC).

[0060] In some embodiments, the material comprises a drug. In some embodiments, the material is mixed with a drug.

[0061] In a material control system, a pressure controller can be used to pressurize the material. The material is pre-loaded into a barrel, and the pressure controller can apply pressure to the material pre-loaded in the barrel. The pressure controller can be an electric motor (e.g., a stepper motor), a valve, or any other suitable control device that drives a mechanism such as a piston, pressure screw, or compressed air (i.e., a pneumatic controller) to apply pressure to the material within the barrel. The barrel includes one or more heaters that can melt the material. In some embodiments, the heaters are disposed within the barrel. In some embodiments, the heaters are disposed on the side of the barrel or surrounding the barrel. In some embodiments, the heaters are radiant electric heaters, such as electric heating tubes or heating coils. The barrel heaters are preferably high-efficiency heaters with high voltage and high power output. In some embodiments, the barrel heaters have a rated voltage between 110V and 600V. In some embodiments, the barrel heaters have a rated voltage between 210V and 240V. In some embodiments, the barrel heaters are 220V heaters. In some embodiments, the power of the barrel heater is between about 30W and about 100W, for example between 40W and 80W, or about 60W. In some embodiments, the heater is an electric heating coil surrounding the outside of the barrel. Preferably, the barrel is made of a heat-resistant material, such as stainless steel (e.g., 316L stainless steel).

[0062] The feeding module includes a feeding channel connecting a barrel and a nozzle within the printhead. Material is melted or softened within the barrel, flows through the feeding channel, and proceeds to the nozzle. In some embodiments, one or more heaters are located inside, around, or near the feeding channel or a portion of the feeding channel (e.g., a lateral portion of the feeding channel). One or more heaters are used to heat the material within the feeding channel. In some embodiments, the heaters are radiant electric heaters, such as electric heating tubes or coils. For example, in some embodiments, the electric heating tubes are positioned along the length of the feeding channel or at least a portion of the length of the feeding channel. The heaters are preferably high-efficiency heaters with high voltage and high power. In some embodiments, the feeding channel heater has a rated voltage between 110V and 600V. In some embodiments, the feeding channel heater has a rated voltage between 210V and 240V. In some embodiments, the feeding channel heater is a 220V heater. In some embodiments, the power of the feeding channel heater is between about 30W and about 100W, for example, between 40W and 80W, or about 60W. In some embodiments, the device includes one or more temperature sensors located near or within the feed channel for measuring the temperature of the material within the feed channel. The feed channel is relatively wide compared to the extrusion orifice of the nozzle. In some embodiments, the feed channel has a diameter between about 1 mm and about 15 mm, for example, between about 1 mm and about 5 mm, between about 5 mm and about 10 mm, or between about 10 mm and about 15 mm. In an exemplary embodiment, the feed channel has a diameter of about 8 mm.

[0063] The printhead of the device includes a nozzle with an extrusion orifice through which molten material is extruded. The extrusion orifice is located at the distal end of the nozzle relative to the feed channel. When the sealing pin is in the open position (including open positions with various opening distances, such as the maximum open position), molten material flows from the feed channel through the nozzle and out of the extrusion orifice. The nozzle includes a tapered inner surface, with the extrusion orifice near the apex of the tapered inner surface. In some embodiments, the inner surface of the nozzle includes a gasket or bushing. The gasket or bushing may be made of polytetrafluoroethylene (PTFE) or any other suitable material. In some embodiments, the printhead includes one or more heaters, which may be located within, around, or near the nozzle of the printhead. The one or more heaters are used to heat the material within the nozzle, which may reach 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 heating coil. The heater may use a lower voltage and / or lower power than the barrel heater or feed channel heater. In some embodiments, the nozzle heater has a rated voltage between 6V and 60V. In some embodiments, the nozzle heater is a 12V heater. In some embodiments, the power of the nozzle heater is between about 10W and about 60W, for example between 20W and 45W or about 30W. In some embodiments, the printhead includes one or more temperature sensors located near or inside the nozzle for measuring the temperature of the material inside the nozzle.

[0064] The device includes a pressure sensor for detecting the pressure of material within the printhead or feed channel near the printhead. In some embodiments, the pressure sensor is connected to a computer system that controls a feed module to pressurize the material to a specific pressure in response to the pressure reported by the pressure sensor. For example, the computer system may control a pressure controller to regulate the pressure value of the material applied within the barrel. In some embodiments, the system functions as a closed-loop feedback system to maintain an approximately constant pressure within the device. In some embodiments, the feedback system operates using proportional-integral-derivative (PID) control, bang-bang control, predictive control, fuzzy control, expert control, or any other suitable algorithm. In some embodiments, the pressure sensor has an accuracy within 0.005 MPa, 0.008 MPa, 0.05 MPa, 0.1 MPa, 0.2 MPa, 0.5 MPa, or 1 MPa. In some embodiments, the pressure sensor has a sampling time of approximately 20 ms or faster, such as approximately 10 ms or faster, approximately 5 ms or faster, or approximately 2 ms or faster. In some embodiments, the pressure of the material fluctuates 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.

[0065] In some embodiments, the device includes one or more temperature sensors. In some embodiments, the device includes a temperature sensor located inside or near the feed tube, or a temperature sensor for detecting the temperature inside the feed tube. In some embodiments, the device includes a temperature sensor located inside or near the feed channel, or a temperature sensor for detecting the temperature inside the feed channel. In some embodiments, the device includes a temperature sensor located inside or near the printhead, or a temperature sensor for detecting the temperature inside the nozzle. In some embodiments, one or more temperature sensors are connected to a computer system that controls one or more heaters based on the temperatures reported by the one or more temperature sensors. For example, the computer system may control one or more heaters to regulate the temperature of the material inside the barrel, feed channel, and / or nozzle. In some embodiments, the system operates as a closed-loop feedback system to maintain an approximately constant temperature of the device or device components (i.e., barrel, nozzle, or feed channel). The temperatures of the material inside different components of the device may be the same or different. In some embodiments, the feedback system uses proportional-integral-derivative (PID) control, bang-bang control, predictive controllers, fuzzy control systems, expert control, or any other suitable algorithm for control.

[0066] The device includes a control switch. The control switch can be controlled to prevent or allow molten material to flow out of the device's extrusion port. The control switch includes a sealing needle switchable between an open position (including open positions with various opening distances, such as a maximum open position) and a closed position, wherein when the sealing needle is in the closed position, material flow through the nozzle is prevented. 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 with the tapered inner surface of the nozzle (e.g., at the nozzle's extrusion port).

[0067] The “opening distance” of the sealing needle mentioned herein refers to the distance when the sealing needle is in the open position (hereinafter referred to as position d). x The distance between the position of the tapered end (e.g., the tip of the tapered end) when the sealing pin is in the closed position and the position of the tapered end when the sealing pin is in the closed position (D) open The sealing needle being in the closed position refers to the position where the nozzle extrusion port is completely sealed (hereinafter referred to as position d0), i.e., D. open =d x -d0. The movement or distance D of the sealing needle. open The amount and / or speed of material extruded from the nozzle can be adjusted by controlling an actuator (e.g., an electric actuator, such as a linear stepper motor actuator) within the control switch. This is achieved by measuring the amount of material extruded from the nozzle (e.g., average material extrusion rate, in mg) and the corresponding distance D. open(For example, in mm), the relationship between the opening distance of the sealing pin (x-axis) and the material extrusion amount (y-axis) is derived. In some embodiments, when the pressure of the material in or near the printhead feed channel is constant, the material extrusion amount (e.g., average amount) increases with the increase of the opening distance of the sealing pin; when the maximum material extrusion amount (e.g., average amount) is reached, the material extrusion amount (e.g., average amount) remains at a fairly stable value even with further increases in the sealing pin opening distance. In some embodiments, when the material pressure in or near the printhead feed channel is about 0.4 MPa, the opening distance of the sealing pin reaches the maximum material extrusion amount (e.g., average amount), at which point the opening distance of the sealing pin is about greater than 0.8 mm. In some embodiments, the relationship between the maximum material extrusion amount (e.g., average amount) and the opening distance of the sealing pin can be affected by factors such as the printing material, printing temperature, nozzle and / or sealing pin diameter, nozzle and / or sealing pin shape, nozzle and / or sealing pin material, material pressure, and sealing pin movement speed.

[0068] In some embodiments, the sealing pin may be positioned in an open position with an opening distance of up to approximately 5 mm, for example, up to approximately 4 mm, up to approximately 3 mm, up to approximately 2 mm, up to approximately 1.5 mm, up to approximately 1.4 mm, up to approximately 1.3 mm, up to approximately 1.2 mm, up to approximately 1.1 mm, up to approximately 1.0 mm, up to approximately 0.9 mm, up to approximately 0.8 mm, up to approximately 0.7 mm, up to approximately 0.6 mm, approximately 0.5 mm, approximately 0.4 mm, approximately 0.3 mm, approximately 0.2 mm, or approximately 0.1 mm. In some embodiments, the sealing pin may be positioned in an open position with an opening distance of approximately 0.1 mm to approximately 2.0 mm, approximately 0.2 mm to approximately 1.6 mm, approximately 0.4 mm to approximately 1.2 mm, or approximately 0.4 mm to approximately 1.0 mm. Approximately 0.4mm to approximately 0.9mm, approximately 0.4mm to approximately 0.8mm, approximately 0.4mm to approximately 0.7mm, approximately 0.4mm to approximately 0.6mm, approximately 0.7mm to approximately 1.1mm, approximately 0.7mm to approximately 1.0mm, approximately 0.7mm to approximately 0.9mm, approximately 0.5mm, approximately 0.6mm, approximately 0.7mm, approximately 0.8mm, approximately 0.9mm, approximately 1.0mm, approximately 1.1mm, approximately 1.2mm, approximately 0.89mm, approximately 0.88mm, approximately 0.87mm, approximately 0.86mm, approximately 0.85mm, approximately 0.84mm, approximately 0.83mm, approximately 0.82mm, approximately 0.81mm, approximately 0.79mm, approximately 0.78mm, approximately 0.77mm, approximately 0.76mm, or approximately 0.75mm.

[0069] In some embodiments, no portion of the sealing needle in contact with the material has a protrusion. A protrusion is any portion of the sealing needle whose diameter is greater than the shaft of the sealing needle, or any portion of the sealing needle that extends axially outward. Preferably, protrusions on the sealing needle are avoided from pushing molten material through the extruder when the sealing needle is closed. In some embodiments, the entire sealing needle (whether in contact with the material or not) has no protrusions. In some embodiments, the non-material-contact portion of the sealing needle includes one or more protrusions, which may, for example, engage with components of the actuator or serve as a deep break to prevent the sealing needle from being driven too far into the feed chamber.

[0070] The material-contacting sealing needle portion (i.e., the portion located within the feed channel when the sealing needle is in an open position (including open positions with various opening distances, such as the maximum open position) or a closed position) is relatively thin compared to the feed channel, allowing molten material to flow around the sealing needle rather than be extruded from the extruder. In some embodiments, the material-contacting portion of the sealing needle has a maximum diameter of about 0.2 mm to about 3.0 mm, for example, 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 material-contacting portion of the sealing needle and the material-non-contacting portion of the sealing needle) has a maximum diameter of about 0.2 mm to 3.0 mm, for example, 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.

[0071] In some embodiments, the sealing needle includes a pointed tip at the tapered end, such as Figure 3A As shown. In some embodiments, the tapered end of the tip is a truncated cone, such as... Figure 3B As shown. Both the nozzle and the sealing needle include tapered surfaces, such that the tapered end of the sealing needle faces the tapered inner surface of the nozzle. Here, "taper angle" refers to the angle of the vertex of the mating surface. In the case of a truncated conical tip, "taper angle" refers to the vertex of the extrapolated mating surface. The taper angle of the tapered end of the sealing needle is... Figure 3A and Figure 3B The Chinese character is used to represent this. For example... Figure 3CAs shown, the cone angle of the nozzle is represented by β. In some embodiments, the cone angle of the tapered end of the sealing 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 cone angle (α) of the sealing needle is equal to or less than the cone angle (β) of the inner surface of the nozzle. In some embodiments, the ratio of the cone angle of the inner surface (β) of the nozzle to the cone 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.

[0072] By lowering the sealing needle toward the extrusion orifice, the sealing needle is positioned in the closed position, where it is aligned with the extrusion orifice. When the sealing needle is in the open position (including open positions with various opening distances, such as the maximum open position), pressurized and molten material can flow through the extrusion orifice; however, when the sealing needle is in the closed position, its flow is blocked, in which position it engages with the inner surface of the nozzle. When the cone angle (β) of the inner surface of the nozzle is greater than the cone angle (α) of the sealing needle, the tapered end of the sealing needle engages with the inner surface of the nozzle at the extrusion orifice. In some embodiments, the extrusion orifice 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 0.75 mm or greater. In some embodiments, the extrusion orifice 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. Preferably, the sealing needle has a thin, tapered end base to limit the extrusion of molten material as the sealing needle moves to the closed position. In some embodiments, the ratio of the maximum diameter of the tapered end of the sealing needle (i.e., the bottom of the tapered portion) to the diameter of the extrusion is from about 1:0.8 to about 1:0.1, such as from about 1:0.8 to about 1:0.7, from about 1:0.7 to about 1:0.6, from about 1:0.6 to about 1:0.5, from about 1:0.5 to about 1:0.4, from about 1:0.4 to about 1:0.3, from about 1:0.3 to about 1:0.2, or from about 1:0.2 to about 1:0.1.

[0073] The sealing needle preferably comprises a robust 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 includes a flexible pad or bushing that can limit damage to the needle or nozzle when the sealing needle repeatedly switches between open and closed positions. In some embodiments, the pad or bushing is made of polytetrafluoroethylene (PTFE).

[0074] The sealing needle of the control switch is controlled by an actuator that positions the sealing needle in an open position (i.e., by raising the sealing needle so that the tapered end of the sealing needle no longer engages the inner surface of the nozzle, including open positions with various opening distances, such as the maximum open position) or a closed position (i.e., by 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 that can be controlled using air pressure within the actuator. In some embodiments, the actuator is a mechanical actuator that can raise or lower the sealing needle by 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 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.

[0075] Figure 2A A cross-sectional view of an exemplary apparatus for depositing material by additive manufacturing according to the present invention is shown. Material may be loaded into a barrel 202 of a feed module, and a piston 204 applies pressure to the material by pushing it into the barrel 202. The piston 204 is connected to a pressure controller via a guide arm 206. The piston 204 is 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 may be heated to or above its melting temperature using a heater inside or around the barrel. Molten material from the barrel 202 flows through a feed channel 208 connected to a printhead 210 including a nozzle 212. A pressure sensor 214 is located at the end of the feed channel 208 and near the printhead 210, and is used to detect the pressure of the material near the printhead. In some embodiments, the pressure sensor 214 is positioned to detect the pressure of the material within the printhead 210. Pressure sensor 214 can transmit the detected pressure to a computer system that can operate a pressure controller (or the motor of the pressure controller) to reposition piston 204 and control the pressure of the material within barrel 202. This can be operated in a feedback system, where pressure changes are detected by pressure sensor 214 and the computer system further operates the pressure controller.

[0076] The device includes a control switch 216 comprising a sealing pin 218 and a linear actuator 220. The sealing pin 218 includes an upper end 222 engaging the actuator 220 and a tapered lower end 224. The sealing pin 218 extends through a feed channel 208 into a printhead 210. The actuator 220 controls the sealing pin 218 between an open position (raised) and a closed position (lowered). When the sealing pin 218 is in the closed position, the tapered end 224 of the sealing pin 218 engages the tapered inner surface of the nozzle 212 to prevent molten material from flowing through the nozzle. To open the nozzle 212 and allow molten material to flow through the extrusion orifice, the actuator 220 controls the sealing pin 218 to be positioned in the open position by raising the sealing pin 218, thereby disengaging the tapered lower end 224 from the inner surface of the nozzle 212. Figure 2B An enlarged view of the printhead 210 with the sealing pin 218 in the closed position and engaged with the nozzle 212 is shown. In the closed position, the tapered end 224 of the sealing pin 218 is inserted into the extrusion port 226 by engaging with the tapered inner surface 212 of the nozzle. This prevents molten material in the feed channel 208 from flowing through the extrusion port 226. The pressure of the material inside or near the printhead 210 is detected by a pressure sensor 214, and a pressure controller can be operated to prevent excessive pressure buildup in the device when the sealing pin 218 is in the closed position.

[0077] The sealing pin 218 extends through the feed channel 208 and into the printhead 210. When the sealing pin 218 switches from the open position to the closed position, it is carefully designed to prevent molten material in the feed channel 208 from being pushed out of the extrusion port 226. The tapered end 224 of the sealing pin 218 allows it to pierce the molten material, thereby allowing the molten material to flow upwards and around the closed sealing pin 218, rather than being pushed downwards.

[0078] The pneumatic actuator 220 includes a solenoid valve for controlling gas flow into an air chamber 226, which can drive a central rod 228 attached to the upper end 222 of a sealing needle 218 upwards or downwards. High-pressure gas flowing into the air chamber 226 from below the partition 230 or removing gas from above the partition 230 causes the partition 230 to move upwards, thus positioning the sealing needle 218 in the open position. Removing gas from below the partition 230 or applying high-pressure gas above the partition 230 causes the partition 230 to move downwards, positioning the sealing needle 218 in the closed position.

[0079] although Figure 2AThe device includes a pneumatic actuator, but other linear actuators can be used. For example, the actuator can be an electric actuator, such as a linear stepper motor actuator. Similarly, the linear stepper motor actuator can move the center rod 228 attached to the upper end 222 of the sealing needle 218, allowing it to move the sealing needle 218 upward to an open position (including open positions with various opening distances, such as a maximum open position) or downward to a closed position. Furthermore, the linear stepper motor actuator can provide more precise control over the opening distance of the sealing needle to regulate the amount and flow rate of material extruded from the nozzle.

[0080] Figure 4 An exploded view of the components of a pneumatic actuator connected to and controlling a sealing needle is shown. A partition 402 is located within the air chamber of the pneumatic actuator and is connected, for example, to a center rod 404 via a threaded connection. The center rod 404 is connected, for example, to an adapter 406 via a threaded connection. The adapter 406 is attached to the sealing needle 408, for example, via a threaded connection or a compression fit. For example, the lower portion of the adapter 406 may include an opening, and the upper portion of the sealing needle 408 can be tightly fitted into the opening by inserting the sealing needle 408 into the opening of the adapter 406. The sealing needle 408 is positioned by a washer 410, which is held in place by a retaining nut 412. The retaining nut 412 is secured to the adapter block with the washer, thereby connecting to other parts of the device. Figure 2A As shown, the adapter block 232 is positioned above the feed channel 208, aligned with the nozzle 212 of the printhead 210. The adapter block channel 234 passes through the adapter block 232 into the feed channel. A washer 236 is fitted into an opening at the top of the adapter block 232, which is wider than the channel 234, thus preventing the washer 236 from moving toward the printhead 210. The washer 236 may be made of an inert, flexible material, such as plastic or synthetic rubber, and seals the feed channel 208 to prevent leakage of molten material from the feed channel 208. In some embodiments, the washer is made of polytetrafluoroethylene (PTFE). A retaining nut 238 is secured, for example by a threaded engagement, to the adapter block 232, fixing the position of the washer 236. Thus, the washer 236 is in a fixed position relative to the printhead 210 and the nozzle 212. A sealing pin 218 passes through holes in the retaining nut 238 and the washer 236 to reach the feed channel 208. The size of the hole is set to allow the needle to pass through and can be controlled to move by actuator 220, but it cannot be too large to cause leakage of molten material.

[0081] The feeding module includes one or more heaters for melting material. The heaters may be placed around or inside the material-containing hopper, feeding channel, and / or printhead. Figure 5A A longitudinal cross-sectional view of a portion of the device is shown. Figure 5B A cross-sectional view at plane "AA" is shown. Figure 5CA non-sectional view of the device is shown. A pneumatic actuator is used in this exemplary device. In some embodiments, the device includes a heater 502 surrounding a barrel 504, which heats and melts material contained within the barrel 504. The heater 502 may be, for example, a coil heater surrounding the exterior of the barrel 504. In some embodiments, the heater is disposed within the barrel. The material placed within the barrel is initially melted within the barrel by the heater, and pressure is applied to the material via a piston 506. The molten material then flows from the barrel 504 to a feed channel 508. In some embodiments, to ensure that the material is maintained at a specific temperature in the feed channel 508, one or more heaters may be placed near or within the feed channel 508. Figure 5B and Figure 5C Two heaters 510a and 510b are shown, each located on either side of and adjacent to the feed channel 508. In some embodiments, heaters 510a and / or 510b cover the length of the feed channel 508 or its sides. In some embodiments, one or more heaters adjacent to or within the feed channel 508 are heating rods. In some embodiments, one or more heaters adjacent to or within the feed channel 508 are coils surrounding the feed channel 508. Heating one or more heaters within the feed channel 508 ensures that the material remains molten and has a suitable viscosity at a given pressure to achieve the desired flow. In some embodiments, the printhead 512 of the device includes one or more heaters 514 that ensure the material remains molten and has a suitable viscosity within the nozzle 516.

[0082] In some embodiments, the device includes one or more temperature sensors that may be located at one or more locations within the device and can detect the temperature of materials within the device, such as inside a barrel, a feed channel, or a printhead. Figures 5A-5CIn the embodiments described, a first temperature sensor 518 adjacent to the feed channel 508 and a second temperature sensor 520 adjacent to the printhead 512 are included. The temperature sensor 518 adjacent to the feed channel 508 is shown on one side of the feed channel 508 in the figure, but the temperature sensor 518 may optionally be located anywhere along the length of the feed channel 508. The temperature sensor 518 and one or more heaters (e.g., 510a and 510b) can serve as a closed-loop feedback system for melting the material within the feed channel 508, ensuring that the material within the feed channel maintains a nearly constant temperature. For example, the temperature sensor 518 can transmit the measured temperature to a computer system, and the computer system can operate one or more heaters 510a and 510b to ensure a nearly constant temperature. The temperature sensor 520 in the printhead 512 of the device can work in a closed-loop feedback system with one or more heaters 514 in the printhead to ensure a nearly constant temperature of the material within the printhead. The feedback system can use 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 control algorithm. In some embodiments, one or more heaters in the apparatus heat the material within the system to a temperature equal to or higher than the material's melting temperature. In some embodiments, one or more heaters heat the material to a temperature of about 60°C or higher, such as about 70°C or higher, 80°C or higher, 100°C or higher, 120°C or higher, 150°C or higher, 200°C or higher, or 250°C or higher. In some embodiments, one or more heaters heat the material to a temperature of about 300°C or lower, such as about 260°C or lower, 200°C or lower, 150°C or lower, 100°C or lower, or 80°C or lower. In some embodiments, one or more heaters heat the material to different temperatures at different locations in the apparatus. For example, in some embodiments, the material is heated to a first temperature within the barrel, a second temperature within the feed channel, and a third temperature within the printhead, each temperature being the same or different. For example, a material may be heated to 140°C in the barrel and feed channel, but to 160°C at the printhead. A feedback control system can achieve high-precision temperature control. In some embodiments, the temperature is controlled within 0.1°C, 0.2°C, 0.5°C, or 1°C of the target temperature.

[0083] The device includes one or more pressure sensors that can detect the pressure of the material within the device. In some embodiments, the pressure sensors are used to detect the pressure of the material within or near the printhead in the feed channel. In some embodiments, the pressure sensors are positioned within or near the printhead in the feed channel and close to the printhead. The pressure sensors can work with a pressure controller in a closed-loop feedback system to provide a nearly constant pressure to the material in the device. For example, when the pressure sensor detects a pressure drop, the feedback system can signal 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, when the pressure sensor detects an increase in pressure, the feedback system can signal 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.). Constant pressure ensures that the molten material in the device passes through the nozzle extrusion orifice at a constant rate when the sealing needle is in the open position (including open positions with various opening distances, such as the 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.) may cause molten material to leak through the nozzle. Furthermore, the feedback system, including a pressure sensor and a pressure controller, maintains a nearly constant pressure in the system when the sealing needle switches back to the closed position (including open positions with various opening distances, such as the maximum open position) or vice versa. This minimizes the "slope rise" of the extrusion rate when the sealing needle switches from the closed position to the open position (including open positions with various opening distances, such as the maximum open position), as there is no need to increase the pressure of the material in the system. In some embodiments, when the opening distance of the sealing needle changes, the pressure sensor detects the pressure change within the printhead and sends a signal to the device to control the opening position of the sealing needle in sync with the printing speed (e.g., according to the product's printing instructions) via a closed-loop feedback system. The feedback system can use 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 control algorithm. In some embodiments, the sampling rate of the pressure sensor is approximately 20 ms or faster, such as approximately 10 ms or faster, approximately 5 ms or faster, or approximately 2 ms or faster. In some embodiments, the pressure is controlled within 0.05 MPa, 0.1 MPa, 0.2 MPa, 0.5 MPa, or 1 MPa of the target pressure.

[0084] Figure 6Another example of the device described in this invention is shown. Material is loaded into a barrel 602 of a feeding module, 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 is rotatably connected to a second gear 612 of 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 feeding channel 616 to a printhead 618 including a nozzle 620. The device may include a pressure sensor 630 for detecting the pressure of the material in the barrel 602, the channel 616, and / or the printhead 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 within the barrel 602. This control can operate in a feedback system, where pressure changes are detected by pressure sensor 630, and a computer system further operates the pressure controller. Figure 6 The illustrated embodiment includes a control switch comprising a sealing pin 622 and an actuator 624 along the same axis as the barrel 602. The sealing pin 622 includes an upper end and a lower tapered end (not shown) connected to the actuator 624. The actuator 624 controls the sealing pin 622 between an open position (raised, including open positions with various opening distances, such as a maximum open position) and a closed position (lowered). When the sealing pin 622 is in the closed position, the tapered end of the sealing pin 622 engages the tapered inner surface of the nozzle 622 to prevent molten material from flowing through the nozzle. The printhead 618 may also include one or more heaters 626 and a temperature sensor 628, which may operate in a feedback system.

[0085] In some embodiments, the additive manufacturing system 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 in this invention, including a feed module equipped with a control switch (including a sealing needle and a brake having a tapered end switchable between an open position (including open positions with various opening distances, such as a maximum open position) and a closed position). In some embodiments, at least two of 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 printhead including a nozzle comprising a tapered inner surface and a nozzle. An extrusion orifice is configured to dispense material; a pressure sensor is configured to detect pressure of material within or near the nozzle in the feed channel; a control switch includes a sealing needle switchable between an open position and a closed position, the sealing needle extending through a portion of the feed channel and including a tapered end. The tapered end of the sealing needle engages with the tapered inner surface of the nozzle to prevent material from flowing through the nozzle when the sealing needle is in the closed position. In some embodiments, the tapered inner surface of the nozzle has a first tapered angle, and the tapered end of the sealing needle has a second tapered angle. The second cone angle is equal to or less than the first cone angle. In some embodiments, the control switch for each device within the system is different. In some embodiments, the control switches for some devices are the same, but different from the control switches for other devices within the system. For example, in some embodiments, the actuators (e.g., linear actuators, such as pneumatic actuators, linear stepper motor actuators) for each control switch are the same, but the sealing needles have different structures (e.g., different diameters). In some embodiments, the actuators (e.g., linear actuators) for each control switch are different (e.g., one device includes a pneumatic actuator, another device includes an electric actuator), but the sealing needles are the same. In some embodiments, the actuators (e.g., linear actuators) and the configured sealing needles are different between different devices in the system. In some embodiments, the control switches for all devices within the system are the same (e.g., the same electric actuator configured with the same sealing needle). The materials in each individual device can 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, the additive manufacturing system includes a first device loaded with a first material and a second device loaded with a second material, wherein the first material and the second material are different. Different feed modules in the additive manufacturing system can extrude different materials to form multi-component printed products, such as multi-component pharmaceutical dosage forms (e.g., tablets). When one feed module is active (i.e., the sealing needle is in an open position (including open positions with various opening distances, such as a maximum open position)), the other feed modules in the device are inactive (i.e., the sealing needle is in a closed position). By coordinating the position of the sealing needle in the open position (including open positions with various opening distances, such as a maximum open position) or the closed position, the device can quickly switch between active feed systems. Figure 7 A portion of an exemplary system is shown, comprising three feeding modules, each with different printheads 702, 704, and 706. A print stage 708 is movable along the x, y, and z axes, and with the product under the correct printhead, it can extrude material to produce product 710 (e.g., a tablet).

[0086] In some embodiments, the device (or system including multiple devices) described herein is connected to a computer system that can control any one or more of the various components of the device. For example, in some embodiments, the computer system controls one or more heaters, a pressure controller, and / or a control switch. In some embodiments, the computer system controls one or more heaters in response to temperature detected by one or more temperature sensors (i.e., in 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 the sealing needle between an open position (including open positions with various opening distances, such as a maximum open position) and a closed position, and controls the opening distance of the sealing needle. In some embodiments, the computer system coordinates the switching of active material supply systems between multiple devices in response to instructions to print a product. The computer system includes one or more processors and computer-readable storage, which may include instructions for operating the device (or a system comprising multiple devices), such as instructions for controlling the open position (including open positions with various open distances, e.g., a maximum open position) and closed position of each sealing pin within each device, and / or the open distance of the sealing pin of each device, by controlling the actuator of each device (e.g., a linear actuator, such as a pneumatic actuator, a linear stepper motor actuator). In some embodiments, the computer system is a desktop computer, a laptop computer, a mobile device (such as a mobile 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, the computing system may also include circuitry or other dedicated hardware for performing some or all of the methods described herein and / or for operating the devices and systems described herein. In some operating setups, the computing system may be configured as a system comprising one or more units, each unit being configured to perform some aspects of the process in software, hardware, or some combination thereof. The main system of an exemplary computer system may include a motherboard with an input / output (“I / O”) section, one or more central processing units (“CPUs”), and a memory section, which may have an associated flash memory card. The I / O section may be connected to a display, keyboard, disk storage unit, media drive unit, and / or one of the devices or systems described herein. The media drive unit can read / write computer-readable media that may contain programs (i.e., instructions) and / or data. At least some values ​​based on the results of the above processes may be stored for subsequent use. Alternatively, non-transitory computer-readable media may be used to store (e.g., tangible) one or more computer programs that perform the methods described above by means of a computer.Computer programs can be written in general-purpose programming languages ​​(e.g., Pascal, C, C++, Java, Python, JSON, etc.) or some specialized language.

[0087] In some embodiments, the computer system includes one or more processors and a computer-readable storage device including instructions for printing a product (e.g., a pharmaceutical dosage form, such as a tablet) via additive manufacturing. In some embodiments, the computer system operates a control switch in response to 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 storage device includes instructions for controlling the opening position (including opening positions with various opening positions, such as a maximum opening position) and closing position of each sealing pin within the device (or each device within the system), and / or the opening distance of the sealing pins of the device (or each device in the system), via actuators (e.g., linear actuators, such as pneumatic actuators, linear stepper motor actuators) of the device (or each device in the system). In some embodiments, the computer-readable storage device includes instructions for positioning the sealing pins based on the printed product. In some embodiments, the instructions for positioning the sealing pins include instructions for selecting the opening distance of the sealing pins based on a desired flow rate of material from the extruder. In some embodiments, the instructions for positioning the sealing pins are based on signals transmitted from a pressure sensor within the printhead. For example, when the pressure inside the printhead is too high, and / or the instruction for printing the product requires a slower printing speed, the computer-readable memory instructs the opening distance of the sealing pin to decrease; when the pressure inside the printhead is too low, and / or the instruction for printing the product requires a higher printing speed, the computer-readable memory instructs the opening distance of the sealing pin to increase.

[0088] Instructions for printing products such as pharmaceutical dosage forms can be generated using any one or more different methods, including direct coding, exporting from solid CAD models, or using the computer interface and application software specific to other 3D printers. These instructions may include information about the number and spatial location of droplets, as well as general printing parameters such as droplet spacing in each linear dimension (X, Y, Z) and the volume or mass of each droplet. For a given set of materials, these parameters can be adjusted to improve the quality of the created structure. The overall resolution of the resulting structure is a function of powder particle size, fluid droplet size, printing parameters, and material properties.

[0089] Methods of additive manufacturing of deposited materials or products may include the steps of melting and pressurizing the material; allowing the material to flow through an extrusion orifice of a nozzle including a conical inner surface; monitoring the pressure of the material within or near the nozzle; engaging the conical end of a sealing needle with the conical inner surface of the nozzle to close the extrusion orifice and prevent the flow of molten material; and retracting the conical end of the sealing needle to restore the flow of material through the extrusion orifice. In some embodiments, the method includes retracting the conical end of the sealing needle to a selected opening distance (e.g., a maximum opening position). In some embodiments, the method is performed using an apparatus as described in this invention. In some embodiments, the apparatus includes a plurality of feeding modules, each configured with a control switch. In some embodiments, the control switch configured for each material supply system is identical. In some embodiments, the control switch configured for each material supply system is different (e.g., by using different actuators or sealing needles of different diameters). The method may include printing a first material from a first feeding module and printing a second material from a second feeding module, wherein when the second material is printed from the second feeding module, the sealing pin of the first feeding module is in a closed position, and when the first material is printed from the first feeding module, the sealing pin of the second feeding system is in a closed position. In some embodiments, the method is performed in a batch processing mode. In some embodiments, the apparatus or system is controlled to operate in a batch mode. The term "batch mode" refers to an operating mode in which a predetermined quantity of products (e.g., pharmaceutical dosage forms) are manufactured. In some embodiments, the method is performed in a continuous operating mode. In some embodiments, the apparatus or system operates in a continuous mode. The term "continuous mode" refers to an operating mode in which the equipment or system operates for a predetermined period of time or until a predetermined amount of one or more materials has been used.

[0090] In some embodiments, a method of manufacturing a product by additive manufacturing includes melting and pressurizing a first material; flowing the first material through a first extrusion orifice 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 to close the first extrusion orifice and prevent the flow of the molten first material; melting and pressurizing a second material; and withdrawing a tapered end of a second sealing needle from the tapered inner surface of a second nozzle to initiate the flow of the second material through a second extrusion orifice. In some embodiments, the method includes, for example, receiving instructions from a computer system for manufacturing the product. In some embodiments, the method includes retracting the tapered end of the second sealing needle to a selected opening distance (e.g., a maximum opening position), which can adjust the flow rate and / or velocity of the material through the extrusion orifice.

[0091] In some embodiments, a method for producing a pharmaceutical dosage form (e.g., tablets) by additive manufacturing includes the following steps: melting and pressurizing a pharmaceutical material; monitoring the pressure of the material within or near a nozzle; allowing the material to flow through an extrusion orifice of a nozzle including a conical inner surface; engaging a conical end of a sealing needle with the conical inner surface of the nozzle to close the extrusion orifice and prevent the flow of molten material; and retracting the conical end of the sealing needle to restore the flow of material through the extrusion orifice. In some embodiments, the method includes retracting the conical end of the sealing needle to a selected opening distance (e.g., a maximum opening position). In some embodiments, the pharmaceutical material comprises a drug. In some embodiments, the method is performed using an apparatus as described in this invention. In some embodiments, the apparatus includes a plurality of feeding modules, each configured with a control switch. In some embodiments, the control switch configured for each material supply system is identical. In some embodiments, the control switch configured for each material supply system is different (e.g., by using different actuators or sealing needles of different diameters). The method may include printing a first material from a first feed module and printing a second material from a second feed module, wherein when the second material is printed from the second feed module, a sealing pin of the first feed module is in a closed position, and when the first material is printed from the first feed module, a sealing pin of the second feed system is in a closed position. In some embodiments, the method further includes monitoring the pressure of the first material in or near a first nozzle; and / or monitoring the pressure of the second material in or near a second nozzle. In some embodiments, the method includes retracting the tapered end of the second sealing pin of the second material supply system to a selected opening distance (e.g., a maximum opening position) to adjust the flow rate and / or velocity of the second material through a second extrusion port.

[0092] In some embodiments, a method of producing a pharmaceutical dosage form by additive manufacturing includes melting and pressurizing a first pharmaceutical material; flowing the first pharmaceutical material through a first extrusion port of a first nozzle including a conical inner surface; engaging a conical end of a first sealing needle with the conical inner surface of the first nozzle to seal the first extrusion port and prevent the flow of the molten first material; melting and pressurizing a second pharmaceutical material; and withdrawing the conical end of a second sealing needle from the conical inner surface of a second nozzle, thereby allowing the second pharmaceutical material to flow through a second extrusion port. In some embodiments, the method includes retracting the conical end of a second sealing needle of a second material supply system to a selected opening distance (e.g., a maximum opening position) to regulate the flow rate and / or velocity of the second material through the second extrusion port. In some embodiments, the first or second pharmaceutical material is an abrasive material. In some embodiments, the first or second pharmaceutical material contains a drug. In some embodiments, the method further includes, for example, receiving instructions from a computer system for manufacturing a pharmaceutical dosage form. In some embodiments, the method further includes monitoring the pressure of the first material within or near the first nozzle; and / or monitoring the pressure of the second material within or near the second nozzle.

[0093] In some embodiments, a pharmaceutical dosage form manufactured according to the method or using the apparatus or system of the present invention comprises a multilayer structure, the multilayer structure including multiple layers of first etchable material mixed with a drug, wherein the first etchable material mixed with the drug is related to the drug release rate. Pharmaceutical dosage forms, such as oral pharmaceutical dosage forms, can provide any target drug release profile based on controlling various parameters, such as the thickness of the first etchable material layer mixed with the drug, the surface area of ​​the first etchable material layer, and the drug mass fraction of the first etchable material layer. Pharmaceutical dosage forms having target drug release profiles for one or more drugs can be readily designed and printed using the additive manufacturing apparatus or system of the present invention.

[0094] A pharmaceutical dosage form manufactured according to the method of the present invention or using the apparatus or system described herein can be designed to meet a target drug release profile. In some embodiments, the pharmaceutical dosage form is custom-designed (e.g., for personalized medicine) to meet a target drug release profile. In some embodiments, the pharmaceutical dosage form comprises one or more layers containing a first etchable material mixed with a drug, wherein the first etchable material is embedded in a second material not mixed with the drug. A pharmaceutical dosage form having a desired drug release profile can be designed, for example, by: (a) selecting a first etchable material and a second material for forming the pharmaceutical dosage form; (b) obtaining the etch rate of the first etchable material; and (c) determining the thickness, surface area, and / or drug mass fraction in each layer based on the drug release rate and the desired drug release profile. In some embodiments, the pharmaceutical dosage form further comprises one or more additional layers of a third etchable material mixed with a second drug.

[0095] In some embodiments, the drug dosage form comprises two or more drugs, such as any one of about 5 or more, 10 or more, 20 or more, 30 or more, or 50 or more, wherein each drug has a desired drug release profile. In some embodiments, the oral drug dosage form comprises two or more drugs, wherein at least two drugs have different desired drug release profiles.

[0096] The desired release profile of a drug can be tailored to the materials and design used in the production of the drug dosage form. In some embodiments, the production of the drug dosage form uses two or more different materials, which can be deposited in one or more layers using the apparatus described herein, the layers being identical or different. In some embodiments, the drug dosage form comprises a first layer of a first material mixed with the drug and a second layer of a second material not mixed with the drug. In some embodiments, the drug dosage form comprises a multilayer structure containing one or more layers of a first etchable material mixed with the drug, wherein the first etchable material is embedded within a second material not mixed with the drug. The etchability of the first etchable material mixed with the drug can be correlated with the release rate of the drug in the drug dosage form.

[0097] In some embodiments, the desired drug release profile includes the total (i.e., cumulative) fraction or percentage of drug released from the oral dosage form at a time point after administration or when the drug subsequently begins to be released from the oral dosage form (e.g., for enteric-coated oral dosage forms). In some embodiments, the target drug release profile is predetermined.

[0098] In some embodiments, once the first etchant layer containing the drug is exposed to a solution such as oral fluid or gastrointestinal (GI) fluid, the drug will begin to be released from the oral dosage form. In some embodiments, the target drug release profile for the oral dosage form is the time period from oral administration to the complete release of the drug contained in the oral dosage form. In some embodiments, the desired drug release profile includes an initial delay period preceding the desired drug release period, wherein the initial delay period is a patient-specific time period or an estimated time period, for example, due to the use of enteric-coated oral dosage forms.

[0099] In some embodiments, the desired drug release profile for an oral drug dosage form includes a zero-order release profile, a first-order release profile, a delayed-release profile, a pulse release profile, an iterative pulse release profile, an immediate-release profile, a sustained-release profile, or a combination thereof.

[0100] In some embodiments, the total time of the target drug release curve of the oral drug formulation 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 of the target drug release curve for the oral drug formulation is approximately any one of 1 hour, 2 hours, 3 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48 ​​hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, or 72 hours. In some embodiments, the total time of the expected drug release curve for the oral drug formulation is greater than or about 6 hours, greater than or about 12 hours, greater than or about 18 hours, greater than or about 24 hours, greater than or about 30 hours, greater than or about 36 hours, greater than or about 42 hours, greater than or about 48 hours, greater than or about 54 hours, greater than or about 60 hours, greater than or about 66 hours, or greater than or about 72 hours. In some embodiments, the total time of the expected drug release curve for the oral drug formulation is less than or about 6 hours, less than or about 12 hours, less than or about 18 hours, less than or about 24 hours, less than or about 30 hours, less than or about 36 hours, less than or about 42 hours, less than or about 48 hours, less than or about 54 hours, less than or about 60 hours, less than or about 66 hours, or less than or about 72 hours.

[0101] In some embodiments, one or more etchant materials are suitable for mixing with a drug. In some embodiments, the etchant material mixed with the drug is not chemically reactive with the drug. In some embodiments, the etchant material is selected based on its suitability for mixing with the drug. In some embodiments, the etchant material is selected based on its lack of chemical reactivity with the drug.

[0102] In some embodiments, the material mixed with the drug is a material that is substantially eroded (e.g., substantially completely eroded or substantially completely dissolved) during the duration of the oral dosage form in an individual. In some embodiments, the eroding material mixed with the drug in the oral dosage form is almost entirely eroded during the duration of the oral dosage form in the individual. In some embodiments, the first eroding material mixed with the drug in the oral dosage form is almost entirely eroded during the desired duration of the oral dosage form in the individual. In some embodiments, the first eroding material mixed with the drug in the oral dosage form is almost entirely eroded within a timeframe of less than about 72 hours, for example, less than about 48 hours, 36 hours, 24 hours, 18 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, or 1 hour.

[0103] In some embodiments, the erosion rate of the first erosive material mixed with the drug is between about 0.1 mm / h and about 4 mm / h. In some embodiments, the erosion rate of the first erosive material mixed with the drug is greater than about 0.1 mm / h, for example greater than any one of about 0.2 mm / h, 0.4 mm / h, 0.6 mm / h, 0.8 mm / h, 1.0 mm / h, 1.5 mm / h, 2.0 mm / h, 2.5 mm / h, 3.0 mm / h, 3.5 mm / h, or 4.0 mm / h. In some embodiments, the erosion rate of the first erosive material mixed with the drug is less than about 0.1 mm / h, for example less than any one of about 0.2 mm / h, 0.4 mm / h, 0.6 mm / h, 0.8 mm / h, 1.0 mm / h, 1.5 mm / h, 2.0 mm / h, 2.5 mm / h, 3.0 mm / h, 3.5 mm / h, or 4.0 mm / h.

[0104] The thickness of the deposited material (material mixed with or without a drug) can significantly alter the release profile of the manufactured drug dosage form. The apparatus and system described herein allow for enhanced control over product thickness because the pressure of the apparatus is precisely controlled and the control switches not only limit leakage of the extruded material but also regulate the amount and / or flow rate of the extruded material. Furthermore, the apparatus of the present invention limits the “gradual increase” in the extrusion rate of the extruded material, which contributes to better control of the material thickness.

[0105] In some embodiments, a method of providing a desired drug release profile for a drug dosage form (e.g., a tablet) via additive manufacturing includes the steps of: melting and pressurizing a first material containing a drug; allowing the material to flow 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 to close the first extrusion port and prevent the flow of the first molten material; melting and pressurizing a second material; and withdrawing a tapered end of a second sealing needle from the tapered inner surface of a second nozzle to allow the second material to flow through a second extrusion port. In some embodiments, the method includes monitoring the pressure of the first material within or near the first nozzle. In some embodiments, the method includes monitoring the pressure of the second material within or near the second nozzle. In some embodiments, the method is performed using an apparatus or system as described in this invention. Specific Implementation

[0107] Example 1. An apparatus for depositing materials by additive manufacturing, comprising:

[0108] A feeding system for melting and pressurizing the material, the feeding system including a feeding channel connected to a printhead including a nozzle, the nozzle including a tapered inner surface and an extrusion port for printing material;

[0109] A pressure sensor, used to detect the pressure of the material in or near the nozzle within the feed channel; and

[0110] A control switch includes a sealing needle that can be switched between an open position and a closed position, the sealing needle extending through a portion of the feed channel and including a tapered end;

[0111] The tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent material from flowing through the nozzle when the sealing needle is in the closed position.

[0112] Example 2. The apparatus according to Example 1, wherein the material is non-wire.

[0113] Example 3. The device according to Example 1 or 2, wherein no part of the sealing needle in contact with the material has a protrusion.

[0114] Example 4. The apparatus according to any one of Examples 1-3, wherein the pressure sensor is connected to a computer system that operates the feeding system in response to pressure reported by the pressure sensor and pressurizes the material to the desired pressure.

[0115] Example 5. The apparatus according to any one of Examples 1-4, wherein the pressure of the material is within about 0.05 MPa of the desired pressure.

[0116] Example 6. The apparatus according to any one of Examples 1-5, wherein the feeding system includes a piston and a cylinder connected to the feeding channel, and wherein the piston is operated to control the pressure of the material in the cylinder.

[0117] Example 7. The apparatus according to Example 6, wherein the piston is driven by a stepper motor.

[0118] Example 8. The device according to any one of Examples 1-7, wherein the tapered end of the sealing needle includes a tip.

[0119] Example 9. The device according to any one of Examples 1-7, wherein the tapered end of the sealing needle is a truncated cone.

[0120] Example 10. The apparatus according to any one of Examples 1-8, wherein the conical inner surface of the nozzle has a first cone angle and the conical end of the sealing needle has a second cone angle; and wherein the second cone angle is the same as or smaller than the first cone angle.

[0121] Example 11. The apparatus according to Example 10, wherein the second cone angle is approximately 60° or less.

[0122] Example 12. The apparatus according to Example 10 or 11, wherein the second cone angle is approximately 45° or less.

[0123] Example 13. The apparatus according to any one of Examples 10-12, wherein the ratio of the first cone angle to the second cone angle is about 1:1 to about 4:1.

[0124] Example 14. The apparatus according to any one of Examples 1-13, wherein the extrusion orifice has a diameter of about 0.1 mm to about 1 mm.

[0125] Example 15. The device according to any one of Examples 1-14, wherein the tapered end has a maximum diameter of about 0.2 mm to about 3.0 mm.

[0126] Example 16. The apparatus according to any one of Examples 1-15, wherein the extrusion orifice has a diameter and the tapered end has a maximum diameter, the ratio of the maximum diameter of the tapered end to the diameter of the extrusion orifice being approximately 1:0.8 to approximately 1:0.1.

[0127] Example 17. An apparatus of any one of Examples 1-16, wherein the material has a viscosity of about 100 Pa·s or higher when extruded from the apparatus.

[0128] Example 18. An apparatus of any one of Examples 1-17, wherein the material has a viscosity of about 400 Pa·s or higher when extruded from the apparatus.

[0129] Example 19. An apparatus of any one of Examples 1-18, wherein the material is melted at about 50°C to about 400°C.

[0130] Example 20. An apparatus of any one of Examples 1-19, wherein material is extruded from a nozzle at a temperature of about 50°C to about 400°C.

[0131] Example 21. An apparatus of any one of Examples 1-19, wherein material is extruded from a nozzle at a temperature of about 90°C to about 300°C.

[0132] Example 22. The apparatus according to any one of Examples 1-21, wherein the control switch includes an actuator for positioning the sealing needle in the open position or the closed position.

[0133] Example 23. The apparatus according to Example 22, wherein the actuator is a pneumatic actuator.

[0134] Example 24. The apparatus according to Example 22, wherein the actuator is a mechanical actuator.

[0135] Example 25. The apparatus according to Example 22, wherein the actuator is an electric actuator.

[0136] Example 26. The apparatus according to Example 25, wherein the electric actuator is a linear stepper motor actuator.

[0137] Example 27. The apparatus according to any one of Examples 22-26, wherein the sealing needle passes through a gasket fixed relative to the nozzle, wherein the gasket seals the feed channel.

[0138] Example 28. The apparatus according to any one of Examples 1-27, wherein the feeding system includes one or more heaters for melting the material.

[0139] Example 29. The apparatus according to Example 28, wherein the feeding system includes one or more temperature sensors used to detect the temperature of the molten material.

[0140] Example 30. The apparatus according to Example 29, wherein the one or more temperature sensors are connected to a computer system that controls the one or more heaters in response to the temperatures reported by the one or more temperature sensors.

[0141] Example 31. The device according to any one of Examples 1-30, wherein the tapered end of the sealing needle or the tapered inner surface of the nozzle includes a flexible pad or bushing.

[0142] Example 32. The device according to any one of Examples 1-31 further includes a computer system, the computer system including one or more processors and a computer-readable storage device, wherein the computer system is used to control the device.

[0143] Example 33. The device according to Example 32, wherein the computer-readable storage includes instructions for using the device to print a product.

[0144] Example 34. The apparatus according to Example 32 or 33, wherein the computer-readable storage includes instructions for controlling the pressure of the material in response to pressure detected by a pressure sensor.

[0145] Example 35. The device according to any one of Examples 32-34, wherein the computer-readable storage includes instructions for controlling the temperature of the material in response to a temperature detected by the temperature sensor.

[0146] Example 36. The device according to any one of Examples 33-35, wherein the computer-readable storage includes instructions for positioning the sealing pin based on the instructions for printing the product.

[0147] Example 37. The apparatus according to Example 36, wherein the instruction for positioning the sealing needle includes an instruction for selecting the opening distance of the sealing needle based on the desired flow rate of the extrusion material.

[0148] Example 38. The apparatus according to any one of Examples 1-37, wherein the pressure sensor is located near the nozzle.

[0149] Example 39. An additive manufacturing system includes a plurality of devices according to any one of Examples 1-31, wherein each feeding system is equipped with a control switch.

[0150] Example 40. The system according to Example 39 includes a first device loaded with a first material and a second device loaded with a second material, wherein the first material and the second material are different.

[0151] Example 41. The system according to Example 39 or 40, wherein the control switch of each of the plurality of devices is different.

[0152] Example 42. The system according to Example 39 or 40, wherein the control switch of each of the plurality of devices is identical.

[0153] Example 43. The system according to any one of Examples 39-42 further includes a computer system, the computer system including one or more processors and a computer-readable storage device, wherein the computer system is configured to control the system.

[0154] Example 44. The system according to Example 43, wherein the computer-readable storage includes instructions for using the system to print a product.

[0155] Example 45. The system according to Example 43 or 44, wherein the computer-readable storage includes instructions for controlling the pressure of the material in each feeding system in response to pressure detected by a pressure sensor in the respective feeding system.

[0156] Example 46. The system according to any one of Examples 39-45, wherein the computer-readable storage includes instructions for controlling the temperature of the material in each feeding system in response to a temperature detected by a temperature sensor in the respective feeding system.

[0157] Example 47. The system according to any one of Examples 44-46, wherein the computer-readable storage includes instructions for positioning the sealing pin based on the instructions for the printed product.

[0158] Example 48. The system according to embodiment 47, wherein the instructions for positioning the sealing needle include instructions for selecting the opening distance of the sealing needle based on the desired flow rate from the extrusion material.

[0159] Example 49. The system according to any one of Examples 39-48, wherein at least two of the plurality of devices include:

[0160] A material supply system configured to melt and pressurize material, the system including a feed channel connected to a printhead having a nozzle, the nozzle including a tapered inner surface and an extrusion port for dispensing material;

[0161] A pressure sensor, configured to detect the material pressure within or near the nozzle in the feed channel; and

[0162] A control switch includes a sealing needle that can be switched between an open and a closed position, the sealing needle extending through a portion of the feed channel and including a tapered end.

[0163] The tapered end of the sealing needle engages with the tapered inner surface of the nozzle to prevent material from flowing through the nozzle when the sealing needle is in the closed position.

[0164] Example 50. The system according to embodiment 49, wherein the conical inner surface of the nozzle has a first cone angle, and the conical end of the sealing needle has a second cone angle, wherein the second cone angle is equal to or less than the first cone angle.

[0165] Example 51. The system according to any one of Examples 39-50, wherein the pressure sensor is located near the nozzle.

[0166] Example 52. A method for manufacturing a product by additive manufacturing, comprising:

[0167] Molten and pressurized materials;

[0168] The material is allowed to flow through the extrusion port of a nozzle, which includes a conical inner surface.

[0169] Monitor the material pressure inside or near the nozzle;

[0170] The conical end of the sealing needle engages with the conical inner surface of the nozzle, thereby sealing the extrusion orifice and preventing the flow of molten material; and

[0171] The tapered end of the sealing needle is retracted, thereby restoring the flow of material through the extrusion port.

[0172] Example 53. The method according to Example 52 includes receiving instructions for manufacturing a product.

[0173] Example 54. A method for producing a drug dosage form by additive manufacturing, comprising:

[0174] Melting and pressurizing pharmaceutical materials;

[0175] Monitor the pressure of the material inside or near the nozzle;

[0176] The material is allowed to flow through the extrusion port of a nozzle, which includes a conical inner surface.

[0177] The conical end of the sealing needle engages with the conical inner surface of the nozzle, thereby sealing the extrusion orifice and preventing the flow of molten material; and

[0178] The tapered end of the sealing needle is retracted, thereby restoring the flow of material through the extrusion port.

[0179] Example 55. The method according to Example 54, wherein the pharmaceutical material comprises a drug.

[0180] Example 56. The method according to Example 55, wherein the drug dosage form has a desired drug release profile.

[0181] Example 57. The method according to any one of Examples 54-56 includes receiving instructions for manufacturing a pharmaceutical dosage form.

[0182] Example 58. The method according to any one of Examples 52-57, wherein the pressure of the material inside the nozzle is kept approximately constant.

[0183] Example 59. The method according to any one of Examples 52-58 includes using a feedback system to control the pressure of the material based on monitored pressure.

[0184] Example 60. The method according to any one of Examples 52-59, wherein the material is non-wire.

[0185] Example 61. The method according to any one of Examples 52-60, wherein no portion of the sealing needle in contact with the material has a protrusion.

[0186] Example 62. The method according to any one of Examples 52-61, wherein the temperature of the material inside the nozzle is kept approximately constant.

[0187] Example 63. The method according to any one of Examples 52-62 includes monitoring the temperature of the material.

[0188] Example 64. The method according to Example 63 includes using a feedback system to control the temperature of the material based on the monitored temperature.

[0189] Example 65. The method according to any one of Examples 52-64 includes retracting the tapered end of the sealing needle to a selected opening distance.

[0190] Example 66. The method according to any one of Examples 52-65, wherein the tapered end of the sealing needle includes a pointed tip.

[0191] Example 67. The method according to any one of Examples 52-65, wherein the tapered end of the sealing needle is a truncated cone.

[0192] Example 68. The method according to any one of Examples 52-67, wherein the conical inner surface of the nozzle has a first cone angle and the conical end of the sealing needle has a second cone angle; and wherein the second cone angle is the same as or smaller than the first cone angle.

[0193] Example 69. The method according to Example 68, wherein the second cone angle is approximately 60° or less.

[0194] Example 70. The method according to Example 68 or 69, wherein the second cone angle is approximately 45° or less.

[0195] Example 71. The method according to any one of Examples 68-70, wherein the ratio of the first cone angle to the second cone angle is about 1:1 to about 4:1.

[0196] Example 72. The method according to any one of Examples 52-71, wherein the extrusion orifice has a diameter of about 0.1 mm to about 1 mm.

[0197] Example 73. The method according to any one of Examples 52-72, wherein the tapered end has a maximum diameter of about 0.2 to about 3.0 mm.

[0198] Example 74. The method according to any one of Examples 52-73, wherein the extrusion orifice has a diameter and the tapered end has a maximum diameter, and the ratio of the maximum diameter of the tapered end to the diameter of the extrusion orifice is approximately 1:0.8 to approximately 1:0.1.

[0199] Example 75. The method according to any one of Examples 52-74, wherein the material has a viscosity of about 100 Pa·s or higher.

[0200] Example 76. A method for producing a product by additive manufacturing, comprising:

[0201] The first material is melted and pressurized;

[0202] The first material is allowed to flow through a first extrusion port of a first nozzle including a conical inner surface;

[0203] The tapered end of the first sealing needle engages with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and preventing the flow of the molten first material;

[0204] The second material is melted and pressurized; and

[0205] The tapered end of the second sealing needle is drawn back from the tapered inner surface of the second nozzle, so that the second material begins to flow through the second extrusion port.

[0206] Example 77. The method according to Example 76 includes receiving instructions for manufacturing a product.

[0207] Example 78. A method for producing a drug dosage form by additive manufacturing, comprising:

[0208] The first pharmaceutical material is melted and pressurized;

[0209] The first pharmaceutical material is allowed to flow through a first extrusion port, which includes a first nozzle with a conical inner surface;

[0210] The tapered end of the first sealing needle engages with the tapered inner surface of the first nozzle, thereby sealing the first extrusion port and preventing the flow of the molten first material;

[0211] The second pharmaceutical material is melted and pressurized; and

[0212] The tapered end of the second sealing needle is drawn back from the tapered inner surface of the second nozzle, thereby initiating the flow of the second pharmaceutical material through the second extrusion port.

[0213] Example 79. The method according to Example 78, wherein the first pharmaceutical material or the second pharmaceutical material is a solvent material.

[0214] Example 80. The method according to Example 78 or 79, wherein the first pharmaceutical material or the second pharmaceutical material comprises a drug.

[0215] Example 81. The method according to Example 80, wherein the drug dosage form has a desired drug release profile.

[0216] Example 82. The method according to any one of Examples 78-81, comprising receiving instructions for manufacturing a pharmaceutical dosage form.

[0217] Example 83. The method according to any one of Examples 76-82 includes 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.

[0218] Example 84. The method according to any one of Examples 76-83, 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.

[0219] Example 85. The method according to any one of Examples 76-84, comprising using a feedback system to control the pressure of the first material or the second material based on the monitored pressure.

[0220] Example 86. The method according to any one of Examples 76-85, wherein the first material or the second material is a non-wire material.

[0221] Example 87. The method according to any one of Examples 76-86, wherein no portion of the first sealing needle contacting the first material or any portion of the second sealing needle contacting the second material has a protrusion.

[0222] Example 88. The method according to any one of Examples 76-87, 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.

[0223] Example 89. The method according to any one of Examples 76-88 includes monitoring the temperature of the first material or the temperature of the second material.

[0224] Example 90. The method according to Example 89 includes using a feedback system to control the temperature of the first material based on the monitored temperature of the first material, or using a feedback system to control the temperature of the second material based on the monitored temperature of the second material.

[0225] Example 91.

[0226] Example 92. The method as described in any one of Examples 76-90, wherein the tapered end of the first sealing needle or the tapered end of the second sealing needle includes a sharp end.

[0227] Example 93. The method as described in any one of Examples 76-91, wherein the tapered end of the first sealing needle or the tapered end of the second sealing needle is a truncated cone.

[0228] Example 94. The method according to any one of Examples 76-93, wherein:

[0229] The first nozzle has a first cone angle on its conical inner surface and the first sealing needle has a second cone angle at its conical end; and wherein the second cone angle is equal to or less than the first cone angle; or

[0230] The conical inner surface of the second nozzle has a third cone angle and the conical end of the second sealing needle has a fourth cone angle; and wherein the fourth cone angle is equal to or less than the third cone angle.

[0231] Example 95. The method according to Example 94, wherein the second cone angle or the fourth cone angle is about 60° or less.

[0232] Example 96. The method according to Example 94 or 95, wherein the second cone angle or the fourth cone angle is approximately 45°.

[0233] Or smaller.

[0234] Example 97. The method according to any one of Examples 94-96, wherein the ratio of the first cone angle to the second cone angle or the ratio of the third cone angle to the fourth cone angle is about 1:1 to about 4:1.

[0235] Example 98. The method according to any one of Examples 76-97, wherein the first extrusion port or the second extrusion port has a diameter of about 0.1 mm to about 1 mm.

[0236] Example 99. The method according to any one of Examples 76-98, 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.

[0237] Example 100. The method according to any one of Examples 76-99, wherein the first material or the second material has a viscosity of about 100 Pa·s or higher.

[0238] Example 101. The method as described in any one of Examples 52-100, wherein the product or pharmaceutical dosage form is manufactured in a batch mode.

[0239] Example 102. The method as described in any one of Examples 52-100, wherein the product or the pharmaceutical dosage form is manufactured in a continuous mode.

[0240] Example 103. A product or pharmaceutical dosage form prepared according to any one of Examples 52-102.

[0241] Case 1

[0242] like Figure 2A-2B and Figures 5A-5C The device shown has an accuracy of 80.75%. A material consisting of VA64, 14.25% triethyl citrate (TEC), and 5% pharmaceutical ingredients was loaded into the barrel of the apparatus for measurement. The material was heated to 110°C in the barrel, 110°C in the feed channel, and 135°C in the printhead. The printhead consisted of a stainless steel nozzle with a 0.4 mm extrusion orifice. The material was pressurized to 0.5 MPa (±0.02 MPa) using a piston inserted into the barrel, controlled by a pressure controller in response to 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 orifice was measured. The results are shown in Table 1.

[0243] Table 1

[0244]

[0245] Case 2

[0246] like Figure 2A-2B and Figures 5A-5C The apparatus shown measures accuracy using a material containing 79.68% HPC, 19.92% triethyl citrate (TEC), and 0.4% pharmaceutical agent, loaded into the apparatus's barrel. The barrel is heated to 90°C, the feed channel to 110°C, and the printhead to 120°C. The printhead comprises a stainless steel nozzle with a 0.3 mm extrusion orifice. The material is pressurized to 1.2 MPa (±0.05 MPa) using a piston inserted into the barrel, controlled by a pressure controller in response to pressure detected by a pressure sensor. The sealing needle is positioned in the open position for 1.25 seconds, 2.5 seconds, or 5 seconds, and the mass of material extruded through the orifice is measured. The results are shown in Table 2.

[0247] Table 2

[0248]

[0249] Case 3

[0250] like Figure 2A-2B and Figures 5A-5C The device shown is 100% accurate. RSPO is loaded into the device's barrel for measurement. The barrel is heated to 140°C, the feed channel to 140°C, and the printhead to 165°C. The printhead consists of a stainless steel nozzle with a 0.3 mm extrusion orifice. The material is pressurized to 1.2 MPa (±0.05 MPa) using a piston inserted into the barrel, controlled by a pressure controller in response to pressure detected by a pressure sensor. The sealing needle is positioned in the open position for 1.67 seconds, 4 seconds, or 7 seconds, and the mass of material extruded through the orifice is measured. The results are shown in Table 3.

[0251] Table 3

[0252]

[0253] Although embodiments of this disclosure have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications should be understood to be included within the scope of the examples of this disclosure as defined by the appended claims.

Claims

1. An apparatus for manufacturing a pharmaceutical product, comprising: a feed system including a cartridge, a feed channel, and a print head, the cartridge including a first heater and configured to melt and pressurize a pharmaceutically acceptable material containing a drug to convert the pharmaceutically acceptable material into a molten material, the feed channel connecting the cartridge to the print head, and the print head including a nozzle and a second heater, the nozzle including a tapered inner surface and an extrusion opening for the printing material, and the second heater configured to heat the molten material in the print head to a temperature higher than the molten material in the feed channel; and a control switch including a sealing needle switchable between an open position and a closed position, the sealing needle extending straight through a portion of the feed channel and including a tapered end; 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, and the second taper angle is equal to or less than the first taper angle, and wherein the tapered end of the sealing needle pierces the molten material in the print head to cause the molten material to flow upward, and the tapered end of the sealing needle engages the tapered inner surface of the nozzle to prevent the molten material from flowing through the nozzle when the sealing needle is in the closed position.

2. The apparatus of claim 1, wherein the sealing needle is operable between an open position and a closed position.

3. The apparatus of claim 1, wherein the tapered end of the sealing needle includes a frustoconical body.

4. The apparatus of claim 1, wherein the tapered end of the sealing needle includes a pointed tip.

5. The apparatus of claim 1, wherein the molten material has a viscosity of 100 Pa-s or more when extruded from the apparatus.

6. The apparatus of claim 1, wherein the control switch includes an actuator that positions the sealing needle.

7. The apparatus of claim 6, wherein the actuator is a pneumatic actuator, a mechanical actuator, or a motorized actuator.

8. The apparatus of claim 1, wherein the tapered end of the sealing needle or the tapered inner surface of the nozzle includes a flexible gasket or bushing.

9. The apparatus of claim 1, further comprising a computer system including one or more processors and a computer readable memory, wherein the computer system is configured to control the apparatus.

10. The apparatus of claim 9, wherein the computer readable memory includes instructions for printing a product using the apparatus. the computer readable memory includes instructions for positioning the sealing needle based on the printed product.

11. The apparatus of claim 10, wherein, initiating a flow of molten material from the feed channel through the extrusion opening when the sealing needle is switched from the closed position to the open position.

12. The apparatus of claim 1, wherein, 13. The apparatus of claim 12, wherein an open distance of the sealing needle in the open position regulates an amount or a speed of extruding the molten material from the nozzle.

14. The apparatus of claim 1, further comprising the pharmaceutically acceptable material and the molten material. ​ 15. An additive manufacturing system comprising a plurality of devices that deposit material by additive manufacturing, wherein at least two of the plurality of devices are devices according to claim 1.

16. The system of claim 15, comprising a first device loaded with a first material and a second device loaded with a second material, wherein the first material and the second material are different.

17. The system of claim 15, further comprising a computer system comprising one or more processors and computer readable memory, wherein the computer system is configured to control the additive manufacturing system.

18. The system of claim 17, wherein the computer readable memory comprises instructions for printing a product using the additive manufacturing system.

19. The system of claim 18, wherein, the computer readable memory comprises instructions for positioning a sealing needle based on the instructions for the printed product.

20. The system of claim 15, wherein at least two of the plurality of devices comprise: a feed system configured to melt and pressurize a material to convert the material into a molten material, the feed system comprising a feed channel connected to a print head comprising a nozzle, the nozzle comprising a tapered inner surface and an extrusion port for the printed material; a control switch comprising a sealing needle that is switchable between an open position and a closed position, the sealing needle extending straight through a portion of the feed channel and comprising a tapered end; and wherein the tapered end of the sealing needle pierces the molten material in the print head to cause the molten material to flow upward, the tapered end of the sealing needle engages the tapered inner surface of the nozzle to block the flow of molten material through the nozzle when the sealing needle is in the closed position, and 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, and the second taper angle is equal to or less than the first taper angle.

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