Integration of electronic device with stopper of cartridge

Abstract

To provide a drug delivery device.SOLUTION: A drug delivery device includes a housing and a plunger 860 arranged inside the housing. The plunger 860 is configured to, when a medicine container 801 exists in the inside of the housing, engage with a stopper 802 in the inside of the medicine container 801 and push the stopper 802 in a distal direction with respect to the drug container 801 for dosage of a medicine 80 from the medicine container 801. The electronic device 806 arranged inside the housing transmits a signal in the distal direction via at least a portion of the stopper 802 in the inside of the medicine container 801, receives reflection of the transmitted signal in a proximal direction via at least a portion of the stopper 802, and determines one or a plurality of states of the drug delivery device on the basis of data representing received reflection with respect to the transmission signal.SELECTED DRAWING: Figure 8A

Description

[Technical field]

[0001] The present description relates to an apparatus for a medical device configured to release a medicament, and more particularly to a stopper for advancing the medicament within a cartridge of an injection device. [Background technology]

[0002] There are various diseases that require treatment by injection of a drug. Such injections can be performed using an injection device applied by a medical professional or by the patient himself. As an example, diabetes mellitus type 1 and type 2 can be treated by the patient himself, for example, by injection of a drug dose once or several times a day. For example, a pre-filled disposable drug pen or auto-injector can be used as the injection device. Alternatively, a reusable pen or auto-injector can be used. A reusable pen or auto-injector allows for replacement of an empty drug cartridge with a new one. Both types of pens or auto-injectors come with a set of disposable needles, which are replaced before each use. Summary of the Invention [Means for solving the problem]

[0003] An exemplary embodiment is a stopper configured to be disposed within a medical cartridge, the stopper including a shell defining a cavity and an exterior surface sized and shaped to fit within the medical cartridge, and an insert configured to be inserted into the cavity. The insert includes an electronic device having a sensor configured to generate a sense signal. The shell is configured to be advanced into the medical cartridge by a plunger to apply pressure to a substance contained within the medical cartridge. The shell is configured to pass the sense signal through a material of the shell, and the sensor is configured to respond to a position of the stopper within the medical cartridge.

[0004] In some embodiments, the insert includes a cap member configured to seal the cavity when the insert is inserted into the cavity, and the cap member is configured to receive a driving force from the plunger to advance the stopper within the medical cartridge.

[0005] In some embodiments, the insert is configured to be secured to the shell using one or more of a snap feature, adhesive, welding, ultrasonic welding, or heat welding.

[0006] In some embodiments, the shell is constructed from a material that can be heat sterilized.

[0007] In some embodiments, the insert is a distal end of a plunger that includes a mating feature and the cavity includes a corresponding mating feature configured to secure the insert to the shell when the distal end of the plunger is inserted into the cavity of the shell of the stopper, hi some embodiments, the cavity includes a guide feature arranged to orient and position the electronic device within the shell.

[0008] In some embodiments, the shell is a rigid shell made from a substantially rigid material. In some embodiments, the stopper includes a sealing member disposed about the outer surface, the sealing member positioned to form a seal between the outer surface and an inner surface of the medical cartridge when the stopper is disposed within the medical cartridge.

[0009] In some embodiments, the shell is a soft shell made from a substantially flexible material, hi some embodiments, an outer surface of the soft shell defines a sealing projection extending radially from the outer surface, the sealing projection being positioned to form a seal between the outer surface and an inner surface of the medical cartridge when the stopper is disposed within the medical cartridge.

[0010] In some embodiments, the sensing signal is an electromagnetic signal or an acoustic signal. In some embodiments, the electronic device is configured to communicate with an external electronic device. In some embodiments, the electronic device includes a wireless transceiver configured to communicate with the external electronic device. In some embodiments, the wireless transceiver is configured to transmit data acquired by the sensor to the external electronic device. In some embodiments, the electronic device is configured to be activated by a force applied to the stopper.

[0011] In some embodiments, the electronic device includes a temperature sensing element configured to wake up the electronic device upon sensing a change in temperature or reaching a temperature threshold.

[0012] In some embodiments, the electronic device includes an energy source. In some embodiments, the energy source includes a wireless charging module having a capacitive electronic circuit. In some embodiments, the energy source includes a piezoelectric element configured to generate electrical energy from a force applied to the stopper. In some embodiments, the energy source is a thermoelectric element configured to generate electrical energy from thermal energy absorbed by the stopper.

[0013] Another exemplary embodiment is a medical cartridge having a cartridge housing and a stopper as described above, where the shell is configured to be inserted into the cartridge housing before the cartridge housing and the shell are subjected to a heat sterilization procedure, and the insert is configured to be inserted into the stopper after the heat sterilization procedure.

[0014] In some embodiments, the medical cartridge is a syringe, the cartridge housing is the housing of the syringe, and the insert is a plunger rod of the syringe configured to be inserted into the shell of the stopper after the syringe undergoes a heat sterilization procedure.

[0015] Yet another exemplary embodiment is a method of manufacturing a medical cartridge comprising the steps of inserting a shell into a housing of the medical cartridge, where a stopper seals an open end of the housing, where the shell defines a cavity accessible from outside the housing, where the shell is configured to pass a sensing signal, heat sterilizing the shell and the housing, and placing an insert into the cavity of the shell after heat sterilization, where the insert includes an electronic device including a sensor configured to generate a sensing signal. Together, the shell and insert form a stopper configured to be advanced into the medical cartridge by a plunger to apply pressure to a substance contained within the medical cartridge, where the sensor is configured to respond to a position of the stopper within the medical cartridge. [Brief description of the drawings]

[0016] [Figure 1] FIG. 2 is an exploded view of the injection device. [Figure 2A] FIG. 13 is a cross-sectional view showing a stopper configured to be disposed within an injection device, the stopper having a rigid shell and a soft, insertable core with an electronic device embedded within the core. [Figure 2B] FIG. 2B is a top view of the stopper of FIG. 2A. [Figure 2C] 4 is a cross-sectional view of a stopper disposed within a cartridge. FIG. [Figure 3A] FIG. 13 is a cross-sectional view showing a stopper configured to be disposed within an injection device, the stopper having a soft shell and a rigid insertable core with an electronic device embedded within the core. [Figure 3B] FIG. 3B is a top view of the stopper of FIG. 3A. [Figure 4] FIG. 1 is a cross-sectional view showing a stopper configured to be disposed within an injection device, the stopper having a rigid shell and a soft insertable core with an electronic device embedded within the core, the stopper having a rigid cover. [Diagram 5]FIG. 13 is a cross-sectional view showing a stopper configured to be disposed within an injection device, the stopper having a soft shell and a rigid insertable core with an electronic device embedded within the core. [Figure 6] 4 is a cross-sectional view of a stopper disposed within a cartridge. FIG. [Figure 7A] 1 is a cross-sectional view of a shell of a stopper disposed within a cartridge and an insert coupled to the shell. [Figure 7B] FIG. 7B is a cross-sectional view of the stopper of FIG. 7A receiving an insert prior to being driven by a plunger. [Figure 7C] FIG. 7C is a cross-sectional view of the stopper of FIG. 7B during or after being driven into the cartridge by the plunger during a sensing operation. [Figure 8A] FIG. 1 is a cross-sectional view of a disposable syringe having electronics embedded into the threaded distal end of the plunger. [Figure 8B] FIG. 1 is a cross-sectional view of a disposable syringe having electronics embedded into the threaded distal end of the plunger. [Figure 9] 13 is a flow diagram showing a method for assembling and sterilizing a cartridge with a stopper and then coupling an electronic element into the stopper. [Figure 10] 1 is a cross-sectional view of a stopper disposed within a cartridge and in communication with a wireless system; [Figure 11] 11A and 11B are cross-sectional views of a stopper disposed within a cartridge and powered by a piezoelectric system. [Figure 12] 12A and 12B are cross-sectional views of a stopper and a Peltier thermoelectric device disposed within a cartridge. [Figure 13] 13A and 13B are cross-sectional views of the shell of a stopper disposed within a cartridge and an insert clipped into the shell. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Some cartridge-based injection and medical syringe systems can be difficult to sterilize before use if they include electronics within the replaceable parts of the device (e.g., cartridge stopper or cartridge housing). Electronic assemblies may include temperature-sensitive materials (e.g., polymers) that can degrade after application of heat. Additionally, batteries can lose performance at high temperatures. In some examples, the cartridge stopper (sometimes called a bung) can be sterilized before the electronics are added. For example, a stopper made from a rigid material can be sealed against the cartridge wall by a soft O-ring seal, and an insertable electronic device can be used that is separate from the stopper and therefore can be assembled into the stopper or cartridge after the heat sterilization process (and therefore does not affect the sterilized liquid in the cartridge). Some examples also enable adding electronic components (e.g., RFID, sensors) to the pre-heat sterilized plunger of a disposable or reusable drug cartridge.

[0018] 1 is an exploded view of an injection device 100, which may be a disposable or reusable injection device. The injection device 100 includes a housing 110 and a cartridge 114 having a cartridge housing 104. A dollar assembly 115 may be attached. The needle 109 of the needle assembly 115 is protected by an inner needle cap 116 and an outer needle cap 117, which may be further covered by a cap 118. The drug or medication dose to be released from the injection device 100 is selected by turning the dose knob 112, and the selected dose is displayed via a dose window or display 113. The display may include, for example, a digital display. The dose display 113 relates to a section of the injection device in which the selected dose can be viewed.

[0019] As will be further described below, the injection device 100 may include one or more electronic components 122, 124, some of which may be included within the stopper 108, for example.

[0020] Turning the dose knob 112 triggers a mechanical click, providing acoustic feedback to the user. The numbers displayed in the dose display 113 are printed on a sleeve housed in the housing 110 and mechanically interact with a plunger in the cartridge 114. When the needle 109 is pierced into a portion of the patient's skin and the injection button 111 is then pressed, the drug dose displayed in the display 113 is released from the injection device 100. During injection, a drive mechanism 106, shown as an outline of a plunger arm, drives the stopper 108 into the cartridge to release the drug. The stopper is a key element of the container closure system, as it provides a barrier to fluids leaking in and out, a gas barrier (e.g., oxygen), and prevents evaporation of H2O and other fluids. In some embodiments, the sealing function is provided by a resilient sealing element (808 in FIG. 8A or FIG. 8B) in contact with the container wall, but still allows the stopper to slip. Once the injection button 111 is pressed and the needle 109 of the injection device 100 remains within the skin area for a certain period of time, most of the dose is actually injected into the patient's body.

[0021] FIG. 2A is a cross-sectional view of one embodiment of a stopper 200 configured to be disposed in an injection device (e.g., injection device 100). The stopper 200 includes a rigid or substantially rigid shell 202 and a core 204 housing electronic devices 206a, 206b, and 206c, which in some embodiments are embedded in the material of the core. The core 204 is configured to be inserted into the shell 202 after manufacture. The core 204 can include or form an insert configured to be inserted into a cavity of the shell 202, the insert including an electronic device having a sensor configured to generate a sensing signal. For example, the core 204 can be inserted into the shell 202 after the shell is disposed in a cartridge (e.g., cartridge 114 of FIG. 1) of the injection device. The shell 202 includes a sealing element 208 (e.g., an O-ring) positioned to provide a sealing interface against an inner surface of the cartridge 114 when the shell 202 is inserted into the cartridge 114. The sealing element 208 may form a sealing member disposed about an outer surface of the shell 202. The sealing element 208 may define a sealing projection extending radially from the outer surface of the shell 202.

[0022] The materials selected for the shell 202 and core 204 are selected based on hardness, elasticity, and heat resistance or thermal insulation. In some embodiments, the shell 202 and core 204 are made from polymeric materials with various elasticities. In some embodiments, a heat resistant coating, such as a Teflon coating (e.g., polytetrafluoroethylene), may be applied to the exterior of the core 204 or shell 202 to increase heat resistance. In some cases, the shell 202 is made from a material selected to be compatible with the drug at the drug contacting surface 203, such as PP, PE, POC, POP, PTFE, or butyl rubber. In some embodiments, the materials selected for the shell 202 and core 204 are also selected to allow the sensor signal to pass through non-metallic materials such as polymers or ceramics or very thin metals (e.g., less than 0.1 mm thick).

[0023] The implantable electronic devices 206a, 206b, and 206c may include, for example, a sensor, an energy source, a microcontroller, or a wireless transceiver. The implantable electronic devices 206a, 206b, 206c are merely representative. Any number of implantable electronic devices may be present. In some embodiments, the sensor may be a sensor / transceiver device, such as, for example, a piezoelectric device, an acoustic sensor, or an electromagnetic sensor. The sensor / transceiver may transmit a signal, such as, for example, an ultrasonic, acoustic, optical, or other signal, through the stopper 200 and measure a response, which in some embodiments may be used to determine the position of the stopper 200 in the cartridge 114 or whether an injection of the syringe has occurred. The position of the stopper 200 before and after the injection corresponds to a change in the volume of the drug remaining in the cartridge 114 and may indicate the volume or dose of drug released from the cartridge 114 into the needle 109. In some embodiments, the response received by the sensor is provided to a controller (e.g., an embedded or external microcontroller), which can receive the response and calculate a status of the cartridge 114. The status of the cartridge 114 can correspond to the fill level of the drug within the cartridge 114, the position of the stopper 200, or the dose volume.

[0024] In some embodiments, the energy source can be a battery, an energy harvesting device that generates energy by any energy harvesting technique that can load a capacitor for temporary energy storage, or solar powered. The wireless transceiver can communicate with the external electronic device as well as the sensor and the energy source. The external electronic device can be a controller and can communicate data received from the sensor to an external database. The communication with the controller can be one-way or two-way. The data communicated from the sensor device to the external database can include information related to the device's identification, such as a unique number, calibration data, production lot information, device material information, data related to storage time and production time, and information related to the sensor measurement (e.g., sensor measurement results such as measurement time, temperature, distance, optical signal, acoustic signal). In some embodiments, the data coming from the external database device to the controller includes information regarding a "wake-up" signal, a trigger for measurement, time information, or calibration data. The wireless transceiver can communicate using any known wireless communication technique, including, for example, Bluetooth, NFC, or radio frequency.

[0025] In some embodiments, the shell 202 and the core 204 are manufactured separately, with the core 204 being inserted into the shell 202 in a later assembly step. For example, the core 204 can be formed when the substantially soft material (e.g., by pouring, injecting, etc. the substantially soft material) and the embedded electronic devices 206a, 206b, and 206c are loaded into a mold, after which the substantially soft material solidifies (e.g., hardens, solidifies, etc.). In another embodiment, the substantially soft material is introduced around the electronic devices 206a, 206b, and 206c and shaped (e.g., cut, poured into a mold, etc.) to form the core 204. The stopper 200 can include a sealing element 208 disposed on the periphery of the shell 202 to provide a sealing interface to the cartridge 114 when the stopper 200 is introduced into the cartridge 114.

[0026] FIG. 2B is a top view of the stopper 200 of FIG. 2A. The shell 202 has a core 204. The surrounding and interlocking sealing element 208 form a sealing interface with the cartridge 114 when the stopper 200 is introduced into the cartridge 114. The sealing interface can form at least a portion of a sterility barrier within the cartridge 114 required to preserve the sterility of a medicament to be delivered by the injection device.

[0027] In some embodiments, the shell 202 is constructed from a rigid material such as metal, polymer (e.g., COC, PA, PP, PE, POM, PS, ABS, COP, etc.), glass, or ceramic. In some embodiments, the electronic devices (or electronic assemblies) 206a, 206b, 206c include sensors, power sources (e.g., batteries), controllers, wireless communication modules (e.g., Bluetooth, NFC, Bluetooth The electronic devices 206a, 206b, 206c and the core 204 are coupled to the shell 202 using snap features, adhesives, welding, US welding, heat welding, or other means. In some embodiments, the core 204 is removably coupled to the shell 202. In some embodiments, the electronic devices 206a, 206b, 206c and the core 204 are coupled to the shell 202 using snap features, adhesives, welding, US welding, heat welding, or other means. In some embodiments, the core 204 is removably coupled to the shell 202. In some embodiments, the sealing member 208 is made of natural rubber or any biocompatible rubber composition. In some embodiments, the core 204 includes an on-off switch configured to trigger the electronic devices 206a, 206b, 206c by any suitable impact against the stopper 200 (eg, a force from the drive mechanism 106).

[0028] 2C is a cross-sectional view of the stopper 200 disposed within the cartridge 600. Various features of the illustrated stopper 200 have been described above with respect to FIGS. 3A and 3B. The stopper 200 may be substituted for any of the stoppers in the following figures and would interface with the cartridge 600 in the same manner as described herein with respect to the stopper 300. The cartridge 600 includes a housing 602 that interfaces with the sealing element 208 of the stopper 200 to seal the open end of the cartridge 600. In some embodiments, a drug is disposed within a space between the cap 604 of the cartridge 600 and the shell 202 of the stopper 200. In some embodiments, the implantable electronics 206a, 206b, and 206c include sensors configured to send and receive signals to sense the position of the stopper 200 within the cartridge 600.

[0029] In one example, a transmitter (e.g., one of the electronic devices 206a, 206b, and 206c) transmits an acoustic wave at a first time t1. The first time t1 (e.g., the time of transmission of the acoustic wave) can be provided to an external device. The acoustic wave propagates from the transmitter in the stopper 200 toward the distal end of the cartridge 600 and is reflected (e.g., bounced off) a surface of the cartridge 600 or a reflector (not shown). A reflection of the acoustic wave (e.g., a reflected wave) propagates from the distal end of the cartridge 600 (i.e., the end having the cap 604) toward a sensor in the stopper 200. The reflected wave is received at a second time t2. The speed of the acoustic wave is the known speed of sound in the drug in the cartridge. The elapsed time between the transmission and reception of the acoustic wave is t2-t1. The elapsed time is multiplied by the speed of sound to determine the distance the wave traveled from the transmitter to the distal end of the cartridge 600 and back to the sensor. This travel distance is divided by two to determine the distance between the stopper 200 and the distal end of the cartridge 600. The volume of drug within the cartridge 600 (e.g., the volume of drug sealed within the cartridge 600 between the stopper 200 and the proximal end) is determined by multiplying the determined distance by the cross-sectional area of ​​the cartridge 600. The difference in the volume of drug within the cartridge 600 determined before and after administration corresponds to the dose administered to the patient.

[0030] 3A and 3B show a stopper 300 configured to be disposed in an injection device 100, the stopper 300 having a soft shell 302 and a rigid core 304, in which the electronic devices 306a, 306b, 306c are embedded. In some embodiments, the rigid core 304 has the advantage of protecting the electronic devices 306a, 306b, 306c from deformation due to being pushed by the plunger. This ensures a reliable sensor signal. Another advantage is that the rigid core 304 provides better injection dose accuracy, since there is less elastic action from the stopper 300 during injection. This also helps to reduce the retention time during injection. In this context of the soft shell 302, soft means a viscoelastic material characterized by a low e-module (high elastic deformation and low residual deformation and stress), such as natural rubber, thermoplastic elastomers (TPE), butyl rubber, neoprene, fluoroelastomers, silicone rubber, etc. The stopper 300 includes a substantially soft shell 302 and a substantially rigid core 304. In some embodiments, the shell 302 and the core 304 are substantially inseparable after assembly. For example, the core 304 can be inserted into the shell 302 and secured using an adhesive to bond the core 304 and the shell 302 together. An adhesive bond can be used between any of the core and shell / insert embodiments described herein. The core 304 houses embedded electronic devices 306a, 306b, and 306c. The core 304 can include or form an insert configured to be inserted into a cavity of the shell 302, the insert including an electronic device having a sensor configured to generate a sensing signal. In one embodiment, a substantially rigid material can be molded around the electronic devices 306a, 306b, and 306c in an uncured, soft state, which can be solidified to form the rigid core 304. In another embodiment, the electronic devices 306a, 306b, 306c can be introduced into the substantially rigid material in an uncured, soft state, after which the substantially rigid material solidifies to form the rigid core 304.When the stopper 300 is inserted into the cartridge 114, the integrated sealing element 308 forms a sealing interface (i.e., a gas-tight barrier) between the stopper and an inner wall of the cartridge 114. The sealing interface may form at least a portion of a sterility barrier within the cartridge 114 required to preserve the sterility of a medicament to be delivered by the injection device 100. The sealing element 308 may form a sealing member disposed about an outer surface of the shell 302. The sealing element 308 may define a sealing projection extending radially from the outer surface of the shell 302. The sealing element may form a seal between the outer surface of the shell 302 and an inner surface of the medical cartridge when the stopper is disposed within the medical cartridge.

[0031] The various materials from which the shell 302 and core 304 can be made, as well as the various electronic devices that can be embedded within the core, are described above with respect to Figure 2A. Additionally, because the shell 302 is configured to contact a drug, the material for the shell 302 can be medical grade.

[0032] The shells of Figures 2A, 2B, 3A, and 3B can be sterilized, for example, by using a heat sterilization process prior to insertion of the core. In an exemplary heat sterilization process, the shell would be sterilized at a temperature of about 120 degrees Celsius for about 20-30 minutes, after which the core and associated electronics would be inserted into the shell.

[0033] In some embodiments, the core 304 is constructed from a rigid material such as metal, polymer (e.g., COC, PA, PP, PE, POM, PS, ABS, COP, etc.), glass, or ceramic. In some embodiments, the electronic devices (or electronic assemblies) 306a, 306b, 306c include sensors, power sources (e.g., batteries), controllers, wireless communication modules (e.g., Bluetooth, NFC, Bluetooth The electronic devices 306a, 306b, 306c and the core 304 are coupled to the shell 302 using snap features, adhesives, welding, US welding, heat welding, or other means. In some embodiments, the core 304 is removably coupled to the shell 302. In some embodiments, the sealing member 308 is made of natural rubber or any biocompatible rubber composition. In some embodiments, the core 304 includes an on-off switch configured to trigger the electronic devices 306a, 306b, 306c by any suitable impact against the stopper 300 (eg, a force from the drive mechanism 106).

[0034] 4 is a cross-sectional view of a stopper 400 configured to be disposed in an injection device 100, the stopper 400 having a rigid shell 402 and a soft insertable core 404 with electronic devices 406a, 406b, 406c embedded in the core 404, and the stopper 400 having a cover 410. In this embodiment, the shell 402 and the core 404 are manufactured separately, and the core 404 is inserted into the shell 402 in a later assembly step. For example, the core 404 can be formed when a substantially soft material (e.g., by injecting, injecting, etc., the substantially soft material) and the embedded electronic devices 406a, 406b, and 406c are filled into a mold, after which the substantially soft material solidifies (e.g., hardens, solidifies, etc.). In another embodiment, a substantially soft material is introduced around the electronic devices 406a, 406b, and 406c and shaped (e.g., cut, poured into a mold, etc.) to form the core 404. The stopper 400 includes sealing elements 408 disposed on the periphery of the shell 402 to provide a sealing interface to the cartridge 114 when the stopper 400 is introduced into the cartridge 114. Thus, depending on the particular configuration of the material, in one embodiment there is a cover for the core and in another embodiment there is no need for a cover.

[0035] The stopper 400 also includes a cover 410 configured to interface with the substantially rigid shell 402 and receive a contact force from a head of a plunger (e.g., a plunger rod 760 shown in FIGS. 7B, 7C) to advance the stopper 400 into the cartridge 114. The cover 410 can be constructed from a substantially rigid material as detailed above with respect to the shell 402. The contact force from the plunger rod imparts a force to the cover 410, which is configured to transmit this force to the substantially rigid shell 402. Because the plunger can deform the insertable core 404 (e.g., by compression), if the cover 410 is removed, the transmission of force should be significantly reduced. The cover 410 also provides a beneficial geometry for interface with the plunger 760 when the plunger 760 contacts the top surface of the rigid shell 402 along the circumference of the shell 402. The head of the plunger 760 can be sized to contact the top surface of the shell 402 (e.g., the diameter of the plunger 760 is larger than the diameter of the shell cavity), but in some embodiments, the inclusion of a cover 410 distributes the force applied to the shell 402 more evenly.

[0036] FIG. 5 is a cross-sectional view of a stopper configured to be disposed within an injection device, the stopper having a soft shell 502 and a rigid insertable core 504 with an electronic device embedded within the core 504. The stopper 500 includes a substantially soft shell 502 and a substantially rigid core 504. In this embodiment, the shell 502 and the core 504 are manufactured separately, with the core 504 being inserted into the shell 502 in a later assembly step. For example, the core 504 may be made of a substantially rigid material (e.g., a material that can be injected, injected, etc., of a substantially rigid material). The core 504 may be formed when the stopper 506 is inserted into the cartridge 114, such as by inserting the stopper 506 into the cartridge 114, and the electronic devices 506a, 506b, and 506c into the cartridge 114. The stopper 506 may be inserted into the cartridge 114, such as by inserting the stopper 506 ....

[0037] A soft shell 502 has the advantage of having the shell function and the sealing function in one component. However, in the manufacturing process, it may be more difficult to handle the soft or elastomeric shell material for assembly. A rigid shell may be easier to handle / hold during the manufacturing process and may result in better dosing accuracy, but requires a separate sealing element, such as an O-ring, to provide a sealing interface to the cartridge. A substantially rigid core has the advantage of easier handling during manufacturing and better protection of the sensitive sensor element from possible stresses during heat sterilization.

[0038] Various materials from which the shell and core can be made, as well as various electronic devices that can be embedded within the core, are described above with respect to Figure 2 A. Additionally, because the stopper is configured to contact a drug, the material for the shell can be medical grade.

[0039] The two-piece stopper cores 404 and 504 of Figures 4 and 5 can be inserted after the shells 402 and 502 are inserted into the cartridge 114. The shells and cartridge 114 can be heat sterilized. The cores 404 and 504 containing the implantable electronics can be pressed into the cavity formed by the shell of the stopper after the cartridge 114 is sterilized.

[0040] FIG. 6 is a cross-sectional view of a stopper disposed within a cartridge 600. Various features of the illustrated stopper have been described above with respect to FIGS. 3A and 3B. The stopper 300 may be substituted for any of the stoppers of the above-mentioned figures and would interface with the cartridge in the same manner as described herein with respect to the stopper 300. The cartridge 600 includes a housing 602 that interfaces with a sealing element 308 of the stopper 300 to seal an open end of the cartridge 600. In some embodiments, a medicinal agent (e.g., a medical fluid or drug) is disposed within a space between a cap 604 of the cartridge 600 and a shell 302 of the stopper 300. In some embodiments, the implantable electronics 306a, 306b, and 306c include sensors configured to transmit and receive signals to sense the position of the stopper 300 within the cartridge 600.

[0041] The sensor can be a sensor / transceiver device, for example a piezoelectric device. The sensor / transceiver can send a sensing signal, for example an ultrasound, acoustic, light or other signal, through the stopper 300 and measure the response. The received response can be provided to a controller (for example an embedded or external microcontroller), which can receive the response and calculate the state of the cartridge 600. The state of the cartridge 600 can correspond for example to the fill level of the drug in the cartridge 600 or the position of the stopper 300. The state of the cartridge can allow for the measurement of the dose of the drug injected. In some embodiments, various measurement methods are used to measure the position of the stopper 300 as described above. It is necessary to generate a certain signal that changes with the movement of the stopper 300 relative to a fixed position in the system or cartridge 600. This fixed position can be inside the cartridge 600, for example a septum area of ​​the cartridge 600 that never moves, or another rigid wall of the cartridge 600, or can be introduced into the cartridge for this purpose. The reference may be an element capable of measuring the distance or the reference may be an element outside the cartridge, e.g. an injection device element such as a housing member. In some embodiments, the sensor measures the change in the light signal by sending light from a light source (e.g. LED) to a fixed area and receiving the attenuated light by a photodetector. The strength of the attenuation may be correlated to the distance. Another possibility is to measure the change in the time required for a signal (e.g. acoustic signal) to travel from a transmitter to a fixed location and back to a receiver located close to the transmitter. In another embodiment, a signal (optical, acoustic, capacitive, etc.) may be sent from a fixed location to a receiver within the moving stopper 300, and the change in the signal during the movement of the stopper may be measured and correlated to the position of the stopper within the cartridge 600.

[0042] 7A is a cross-sectional view of a shell 702 of a stopper 700 disposed within a cartridge 701 and an insert 710 coupled to the shell 702. The shell 702 is shown inside the cartridge 701 with a plurality of sealing elements 708 surrounding the shell 702 forming a seal for containing the medicament 70 within the cartridge 701. A central cavity 758 and a peripheral alignment cavity 759 are formed within the stopper 700. The insert 710 includes alignment features 719 extending from a bottom surface of the insert 710 with an electronic device 706 coupled to the center of the insert 710 such that the electronic device 706 is positioned to be inserted into the central cavity 758 of the stopper 700 when the insert 710 is coupled to the shell 702 (shown in FIG. 7B). In some embodiments, the shell 702 defines a receptacle for the insert 710. Additionally, alignment features 719 are positioned for insertion into peripheral alignment cavities 759 and in some embodiments include snap features for securing insert 710 to shell 702 or in some embodiments are configured to be bonded to insert 710 using adhesive or welding. Insert 710 also includes a center alignment feature 718 on electronic device 706 to aid in positioning insert 710 during the beginning of the assembly operation. This assembly operation is represented by arrow 797 indicating the direction of movement of insert 710 (the result of which is shown in FIG. 7B ). In some embodiments, guiding features (e.g., alignment feature 719 and center alignment feature 718) ensure the correct orientation and precise location of insert 710 relative to shell 702 during assembly.

[0043] In some embodiments, the insert 710 and shell 702 are constructed from a rigid material such as metal, polymer (e.g., COC, PA, PP, PE, POM, PS, ABS, COP, etc.), glass, or ceramic. In some embodiments, the electronic device (or electronic assembly) 706 includes a sensor, a power source (e.g., a battery), a controller, a wireless communication module (e.g., Bluetooth, NFC, Bluetooth The electronic device 706 and the insert 710 are coupled to the shell 702 using snap features, adhesives, welding, US welding, heat welding, or other means. In some embodiments, the insert 710 is removably coupled to the shell 702. In some embodiments, the sealing member 708 is made from natural rubber or any biocompatible rubber composition. In some embodiments, the insert 710 includes an on-off switch configured to trigger the electronic device 706 by any suitable impact against the stopper 700 (e.g., force from the plunger 760). In some embodiments, the sealing member 708 is made from a first material and the shell 702 is made from a second material that is less compressible compared to the material of the first member, and the shell 702 is formed as a receptacle for receiving the insert 710. In some embodiments, the electronic device 706 and the insert 710 are coupled to the shell 702 using snap features, adhesives, welding, US welding, heat welding, or other means. In some embodiments, the insert 710 is removably coupled to the shell 702. In some embodiments, the sealing member 708 is made from natural rubber or any biocompatible rubber composition. In some embodiments, the insert 710 includes an on-off switch configured to trigger the electronic device 706 by any suitable impact against the stopper 700 (e.g., force from the plunger 760).

[0044] FIG. 7B is a cross-sectional view of the stopper 700 of FIG. 7A containing the insert 710 prior to being driven into the cartridge 701 by the plunger 760 (which itself The body can be driven by a drive mechanism 106 as shown in FIG. 1 ). FIG. 7B shows the insert 710 coupled to the shell 702, with the electronic device 706 disposed entirely within a central cavity 758 of the shell 702, and the alignment features 719 located within peripheral alignment cavities 759. In some embodiments, the plunger 760 (e.g., plunger rod and head) is driven by an actuator or drive mechanism of a syringe (shown in FIG. 1 ) having a cartridge 701, or is the plunger of a syringe, and the cartridge 701 is a syringe housing. In operation, the plunger 760 is driven (indicated by arrow 798) relative to the insert 710, thereby applying a force to the shell 702 and moving the stopper 700 into the cartridge 701 and expelling a portion of the medicament 70 from the cartridge 701.

[0045] Figure 7C is a cross-sectional view of the stopper 700 of Figure 7B during or after being driven by plunger 760 into cartridge 701. Figure 7C shows that plunger 760 has contacted stopper 700 and driven stopper 700 into cartridge 701 (indicated by arrow 799). In operation, electronics device 706 emits a sensing signal 770 which, in some embodiments, is responsive to the position of stopper 700 within cartridge 701 enabling the electronics device to generate a signal indication of the movement of stopper 700.

[0046] The embodiments of the present disclosure can also be applied to pre-filled single and dual chamber syringes that may not use a cartridge. The examples described above with respect to integrating electronics into the stopper of a cartridge can also be used with disposable pre-filled syringes. However, in the disposable syringe embodiment of Figures 8A and 8B, a threaded stopper-plunger rod interface is used to position the electronic device into the stopper by disposing the electronic device in the threaded end of the plunger rod and locating a threaded cavity in the stopper, such that the electronic device is introduced into the stopper and positioned in a position that allows sensing by the electronic device in the syringe, for example, to determine the position of the stopper in the syringe (when the plunger rod is threaded into the cavity). For example, as shown in Figures 8A and 8B, a threaded plunger is used to house, among other things, the sensor / connection technology. This configuration enables the use of the sensing and connection functions of the stopper detailed above in a disposable syringe. Additionally, in some embodiments, in dual chamber syringes having intermediate and transition stoppers configured to receive a plunger rod, aspects of the present disclosure can be integrated into the intermediate stopper during construction of the dual chamber syringe to sense and / or measure the state of the device (e.g., "pre-mixing," "mixed solution ready," or "injection complete" based on a sensing signal).

[0047] 8A and 8B are cross-sectional views of a disposable syringe 800 having an electronic device 806 embedded within a threaded distal end 861 of a plunger 860. The stopper 802 includes a threaded feature 852 extending into a central cavity 859. The distal end 861 of the plunger 860 includes a corresponding threaded feature 862 arranged to secure the plunger 860 to the stopper 802. As detailed above, the stopper 802 is sealingly engaged to a cartridge, here shown as a syringe housing 801, using a number of sealing members 808 disposed about the periphery of the stopper 802. In operation, as shown in FIG. 8B, the distal end 861 of the plunger 860 is moved into contact with the stopper 802 (e.g., arrow 897) and rotated into threaded engagement with the stopper 802 (e.g., arrow 898). In this configuration, the electronics device 806 is disposed within the stopper 802 and, in some embodiments, is arranged to emit a sensing signal 870 to determine the position of the stopper 802 within the housing 801 of the syringe 800 or whether an injection action has occurred. As shown in FIG. 8B, a force 899 is applied to the plunger 860. When the plunger 860 is inserted (e.g., by a patient or clinician operator of the syringe 800), the plunger 860 drives the stopper 802 within the housing 801 of the syringe 800 to expel at least a portion of the medicament 80 from the syringe 800. One benefit of the configuration of the disposable syringe 800 of Figs. 8A and 8B is that the syringe housing 801 and the stopper 802 can be subjected to heat sterilization before the plunger 860 is introduced into the stopper 802, thus eliminating the need to subject the electronic device 806 contained within the distal end 861 of the plunger 860 to heat sterilization, a process that the electronic device 806 cannot functionally withstand. Another benefit of this implementation is that the electronic device 806 is outside of the sterilization process. The electronic device 806 can be manufactured more easily and cheaply in a typical manufacturing process. From a shipping perspective, the introduction of the electronic device 806 can be done at a later manufacturing step, which has the advantage of longer battery life since storage time can be optimized.

[0048] 9 is a flow diagram illustrating a method for assembling and sterilizing a cartridge with a stopper and then coupling an electronic element into the stopper. First, the shell 702, 802 is inserted (910) into the cartridge 701, 801 of the medical cartridge 144, and the stopper 700, 802 seals the open end of the cartridge 701, 801. The assembled shell 702, 802 and cartridge 701, 801 are then heat sterilized (920). Next, the insert 710, 861 having the electronic device 706, 806 is inserted (930) into the cavity 758, 859 of the housing, and in some embodiments, the electronic device 706, 806 includes a sensor configured to generate a sensing signal 770, 870 in response to the position of the shell 702, 802 within the cartridge 701, 801. The assembled shell 702, 802 and insert 710, 861 form the stopper 700 that can be advanced into the cartridge 701, 801 by the plunger 760, 860 (940). Finally, in some embodiments, a sensor in the electronic device 706, 806 senses (950) the position of the stopper 700, 802 within the cartridge 701, 801 using a sensing signal, and in some embodiments wirelessly transmits the position signal to an electronic device external to the stopper 700, 802.

[0049] Described below are devices and methods that use energy harvesting to provide energy to electronic circuitry within a cartridge system (such as those disclosed herein) to provide an alternative to standard batteries or as a supplement to batteries.

[0050] Aspects of the system disclosed above enable medical injectors to use "smart" technology by means of attached or embedded electronic components (e.g., RFID, sensors) to give specific functionality to the cartridge of the injection device (e.g., pen injector). When integrating electronics into the stopper of the cartridge, one or more components (e.g., sensors for measuring specific properties of the injector or cartridge) can be active, which requires an energy source. The energy source can typically be a battery. As explained below, one alternative is to use an energy harvesting means as a power source instead of a battery.

[0051] An example of an energy harvesting system is shown in Fig. 10, which is a cross-sectional view of a stopper disposed within a cartridge and powered by a wireless system. Fig. 10 shows a cartridge 1000 including a stopper 1002 disposed within a housing 1001 of the cartridge 1000. The stopper 1002 and sealing elements 1008 together contain a drug 1011 within the housing 1001, and the stopper 1002 includes a number of sealing elements 1008 disposed around the periphery of the stopper 1002, which sealingly engage with an inner surface of the housing 1001. The stopper 1002 also seals an opening in the stopper 1002. The stopper 1002 includes a cap 1010 having openings into which the electronics assemblies 1071, 1078, 1079 are inserted. In some embodiments, in operation, the electronics assemblies 1071, 1078, 1079 are integral with or held by the cap 1010, whereby securing the cap 1010 to the stopper 1002 includes inserting the electronics assemblies 1071, 1078, 1079 into cavities in the stopper 1002. The electronics assemblies 1071, 1078, 1079 include a sensing device (S) 1079, a wireless device (WL) 1078, and a capacitive device (CE) 1071.

[0052] In operation, the sensing device 1079 is configured to sense the position of the stopper 1002 within the housing 1001, and the wireless device 1078 is configured to communicate with an external electronic device (not shown) to communicate information from the sensor device 1079. The capacitive device 1071 is configured to provide power to the sensing device 1079 and the wireless device 1078 by wireless inductive charging from a wireless signal 1081 located in proximity to the cartridge 1000. In some embodiments, the capacitive device 1071 includes a capacitive circuit configured to wirelessly receive power, for example from a smartphone 1080 via a Near Field Communication Protocol (NFC) signal 1081, or by a typical wireless charging device with other inductive loading means, to provide sufficient energy to initiate and perform measurements by the sensing device 1079 within the cartridge 1000 and transmit the results back using the wireless device 1078.

[0053] 11A and 11B are cross-sectional views of a stopper disposed in a cartridge and powered by a piezoelectric system. Another example of an energy harvesting system is to use piezoelectric technology to harvest energy from mechanical forces that occur between the stopper and plunger (or the cartridge-stopper threaded rod system of, for example, FIGS. 8A and 8B) during, for example, syringe handling or injection motion, to provide sufficient energy to initiate and perform measurements in the cartridge and send back results. FIG. 11A shows a cartridge 1100 having a stopper 1102 disposed in a housing 1101 of the cartridge 1100 and a plunger 1160 advancing (e.g., along arrow 1197) to contact a cap 1110 of the stopper 1102. The stopper 1102 and sealing element 1108 together contain the medicament 1111 within the housing 1101, the stopper 1102 including a plurality of sealing elements 1108 disposed about a periphery of the stopper 1102, the sealing elements 1108 sealingly engaged with an inner surface of the housing 1101. The cap 1110 seals an opening in the stopper 1102 into which the electronics assemblies 1172, 1178, 1179 are inserted, the cap 1110 configured to at least partially deflect under the force of the plunger 1160 or otherwise effect transfer of force from the plunger to a portion of the electronics assemblies 1172, 1178, 1179. In some embodiments, in operation, the electronics assemblies 1172, 1178, 1179 are integrated or held by the cap 1110, whereby securing the cap 1110 to the stopper 1102 includes inserting the electronics assemblies 1172, 1178, 1179 into cavities in the stopper 1102. The electronics assemblies 1172, 1178, 1179 include a sensing device (S) 1179, a wireless device (WL) 1178, and a piezoelectric element (PE) 1172.

[0054] In operation, the sensing device 1179 is configured to sense the position of the stopper 1102 within the housing 1101, and the wireless device 1178 is configured to communicate with an external electronic device (not shown) to communicate information from the sensor device 1179. The piezoelectric element 1172 is configured to provide power to the sensing device 1179 and the wireless device 1178 by converting a portion of the force applied to the stopper 1102 into electrical energy. As shown in FIG. 11B, the piezoelectric element 1172 is deflected from position 1198 in FIG. 11A to the deflection in FIG. 11B by the force applied to the cap 1110 by the plunger 1116. 1197 to deflected position 1199 (during movement indicated by arrow 1197). As the piezoelectric element 1172 is deflected from position 1198 to deflected position 1199, it absorbs energy and converts a portion of that energy into electrical energy.

[0055] 12A and 12B are cross-sectional views of a stopper disposed within a cartridge, the stopper including a Peltier thermoelectric device. Another example of an integrated energy harvesting device is to include a thermoelectric element (TE) to convert the temperature difference between refrigeration (e.g., pen or syringe in storage) and warming (e.g., exposure to room temperature) into electrical energy to provide sufficient energy to initiate and perform measurements within the syringe / pen cartridge and transmit the results back. FIG. 12A shows a cartridge 1200 stored in a cold environment (e.g., 4° C.), with a stopper 1202 disposed within a housing 1201 of the cartridge 1200 and a plunger 1260 located in a cap 1210 of the stopper 1202. The stopper 1202 and sealing element 1208 together contain the agent 1211 within the housing 1201, the stopper 1202 including a plurality of sealing elements 1208 disposed about a periphery of the stopper 1202, the sealing elements 1208 being sealingly engaged with an inner surface of the housing 1201. The cap 1210 seals an opening in the stopper 1202 into which the electronics assemblies 1273, 1278, 1279 are inserted, and the cap 1210 or stopper 1202 is configured to at least partially transfer thermal energy to the electronics assemblies 1273, 1278, 1279. In some embodiments, in operation, the electronics assemblies 1273, 1278, 1279 are integrated or held by the cap 1210, whereby securing the cap 1210 to the stopper 1202 includes inserting the electronics assemblies 1273, 1278, 1279 into cavities in the stopper 1102. The electronics assemblies 1273, 1278, 1279 include a sensing device (S) 1279, a wireless device (WL) 1278, and a thermoelectric element (TE) 1273.

[0056] In operation, the sensing device 1279 is configured to sense the position of the stopper 1202 within the housing 1201, and the wireless device 1278 is configured to communicate with an external electronic device (not shown) to communicate information from the sensor device 1279. The thermoelectric element 1273 is configured to provide power to the sensing device 1279 and the wireless device 1278 by generating energy when the temperature of the thermoelectric element changes. As shown in FIG. 12B, the cartridge 1200 is moved to a relatively high temperature environment (e.g., 20° C.), and the thermoelectric element 1273 is heated (during a temperature transition indicated by arrow 1299) by absorbing thermal energy from the environment outside the cartridge 1200. Absorption of thermal energy by the thermoelectric element 1273 generates electrical energy, for example, to power the sensing device 1279 and the wireless device 1278.

[0057] 13A and 13B are cross-sectional views of the shell 1302 of the stopper 1300 disposed within the cartridge 1301 and the insert 1310 clipped into the shell 1302. The shell 1302 is shown inside the cartridge 1301 with a number of sealing elements 1308 surrounding the shell 1302 to form a seal for containing the medicament 70 within the cartridge 1301. A cavity 1358 is formed within the stopper 1302. The insert 1310 includes a snap feature 1319 extending from a bottom surface of the insert 1310 and a body 1318 with the electronic device 1306 centered within the body 1318 and the body 1318 positioned to be inserted into the cavity 1358 of the stopper 1302 when the insert 1310 is coupled to the shell 1302 (shown in FIG. 13B). The body 1318 of the insert 1310 includes a sensor 1307 disposed at the bottom of the insert in electrical communication with the electronic device 1306, and in some embodiments, the sensor 1307 is disposed within the insert 1310 to transmit and receive a sensing signal through the shell 1302 into the cartridge 1301. In addition, a snap feature 1319 is provided to secure the insert 1310 to the cartridge 1301 as shown in FIG. 13B. Insert 1310 is positioned for insertion into side alignment cavity 1359 to secure insert 1310 to shell 1302. Body 1318 of insert 1310 aids in positioning insert 1310 during the initiation of the assembly operation, which is represented by arrow 1397 indicating the direction of movement of insert 1310 (the result of which is shown in FIG. 13B).

[0058] In some embodiments, the insert and shell 1302 are constructed from rigid materials such as metal, polymer (e.g., COC, PA, PP, PE, POM, PS, ABS, COP, etc.), glass, or ceramic. In some embodiments, the electronic device (or electronic assembly) 1306 includes one or more of a sensor, a power source (e.g., a battery), a controller, a wireless communication module (e.g., Bluetooth, NFC, Bluetooth LE, any RF, IrDA, acoustic module, memory, an on-off switch, a thermal element, a pressure sensor, etc.). In some embodiments, the sealing member 1308 is made from a first material and the shell 1302 is made from a second material that is less compressible compared to the material of the first member, and the shell 1302 is formed as a receptacle for receiving the insert 1310. In some embodiments, the insert 1310 is removably coupled to the shell 1302 after they are snapped together. In some embodiments, the sealing member 1308 is made from natural rubber or any biocompatible rubber composition. In some embodiments, the insert 1310 includes an on-off switch configured to trigger the electronic device 1306 by any suitable impact against the stopper 1300 (eg, force from the plunger 1360).

[0059] Figure 13B is a cross-sectional view of the stopper 1300 of Figure 13A housing the insert 1310 before it is driven into the cartridge 1301 by the plunger 1360. Figure 13B shows the insert 1310 coupled to the shell 1302, with the electronic device 1306 and the sensor 1307 disposed entirely within the cavity 1358 of the shell 1302, and the snap feature 1319 located within the alignment cavity 1359. In some embodiments, the plunger 1360 (e.g., plunger rod and head) is driven by an actuator or drive mechanism of a syringe (shown in Figure 1) having the cartridge 1301, or is the plunger of a syringe, and the cartridge 1301 is a syringe housing. In operation, the plunger 1360 is driven (indicated by arrow 1398 ) against the insert 1310 , thereby applying a force to the shell 1302 , moving the stopper 1300 into the cartridge 1301 and expelling a portion of the medicament 130 from the cartridge 1301 .

[0060] Some of the described functions can be implemented in digital electronic circuitry, or in computer hardware, firmware, software, or combinations thereof. The apparatus can be implemented in a computer program product tangibly embodied in an information carrier for execution by a programmable processor, such as a machine-readable storage device, and the method steps can be performed by the programmable processor executing a program of instructions for performing the functions of the described embodiments by operating on input data and generating output. The described arrangements can advantageously be implemented in one or more computer programs executable on a programmable system including at least one programmable processor coupled to receive data and instructions from, and transmit data and instructions to, a data storage system, at least one input device, and at least one output device. A computer program is a set of instructions that can be used directly or indirectly in a computer to perform a particular operation or bring about a particular result. Computer programs can be written in any form of programming language, including compiled or interpreted languages, and can be implemented in any form, including independent programs or modules, components, subroutines, or other units suitable for use in a computing environment.

[0061] The term "drug" or "medication" as used herein is used herein to describe one or more pharmacologic active compounds. As described below, a drug or medicament can include at least one small molecule or macromolecule, or combinations thereof, in various types of formulations for treating one or more diseases. Exemplary pharmacologic active compounds can include small molecules; polypeptides, peptides, and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double-stranded or single-stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids can be incorporated into vectors, plasmids, or molecular delivery systems such as liposomes. Mixtures of one or more of these drugs are also contemplated.

[0062] The term "drug delivery device" is intended to encompass any type of device or system configured to administer a volume of a drug into the human or animal body. The volume can typically range from about 0.5 ml to about 10 ml. Without limitation, drug delivery devices can include syringes, needle safety systems, pen injectors, auto-injectors, large volume devices (LVDs), pumps, perfusion systems, or other devices configured for subcutaneous, intramuscular, or intravascular delivery of drugs. Such devices often include a needle, which can include a small gauge needle (e.g., greater than about 24 gauge, including 27, 29, or 31 gauge).

[0063] In combination with a specific drug, the devices described herein can also be customized to operate within required parameters, such as within a particular time period (e.g., about 3 to about 20 seconds for a syringe and about 5 to about 60 minutes for an LVD), with low or minimal levels of discomfort, or within specific conditions related to human factors, shelf life, expiration date, biocompatibility, environmental considerations, etc. Such variations can arise due to a variety of factors, such as, for example, the viscosity of the drug, which ranges from about 3 cP to about 50 cP.

[0064] The drug or agent can be contained within a primary package or "drug container" adapted for use in a drug delivery device. The drug container can be, for example, a cartridge, syringe, reservoir, or other container configured to provide a chamber suitable for storage (e.g., short-term or long-term storage) of one or more pharma- ceutically active compounds. For example, in some embodiments, the chamber can be designed to store the drug for at least one day (e.g., from one day to at least 30 days). In some embodiments, the chamber can be designed to store the drug for about one month to about two years. Storage can be at room temperature (e.g., about 20° C.) or at refrigerated temperatures (e.g., from about −4° C. to about 4° C.). In some embodiments, the drug container can be or include a dual-chamber cartridge configured to store two or more components of a drug formulation (e.g., a drug and a diluent, or two different types of drugs) separately, one in each chamber. In such embodiments, the two chambers of the dual-chamber cartridge can be configured to allow mixing between the two or more components of the drug or agent prior to and / or during administration into the human or animal body. For example, the two chambers can be configured such that they are in fluid communication with one another (e.g., by a conduit between the two chambers) to allow for mixing of the two components by a user prior to administration, if desired. Alternatively, or in addition, the two chambers can be configured to allow for mixing of the components as they are being administered into the human or animal body.

[0065] The drug delivery devices and drugs described herein can be administered in a number of different types. It can be used for the treatment and / or prevention of disorders.Exemplary disorders include, for example, diabetes or complications associated with diabetes, such as diabetic retinopathy, thromboembolism, such as deep vein thromboembolism or pulmonary thromboembolism.Further exemplary disorders are acute coronary syndrome (ACS), angina pectoris, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and / or rheumatoid arthritis.

[0066] Exemplary drugs for the treatment and / or prevention of diabetes or complications associated with diabetes include insulin, e.g., human insulin, or a human insulin analog or derivative, glucagon-like peptide (GLP-1), a GLP-1 analog or GLP-1 receptor agonist, or an analog or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharma- ceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the term "derivative" refers to any substance that is sufficiently structurally similar to the original substance so that it can have a similar function or activity (e.g., therapeutic efficacy).

[0067] Exemplary insulin analogs are Gly(A21),Arg(B31),Arg(B32) human insulin (insulin glargine); Lys(B3),Glu(B29) human insulin; Lys(B28),Pro(B29) human insulin; Asp(B28) human insulin; human insulin in which the proline at position B28 is replaced by Asp, Lys, Leu, Val, or Ala, and in position B29, Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.

[0068] Exemplary insulin derivatives include, for example, B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl-LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29Ly sB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-γ-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin, and B29-N-(ω-carboxyheptadecanoyl) human insulin.Exemplary GLP-1, GLP-1 analogs and GLP-1 receptor agonists include, for example: Lixisenatide / AVE0010 / ZP10 / Lyxumia, Exenatide / Exendin-4 / Byetta / Bydureon / ITCA650 / AC-2993 (a 39 amino acid peptide produced by the salivary glands of the Gila monster), Liraglutide / Victoza, Semaglutide, Taspoglutide, Syncria / Albiglutide, and the like. tide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide / HM-11260C, CM-3, GLP-1 Erigen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexene en), Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709 , ZP-2929, ZP-3022, TT-401, BHM-034, MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, Ex. Exenatide-XTEN and Glucagon-XTEN.

[0069] An exemplary oligonucleotide is, for example: mipomersen / Kynamro, a cholesterol-lowering antisense therapeutic for the treatment of familial hypercholesterolemia.

[0070] Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.

[0071] Exemplary hormones include pituitary or hypothalamic hormones or regulatory active peptides and their antagonists, such as gonadotropins (follitropin, lutropin, chorion gonadotropins, menotropins), somatropins (somatropins), desmopressin, terlipressin, gonadorelin, triptorelin, leuprorelin, buserelin, nafarelin, and goserelin.

[0072] Exemplary polysaccharides include glycosaminoglycans, hyaluronic acid, heparin, low molecular weight heparin, or very low molecular weight heparin, or derivatives thereof, or sulfated forms of the above polysaccharides, such as polysulfated forms, and / or pharmaceutically acceptable salts thereof. An example of a pharmaceutically acceptable salt of polysulfated low molecular weight heparin is enoxaparin sodium. An example of a hyaluronic acid derivative is HylanG-F20 / Synvisc, sodium hyaluronate.

[0073] The term "antibody" as used herein refers to an immunoglobulin molecule or an antigen-binding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab')2 fragments that retain the ability to bind antigen. The antibody can be polyclonal, monoclonal, recombinant, chimeric, non-immunoglobulin or humanized, fully human, non-human (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix complement. In some embodiments, the antibody has reduced ability to bind or cannot bind Fc receptors. For example, the antibody can be an isotype or subtype, an antibody fragment, or a variant that does not support binding to Fc receptors, e.g., it has a mutated or deleted Fc receptor binding region.

[0074] The term "fragment" or "antibody fragment" refers to a polypeptide derived from an antibody polypeptide molecule (e.g., antibody heavy and / or light chain polypeptides) that does not include the full-length antibody polypeptide, but still includes at least a portion of the full-length antibody polypeptide that can bind to an antigen. An antibody fragment can include a truncated portion of a full-length antibody polypeptide, but the term is not limited to such truncated fragments. Antibody fragments that are useful in the present invention include, for example, Fab fragments, F(ab')2 fragments, scFv (single-chain Fv) fragments, linear antibodies, monospecific or multispecific antibody fragments such as bispecific, trispecific, and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), minibodies, chelating recombinant antibodies, tri- or bibodies, intrabodies, nanobodies, small modular immunopharmaceuticals (SMIPs), binding domain immunoglobulin fusion proteins, camelized antibodies, and VHH-containing antibodies. Further examples of antigen-binding antibody fragments are known in the art.

[0075] The term "complementarity determining region" or "CDR" refers to a region primarily responsible for mediating specific antigen recognition. The term "framework region" refers to short polypeptide sequences in the variable regions of both heavy and light chain polypeptides that are not CDR sequences, but rather amino acid sequences in the variable regions of both heavy and light chain polypeptides that are primarily responsible for maintaining the correct positioning of the CDR sequences to allow antigen binding. Framework regions themselves are usually not directly involved in antigen binding, as is known in the art, but certain residues in the framework regions of a particular antibody may be directly involved in antigen binding or may affect the ability of one or more amino acids in the CDRs to interact with the antigen.

[0076] Exemplary antibodies are anti-PCSK-9 mAb (e.g., Alirocumab), anti-IL-6 mAb (e.g., Sarilumab), and anti-IL-4 mAb (e.g., Dupilumab).

[0077] The compounds described herein can be used in pharmaceutical preparations that include (a) the compound or its pharmaceutically acceptable salt, and (b) a pharmaceutically acceptable carrier.The compounds can also be used in pharmaceutical preparations that include one or more other active pharmaceutical ingredients, or in pharmaceutical preparations in which the compound or its pharmaceutically acceptable salt is the only active ingredient present.Thus, the pharmaceutical preparations of the present disclosure encompass any preparation that is made by mixing the compounds described herein and a pharmaceutically acceptable carrier.

[0078] Pharmaceutically acceptable salts of any of the drugs described herein are also contemplated for use in the drug delivery device. Pharmaceutically acceptable salts are, for example, acid addition salts and base salts. Acid addition salts are, for example, HCl or HBr salts. Base salts are, for example, salts with a cation selected from an alkali or alkaline earth metal, for example Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), where R1 to R4 are each independently: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharma-ceutically acceptable salts are known to those skilled in the art.

[0079] Pharmaceutically acceptable solvates are, for example, hydrates or alkanolates, such as methanolates or ethanolates.

[0080] Several embodiments of the present disclosure have been described. Nevertheless, it will be understood that various modifications can be made without departing from the spirit and scope of the present disclosure. Those skilled in the art will understand that modifications (e.g., adjustments, additions, or deletions, etc.) can be made to the materials, configurations, apparatus, methods, systems, devices, and various components of the embodiments described herein without departing from the full scope and spirit of the inventive concept, and that the present invention encompasses such modifications and all equivalents thereof. Accordingly, other embodiments are within the scope of the following claims. [Explanation of symbols]

[0081] 70 Drugs 100 injection device 104 Cartridge housing 106 Drive mechanism 108 Stopper 109 needles 110 Housing 111 Injection button 112 Dosage knob 113 Dosage Window 114 Cartridge 115 Needle Assembly 116 Inner needle cap 117 Outer needle cap 118 Cap 122 Electronic Components 124 Electronic Components 200 Stopper 202 Rigid Shell 204 cores 206a Electronic Devices 206b Electronic Devices 206c Electronic Devices 208 Sealing elements 300 Stopper 302 Soft Shell 304 Rigid Core 306a Electronic Devices 306b Electronic Devices 306c Electronic Devices 308 Sealing elements 400 Stopper 402 Rigid Shell 404 Core 406a Implantable Electronic Devices 406b Implantable Electronic Devices 406c Implantable Electronic Devices 408 Sealing elements 410 Cover 500 Stopper 502 Soft Shell 504 Rigid Insertable Core 506a Implantable Electronic Devices 506b Implantable Electronic Devices 506c Implantable Electronic Devices 508 Sealing elements 600 Cartridges 602 Cartridge Housing 604 Cap 700 Stopper 701 Cartridge 702 Shell 706 Electronic Devices 708 Sealing elements 710 Insert 718 Center alignment function 719 Alignment function 758 Central cavity 759 Peripheral Alignment Cavity 760 Plunger 770 sensing signal 797 Arrow 800 Disposable Syringes 801 Housing 802 Stopper 806 Electronic Devices 808 Sealing member 852 Threaded Features 859 Central cavity 860 Plunger 861 Distal end 862 Corresponding Threaded Features 870 sensing signal 897 Arrow 898 Arrow 899 power 910 Inserted into the cartridge 920 Heat sterilized 930 is inserted into the cavity of the housing 940 The shell and insert are assembled into the stopper 950 Detect the position of the stopper 1000 cartridges 1001 Housing 1002 Stopper 1008 Sealing elements 1010 Cap 1011 Drugs 1071 Capacitive Devices (CE) 1078 Wireless Device (WL) 1079 Sensing Device(S) 1081 Radio Signal 1080 Smartphone 1100 Cartridge 1101 Housing 1102 Stopper 1108 Sealing elements 1110 Cap 1111 Drugs 1160 Plunger 1172 Piezoelectric element (PE) 1178 Wireless Device (WL) 1179 Sensing Device(S) 1197 Arrow 1200 Cartridge 1201 Housing 1202 Stopper 1208 Sealing elements 1210 Cap 1211 Drugs 1260 Plunger 1273 Thermoelectric element (TE) 1278 Wireless Device (WL) 1279 Sensing Device(S) 1299 Arrow 1300 Cartridge 1301 Housing 1302 Stopper 1306 Electronic Devices 1307 Sensor 1308 Sealing elements 1310 Cap 1311 Drugs 1318 Main unit 1319 Snap function 1359 Side Alignment Cavity 1360 Plunger 1397 Arrow 1398 Arrow

Claims

1. A stopper (108, 200, 700) configured to be disposed within a medical cartridge (114, 600): a shell (202, 702) defining an exterior surface and a cavity (758) sized and shaped to fit within the medical cartridge (114, 600), the shell being configured to be advanced into the medical cartridge (114, 600) by a plunger (760) to apply pressure to a substance (70) contained within the medical cartridge (114, 600); an insert (204, 710) configured to be inserted into the cavity, the insert including an electronic device (706) having a sensor (1079, 1307) configured to generate a sensing signal; wherein the shell (202, 302, 702) is configured to pass a sensing signal (770); The stopper, wherein the sensor (1079, 1307) is configured to respond to a position of the stopper within the medical cartridge.

2. The stopper of claim 1 , wherein the sensing signal (770) is an electromagnetic signal or an acoustic signal.

3. The stopper of claim 1 or 2, wherein the electronic device (706) is configured to communicate with an external electronic device.

4. The stopper of claim 3 , wherein the electronic device (706) includes a wireless transceiver (1078) configured to communicate with an external electronic device (1080).

5. The stopper of claim 4, wherein the wireless transceiver (1078) is configured to transmit data acquired by the sensor (1079, 1307) to an external electronic device (1080).

6. The stopper of any one of claims 1 to 5, wherein the electronic device (706) is configured to be activated by a force (799, 899) applied to the stopper (108, 200, 700).

7. The stopper of any one of claims 1 to 6, wherein the electronic device (706) includes a temperature sensing element configured to activate the electronic device (806) upon sensing a change in temperature or reaching a temperature threshold.

8. The stopper according to any one of the preceding claims, wherein the electronic device (706) comprises an energy source (1071, 1172, 1273).

9. The stopper of claim 8, wherein the energy source comprises a wireless charging module having a capacitive electronic circuit (1071).

10. The stopper of claim 8, wherein the energy source comprises a piezoelectric element (1172) configured to generate electrical energy from a force (799, 899) applied to the stopper (108, 200, 700).

11. The stopper of claim 8, wherein the energy source comprises a thermoelectric element (1273) configured to generate electrical energy from thermal energy absorbed by the stopper (108, 200, 700).

12. The stopper of any one of claims 1 to 11, wherein the sensor (1079, 1307) is configured to transmit a sensing signal (770) through the stopper (108, 200, 700), the sensor (1079, 1307) being configured to measure a response.

13. A medical cartridge (114, 600) comprising: A cartridge housing (104, 602); and a stopper (108, 200, 700) according to any one of claims 1 to 12, wherein the shell (202, 302, 702) is configured to be inserted into the cartridge housing (104, 602) before the cartridge housing (104, 602) and the shell (202, 302, 702) are subjected to a heat sterilization treatment, and the insert (204, 710) is configured to be inserted into the stopper (108, 200, 700) after the heat sterilization treatment.

14. 1. A medical cartridge comprising: A cartridge housing (104, 602) containing the medicament; The medical cartridge comprising a stopper (108, 200, 700) according to any one of claims 1 to 12.

15. A method of manufacturing a medical cartridge (114, 600), comprising: inserting a shell (202, 302, 702) into a housing (104, 602) of a medical cartridge (114, 600), the shell (202, 302, 702) sealing an open end of the housing (104, 602), the shell (202, 302, 702) defining a cavity (758, 859) accessible from outside the housing (104, 602), the cavity configured to pass a sensing signal (770); heat sterilizing the shell (202, 302, 702) and the housing (104, 602); and placing an insert (204, 710) into the cavity (758, 859) of the shell (202, 302, 702) after heat sterilization, the insert (204, 710) including an electronic device (706) including a sensor (1079) configured to generate a sensing signal (770); wherein the shell and insert (204, 710) together form a stopper (108, 200, 700) configured to be advanced by a plunger (760) into the housing (104, 602) to apply pressure to a substance (70) contained within the medical cartridge (114, 600); The method, wherein the sensor (1079) is configured to respond to a position of the stopper (108, 200, 700) within the medical cartridge (114, 600).

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