Cartridge with distributed electronic components

Abstract

The invention relates to a cartridge with distributed electronics, and particularly provides a stopper configured to be disposed within a medical cartridge, the stopper comprising: a housing defining a cavity; a core arranged within the cavity; and at least one electronic device embedded within the core, where the at least one electronic device comprises a sensor, and where the housing is configured to pass a sensing signal therethrough.

Description

[0001] This invention application is a divisional application based on an invention patent application with an application date of May 2, 2018, application number 201880041656.4 (international application number PCT / EP2018 / 061113) and name “Cartridge with distributed electronic components”. Technical Field

[0002] The present specification relates to an apparatus for a medical device configured to expel a medicament, and more particularly to a stopper for a manually operable injection device. Background Art

[0003] There are many existing diseases that require treatment by injecting medication. Such injections can be performed using an injection device, either by medical personnel or by the patient himself. For example, type 1 and type 2 diabetes can be treated by the patient himself by injecting a dose of medication, such as once or several times a day. For example, a pre-filled disposable medication pen or auto-injector can be used as an injection device. Alternatively, a reusable pen or auto-injector can be used. A reusable pen or auto-injector allows an empty medication cartridge to be replaced with a new medication cartridge. Either pen or auto-injector can have a set of one-way needles that are replaced before each use. Summary of the invention

[0004] According to a first aspect, there is provided a plug configured to be arranged in a medical cartridge, the plug comprising: a shell defining a cavity; a core arranged in the cavity; and at least one electronic device embedded in the core, wherein the at least one electronic device comprises a sensor, and wherein the shell is configured to allow a sensing signal to pass therethrough.

[0005] The plug may include a housing that thermally insulates the at least one embedded electronic device so that the plug can be heat sterilized. The plug can be heat sterilized at a temperature of at least 120 degrees Celsius for at least 20 minutes. The plug may include a substantially rigid housing and a substantially soft core. The plug may include a cover that is configured to interface with the housing so that mechanical forces can be transmitted therefrom under limited compression of the core. The plug may include a substantially soft housing and a substantially rigid core. The at least one embedded electronic device may communicate with at least one electronic device located outside the plug. The sensing signal may be an electromagnetic signal or an acoustic signal. The sensor may include a piezoelectric device. The at least one embedded electronic device may include an energy source.

[0006] The plug may include a substantially inseparable housing and a core. The at least one embedded electronic device may include a wireless transceiver. The wireless transceiver may be configured to transmit data acquired by the sensor to an electronic device external to the plug.

[0007] According to another aspect, a cartridge is provided, comprising a cartridge housing; a plug configured to be disposed within the cartridge housing, the plug comprising a shell defining a cavity; a core sized and shaped to fit within the cavity of the shell; and at least one embedded electronic device embedded in the core, wherein the at least one electronic device comprises a sensor, and wherein the shell is configured to allow a sensing signal to pass therethrough; and at least one external electronic device located outside the plug, wherein the at least one external electronic device is configured to communicate with the at least one embedded electronic device.

[0008] The at least one external electronic device may be located in the threaded shaft region of the cartridge.The cartridge housing may be configured for use with an autoinjector.

[0009] In another aspect, a method of manufacturing a medical cartridge is provided, comprising: embedding at least one electronic device in a core of a plug, coupling the core to a shell, the shell providing heat resistance to the at least one electronic device embedded in the core, sterilizing the plug via heat sterilization, and assembling the plug into the cartridge.

[0010] Advantages of these technologies include the following: In some embodiments, the electronic components are distributed in the cartridge, which can save space or eliminate the need for an external device coupled to the syringe pen. In some embodiments, one or more electronic components can be embedded in the stopper, which can further save space.

[0011] In some embodiments, embedding at least one electronic component in the plug is advantageous because the manufacturing and sterilization process is simple and reduces assembly complexity. In other embodiments, the sensor is embedded in the plug, which places it in an advantageous position to perform position-based measurements. Position-based measurements allow for the calculation of dosage information, including the amount of drug.

[0012] In some embodiments, the heat resistance provided by the shell (or core) of the stopper allows heat-sensitive electronic devices to be embedded in the core and subjected to heat sterilization. Since the electronic devices can be embedded, the stopper can be heat sterilized as a whole, or can be embedded in the cartridge before heat sterilization, thereby allowing a simple assembly process.

[0013] This application includes the following:

[0014] 1. A stopper (300) configured to be arranged in a medical cartridge (600), the stopper (300) comprising:

[0015] a housing (302) defining a cavity;

[0016] a core (304) disposed within the cavity; and

[0017] at least one electronic device (306a, 306b, 306c) embedded within the core;

[0018] The at least one electronic device includes a sensor (310), and the housing (302) is configured to allow a sensor signal (870) to pass therethrough.

[0019] 2. The stopper (300) according to item 1, wherein the housing (302) thermally insulates the at least one embedded electronic device (306a, 306b, 306c) so that the stopper (300) can be heat sterilized.

[0020] 3. The stopper (300) according to item 2, wherein the stopper (300) can be heat sterilized at a temperature of at least 120 degrees Celsius for at least 20 minutes.

[0021] 4. The stopper (300) according to any one of items 1 to 3, wherein the shell (302) is substantially rigid and the core (304) is substantially soft.

[0022] 5. The plug (300) of claim 4, comprising a cover (410) configured to interface with the housing (302) so as to allow mechanical forces to be transmitted therethrough under limited compression of the core (304).

[0023] 6. The stopper (300) according to any one of items 1 to 3, wherein the shell (302) is substantially soft and the core (304) is substantially rigid.

[0024] 7. The stopper (300) according to any one of items 1 to 6, wherein the sensor (310) comprises a piezoelectric device (1172).

[0025] 8. The plug (300) according to any one of items 1 to 7, wherein the at least one embedded electronic device (306a, 306b, 306c) comprises an energy source (706).

[0026] 9. The plug (300) according to item 1, wherein the shell (302) and the core (304) are substantially inseparable.

[0027] 10. The stopper (300) according to any one of items 1 to 9, wherein the sensor (310) is configured to transmit the sensing signal (870) through the stopper (300), and wherein the sensor (310) is configured to measure a response.

[0028] 11. A cartridge (600), comprising:

[0029] Cartridge housing (602);

[0030] A plug (300) configured to be disposed within the cartridge housing (602), the plug (300) comprising:

[0031] a housing (302) defining a cavity;

[0032] a core (304) sized and shaped to fit within the cavity of the housing (302); and

[0033] at least one embedded electronic device (306a, 306b, 306c) embedded within the core (304);

[0034] wherein the at least one electronic device (306a, 306b, 306c) comprises a sensor (310), and wherein the housing (302) is configured to allow a sensor signal (870) to pass therethrough; and

[0035] At least one external electronic device located outside the plug (300), wherein the at least one external electronic device is configured to communicate with the at least one embedded electronic device (306a, 306b, 306c).

[0036] 12. The cartridge (600) of item 11, wherein the housing (302) provides heat resistance to the at least one embedded electronic device (306a, 306b, 306c) so that the stopper (300) can be heat sterilized.

[0037] 13. The cartridge according to item 11 or 12, wherein the at least one embedded electronic device (306a, 306b, 306c) comprises a wireless transceiver (704).

[0038] 14. The cartridge (600) according to any one of items 11-13, comprising a medicament (80).

[0039] 15. A method (900) of manufacturing a medical cartridge (600), comprising:

[0040] embedding (902) at least one electronic device in the core of the plug;

[0041] coupling the core to a housing (904), the housing providing thermal resistance to the at least one electronic device embedded in the core;

[0042] sterilizing the stopper via heat sterilization (906); and

[0043] The stopper is assembled (908) into the cartridge. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, objects, and advantages may be apparent from the description and drawings, and from the claims.

[0045] Figure 1 is an exploded view of the injection device.

[0046] Figure 2A is a cross-sectional view of a plug configured to be disposed in an injection device, the plug having a rigid shell and a soft core in which electronics are embedded.

[0047] Figure 2B yes Figure 2A Top view of the stopper.

[0048] Figure 2C is another example of a stopper.

[0049] Figure 2D is a cross-sectional view of a stopper arranged within a cartridge.

[0050] Figure 3A is a cross-sectional view of a plug configured to be disposed in an injection device, the plug having a soft shell and a rigid core in which electronics are embedded.

[0051] Figure 3B yes Figure 3A Top view of the stopper.

[0052] Figure 4 is a cross-sectional view of a plug configured to be arranged in an injection device, the plug having a rigid housing and an insertable soft core in which an electronic device is embedded and having a rigid cover.

[0053] Figure 5 is a cross-sectional view of a plug configured to be disposed in an injection device, the plug having a soft shell and an insertable rigid core in which an electronic device is embedded.

[0054] Figure 6 is a cross-sectional view of a stopper arranged within a cartridge.

[0055] Fig. 7Ais a schematic diagram of a distributed electronic system for a medical cartridge, wherein a wireless transceiver, an energy source, and a sensor are arranged within the plug.

[0056] Figure 7B is a schematic diagram of a distributed electronic system for a medical cartridge, wherein a sensor is arranged within the plug and connected to an external energy source via at least one wire.

[0057] Figure 7C is a schematic diagram of a distributed electronic system for a medical cartridge, where the wireless transceiver, energy source, and sensor are arranged outside the plug.

[0058] Fig.7D is a schematic diagram of a distributed electronic system for a medical cartridge, wherein a wireless transceiver and a sensor are arranged inside the plug, and an energy source is arranged outside the plug.

[0059] Fig. 8A and Figure 8B is a cross-sectional view of a disposable syringe having electronics embedded in the threaded distal end of the plunger.

[0060] Fig. 9 is a flow chart depicting a process for manufacturing a cartridge having distributed electronics.

[0061] Fig.10 is a cross-sectional view of a bung disposed within a cartridge and in communication with a wireless system.

[0062] Fig.11A and Fig. 11B is a cross-sectional view of a plug disposed within a cartridge and in communication with a piezoelectric system.

[0063] Fig. 12A and Fig. 12B is a cross-sectional view of a plug disposed within a cartridge and a Peltier thermoelectric device.

[0064] The same reference symbols in the various drawings represent the same elements. DETAILED DESCRIPTION

[0065] If some cartridge-based injection and medical syringe systems include electronic devices in the replaceable part of the device (such as the cartridge stopper or the cartridge housing), it is difficult to sterilize them before use. In some examples, the cartridge stopper can be heat sterilized with the electronic components embedded inside. For example, a stopper at least partially made of a heat-resistant material or coated with a heat-resistant coating can provide protection for the embedded electronic components during the heat sterilization process. Some examples also enable additional electronic components (e.g., an energy source) to be added or connected to the heat-sterilized stopper using at least one electronic component embedded inside.

[0066] Figure 1is an exploded view of the injection device 100 . Figure 1 The injection device 100 is a pre-filled disposable injection pen, which includes a housing 110 and has a cartridge 114 with a cartridge housing 104 therein, to which a needle assembly 115 can 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 in turn can be covered by a cap 118. The dose of medicament to be expelled from the injection device 100 can be selected by turning a dose knob 112, which then displays the selected dose via a dose window or display 113. The display can include, for example, a digital display. It will be understood that the dose window 113 refers to a section of the injection device 100 through which or on which the selected dose is visible.

[0067] As described further below, the injection device 100 may include one or more electronic components 122 , 124 , some of which may be included within the bung 108 and some of which may be included outside of the bung 108 , for example.

[0068] Turning the dose knob 112 causes a mechanical click to provide acoustic feedback to the user. The numbers displayed in the dose display 113 are printed on a sleeve contained in the housing 110 and mechanically interact with the piston in the cartridge 114. When the needle 109 is inserted into the skin portion of the patient and the injection button 111 is subsequently pushed, the insulin dose displayed in the display 113 will be discharged from the injection device 100. During injection, the drive mechanism 106 (which is shown as the outline of the plunger arm) drives the stopper 108 into the cartridge to discharge the drug (e.g., cartridge 114). When the needle 109 of the injection device 100 is retained in the skin portion for a certain period of time after pushing the injection button 111, a higher percentage of the dose is actually injected into the patient.

[0069] The injection device 100 may be disposable or removable.

[0070] Figure 2A 200 is a cross-sectional view of an embodiment of a plug 200 configured to be arranged in an injection device (e.g., injection device 100), the plug 200 having a rigid shell 202 and a soft core 204, in which an electronic device is embedded. The plug 200 includes a substantially rigid shell 202 and a substantially soft core 204. In this embodiment, the shell 202 and the core 204 are substantially inseparable after manufacturing. "Substantially inseparable" means that if the core 204 and the shell 202 are separated, they will experience irreversible decoupling. For example, when the core 204 and the shell 202 are substantially inseparable, they may not be separated by simply ejecting the core 204 from the shell 202.

[0071] For example, core 204 can be formed when filling housing 202 with a substantially soft material, which hardens when exposed to air or chemical reagents (e.g., by pouring, injecting, etc., the substantially soft material). For example, the substantially soft material can be an epoxy, resin, or another hardened soft material. Due to this filling process, core 204 will be difficult to remove from housing 202 because they will be integrated into one-piece. Core 204 includes embedded electronic devices 206a, 206b, and 206c. In one embodiment, electronic devices 206a, 206b, and 206c can be inserted into the cavity of housing 202, and then a substantially soft material can be introduced into the cavity to surround electronic devices 206a, 206b, and 206c and form core 204. Housing 202 is interfaced with sealing element 208 (e.g., O-ring) to provide a sealing interface with the cartridge when the stopper is introduced into the cartridge.

[0072] The materials for the shell 202 and core 204 are selected based on their hardness, elasticity, and their heat resistance or insulation properties. In some embodiments, the shell 202 and core 204 are made of polymer materials with different elastic properties. In some embodiments, a heat-resistant coating can also be applied to the core 204 to increase heat resistance, such as, for example, a polytetrafluoroethylene (PTFE) coating, also known as a Teflon coating. In some cases, the shell can be made of a material selected to be compatible with the medicament, such as PP, PE, POC, POP, PTFE, or butyl rubber at the surface 203 that contacts the medicament. Figure 2C As shown, instead of a coating, a compatible material can be co-molded or assembled with another material (e.g., using snap-on features) so that the compatible material forms a first portion 202a of the housing that contacts the medicament at surface 203, while the other material forms a second portion 202b of the housing that does not contact the medicament. The materials selected for the housing 202 and the core 204 are also selected for their ability to allow sensor signals to pass therethrough.

[0073] The embedded electronic device may include, for example, a sensor, an energy source, a microcontroller, a wireless transceiver, and an energy harvesting device. The embedded electronic devices 206a, 206b, and 206c are representative only. There may be any number of embedded electronic devices. The sensor may be a sensor / transceiver device, such as, for example, a piezoelectric device. The sensor / transceiver may transmit a sensing signal (such as, for example, ultrasound, sound, light, or other signal) through the stopper and measure the response. The acoustic signal may include mechanical energy or vibration energy. The received response may be provided to a controller (e.g., an embedded or external microcontroller), which may receive the response and calculate the state of the cartridge. The state of the cartridge may correspond to, for example, the fill level of the medicament in the cartridge or the position of the stopper. The state of the cartridge may allow the injection dose of the medicament to be measured.

[0074] The energy source can be a battery, a device that generates energy by loading a capacitor, is solar-powered, etc. The wireless transceiver can communicate with an external electronic device as well as with the sensor and the energy source. The external electronic device (which can be a controller) can transmit the data received from the sensor to an external database. The wireless transceiver can communicate using any known wireless communication technology, including, for example, Bluetooth, NFC or radio frequency. The communication with the controller can be unidirectional or bidirectional. In some embodiments, the data transmitted from the sensor device to the external database contains information related to the identity of the device, such as a unique number, calibration data, production batch information, device material information, data related to storage time and production time, and information related to sensor measurement (for example, measurement time, such as temperature, distance, light signal, acoustic signal and other sensor measurement results). In some embodiments, the data from the external database device to the controller contains information about a "wake-up" signal, a measurement trigger, time information or calibration data.

[0075] Figure 2B yes Figure 2A 200. The housing 202 surrounds the core 204 and interfaces with a sealing element 208, which forms a sealing interface with the cartridge when the stopper 200 is introduced into the cartridge. The sealing interface can form at least a portion of a sterile barrier within the cartridge that is necessary to maintain the sterility of the medicament to be delivered by the injection device.

[0076] In some embodiments, the housing 202 is made of 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 component) 206a, 206b, 206c includes one or more of the following: a sensor, a power source (e.g., a battery), a controller, a wireless communication module (e.g., Bluetooth, NFC, Bluetooth LE, any RF, IrDA, an acoustic module, a memory, an on-off switch, a thermal sensing element, a pressure sensor, etc.). In some embodiments, the sealing member 208 is made of a first material, and the housing 202 is made of a second material, the second material is less compressible than the material of the first member, and wherein the housing 202 is formed as a container for accommodating the core 204. In some embodiments, the electronic device 206a, 206b, 206c and the core 204 are connected to the housing 202 using snap features, gluing, welding, US welding, thermal welding or other means. In some embodiments, the core 204 is removably coupled to the housing 202. In some embodiments, the sealing member 208 is made of natural rubber or any biocompatible composition of rubber. In some embodiments, the core 204 includes an on-off switch configured to trigger the electronic devices 206a, 206b, 206c by any appropriate impact to the plug 200 (e.g., force from the drive mechanism 106).

[0077] Figure 2D is a cross-sectional view of the stopper 200 disposed in the cartridge 600. Figure 3A and Figure 3B Various features of the stopper 200 shown are described. The stopper 200 can be replaced by any of the stoppers in the following figures, which will interface with the cartridge 600 in much the same manner as described herein for the stopper 300. The cartridge 600 includes a housing 602 that interfaces with a sealing element 208 of the stopper 200 to seal the open end of the cartridge 600. In some embodiments, a medicament (e.g., a medical fluid or drug) is disposed in a space between the cap 604 of the cartridge 600 and the housing 202 of the stopper 200. In some embodiments, the embedded electronic devices 206a, 206b, and 206c include sensors that are configured to send and receive signals to sense the position of the stopper 200 in the cartridge 600.

[0078] In an 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 emission time 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 reflects from (e.g., bounces off) the surface of the cartridge 600 or a reflector (not shown). The reflection of the acoustic wave (e.g., the reflected wave) propagates from the distal end of the cartridge 600 (i.e., the end with the cap 604) toward the 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 of the medicament in the cartridge. The time elapsed between the emission and reception of the acoustic wave is t2-t1. The elapsed time is multiplied by the speed of sound to determine the distance traveled by the wave from the transmitter to the distal end of the cartridge 600 and then back to the sensor. The distance traveled is divided by two to determine the distance between the stopper 200 and the distal end of the cartridge 600. The amount of medication in cartridge 600 (e.g., the amount of medication in cartridge 600 enclosed between stopper 200 and the proximal end) is determined by multiplying the determined distance by the cross-sectional area of ​​cartridge 600. The difference between the amount of medication determined in cartridge 600 before and after metering corresponds to the dose administered to the patient.

[0079] Figure 3A1 is a cross-sectional view of a stopper 300 configured to be arranged in an injection device 100, the stopper 300 having a soft shell 302 and a rigid core 304, in which 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 the push of the plunger. This can ensure a reliable sensor signal. Another advantage is that the rigid core 304 leads to better injection dose accuracy due to the smaller elastic effect from the stopper 300 during injection. This also helps to shorten the holding time during injection. In the context of the soft shell 302, soft refers to viscoelastic materials, such as natural rubber, thermoplastic elastomer (TPE), butyl rubber, chloroprene rubber, fluoroelastomer, silicone rubber, etc., characterized in that low e-modulus (high elastic deformation and low residual deformation and stress). The stopper 300 includes a substantially soft shell 302 and a substantially rigid core 304. In the present embodiment, the shell 302 and the core 304 are essentially inseparable after manufacture. For example, the shell 302 can be formed by molding the shell 302 around the substantially rigid core 304 using a substantially soft material (e.g., by casting, injecting, etc., the substantially soft material). The core 304 includes embedded electronic devices 306a, 306b, and 306c. In one embodiment, the substantially rigid material can be molded around the electronic devices 306a, 306b, and 306c when it is in an uncured softened state, and can be cured to form a rigid core 304. In another embodiment, before the substantially rigid material is cured to form the rigid core 304, the electronic devices 306a, 306b, 306c can be introduced into the substantially rigid material in an uncured, softened state. The integrated sealing element 308 is configured to provide a sealing interface between the stopper and the inner wall of the cartridge when the stopper is introduced into the cartridge.

[0080] The advantage of a soft shell 502 is that it has the shell function and the sealing function in one component. However, during the manufacturing process, it may be more difficult to handle soft or elastic shell materials for assembly. Rigid shells are easier to handle / save during the manufacturing process and may result in better metering accuracy, but require separate sealing elements (such as O-rings) to provide a sealing interface with the cartridge. The advantage of a substantially rigid core is that it is easier to handle during the manufacturing process and better protects the possible stress sensitive sensor elements.

[0081] Above relative to Figure 2A Various materials that can be used to make the housing 302 and the core 304 are described, as well as various electronic devices that can be embedded in the core. In addition, the material used for the housing can be medical grade, wherein the plug is configured to contact the medicament.

[0082] Figure 3B yes Figure 3A A top view of a stopper of FIG. 304. The housing 302 surrounds the core 304 and includes an integrated sealing element 308 that forms a sealing interface with the cartridge when the stopper is introduced into the cartridge. The sealing interface can form at least a portion of a sterile barrier within the cartridge that is necessary to maintain the sterility of the medicament to be delivered by the injection device.

[0083] The Figure 2A , Figure 2B , Figure 3A and Figure 3B The one-piece stopper is sterilized. In an exemplary heat sterilization process, the stopper will be sterilized at a temperature of about 120 degrees Celsius for about twenty to thirty minutes.

[0084] In some embodiments, the core 304 is made of 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 component) 306a, 306b, 306c includes one or more of the following: a sensor, a power source (e.g., a battery), a controller, a wireless communication module (e.g., Bluetooth, NFC, Bluetooth LE, any RF, IrDA, an acoustic module, a memory, an on-off switch, a thermal sensing element, a pressure sensor, etc.). In some embodiments, the sealing member 308 is made of a first material, and the housing 302 is made of a second material, the second material is less compressible than the material of the first member, and wherein the housing 302 is formed as a container for accommodating the core 304. In some embodiments, the electronic device 306a, 306b, 306c and the core 304 are connected to the housing 302 using snap features, gluing, welding, US welding, thermal welding or other means. In some embodiments, the core 304 is removably coupled to the housing 302. In some embodiments, the sealing member 308 is made of natural rubber or any biocompatible composition of rubber. In some embodiments, the core 304 includes an on-off switch configured to trigger the electronic devices 306a, 306b, 306c by any appropriate impact to the plug 300 (e.g., force from the drive mechanism 106).

[0085] Figure 44 is a cross-sectional view of a plug 400 configured to be arranged in an injection device 100, the plug 400 having a rigid shell 402 and an insertable soft core 404 (in which electronic devices 406a, 406b, 406c are embedded) and having a rigid cover 410. The plug 400 includes a substantially rigid shell 402 and a substantially soft core 404. 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 subsequent assembly step. For example, the core 404 can be formed when a mold is filled with a substantially soft material (e.g., by pouring, injecting, etc. the substantially soft material) and the electronic devices 406a, 406b, and 406c are embedded before the substantially soft material solidifies (e.g., solidifies, hardens, etc.). In another embodiment, the 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 housing 402 interfaces with a sealing element 408 to provide a sealed interface with the cartridge when the stopper is introduced into the cartridge.

[0086] The stopper 400 also includes a substantially rigid cover 410 configured to interface with the substantially rigid housing 402 and with the plunger 1160 ( Fig.11A and 11B ). The plunger applies a force to the cover 410, which is configured to transfer the force to the substantially rigid housing 402. If the cover 410 is removed, the force transfer will be significantly reduced because the plunger may deform (e.g., by compression) the substantially soft core 404. Limited compression of the core 404 (meaning that the core does not deform more than 5% in the direction of travel of the plunger) allows for more efficient transmission of force between the stopper 400 and the plunger. The cover 410 also provides a beneficial geometry for interfacing with the plunger when it contacts the top surface of the rigid housing 402 along the circumference of the housing 402. Although the size of the plunger head can be designed so that it contacts the top surface of the housing 402 (e.g., the diameter of the plunger is larger than the diameter of the cavity of the housing), including the cover 410 can allow the force to be more evenly distributed on the housing.

[0087] Figure 5500 is a cross-sectional view of a plug configured to be arranged in an injection device, the plug having a soft shell and an insertable rigid core in which an electronic device is embedded. The plug 500 includes a substantially soft shell 502 and a substantially rigid core 504. In the present embodiment, the shell 502 and the core 504 are manufactured separately, and the core 504 is inserted into the shell 502 in a subsequent assembly step. For example, the core 504 can be formed when the mold is filled with a substantially rigid material (e.g., by pouring, injecting, etc. substantially rigid materials) and the electronic devices 506a, 506b, and 506c are embedded before the substantially rigid material solidifies (e.g., solidifies, hardens, etc.). In another embodiment, the substantially rigid material is introduced around the electronic devices 506a, 506b, and 506c and shaped (e.g., cut, poured into the mold, etc.) to form the core 504. The integrated sealing element 508 is configured to provide a sealing interface with the cartridge when the plug is introduced into the cartridge.

[0088] Can be inserted after housings 402 and 502 have been inserted into the cartridge Figure 4 and Figure 5 The cores 404 and 504 of the two-piece plug. The housing and the cartridge can be heat sterilized. After the cartridge has been sterilized, the cores 404 and 504 (including their embedded electronics) can be pushed into the cavity formed by the housing of the plug.

[0089] Figure 6 is a cross-sectional view of the stopper arranged in the cartridge. Figure 3A and Figure 3B Various features of the stopper shown are described. Stopper 300 can be replaced by any stopper in the previous figures, which will interface with the cartridge in much the same manner as described herein for stopper 300. Cartridge 600 includes a housing 602 that interfaces with a sealing element 308 of stopper 300. The medicament can be arranged in a space between a cap 604 of the cartridge and the housing 302 of the stopper. Embedded electronics 306a, 306b, and 306c can include a sensor 310 that can send and receive sensor signals to sense the position of stopper 300 in cartridge 600.

[0090] Sensor 310 may be a sensor / transceiver device, such as, for example, a piezoelectric device. The sensor / transceiver may transmit a sensing signal (such as, for example, an ultrasound, sound, light, or other signal) through plug 300 and measure the response. Figure 2DDescribes an implementation of determining dosage based on emitting an acoustic sensing signal and measuring a response. The received response can be provided to a controller (e.g., 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 to, for example, the filling level of the medicament in the cartridge 600 or the position of the stopper 300. The state of the cartridge can allow the injection dose of the medicament to be measured. In some embodiments, as described above, different measurement methods are used to measure the position of the stopper 300. It is necessary to generate a specific signal, which changes with the movement of the stopper 300 relative to the fixed position in the system or cartridge 600. This fixed position can be inside the cartridge 600, for example, a diaphragm area of ​​the cartridge 600 that never moves or another rigid wall of the cartridge 600, or an element in the cartridge can be introduced for this purpose, or a reference can be made to the outside of the cartridge outside the element of the injection device such as the housing part. In some embodiments, the sensor measures the change of the light signal by sending light from a light source (e.g., LED) to a fixed area and receiving the emitted light with a photodetector. The intensity of the emission can be related to the distance. Another possibility is to measure the change in the time required for a signal (e.g., an acoustic signal) to travel from a transmitter to a fixed position and back to a receiver positioned near the transmitter. In another embodiment, a signal (optical, acoustic, capacitive, etc.) can be sent from a fixed position to a receiver in the mobile stopper 300 to measure the change in the signal during the travel of the stopper and correlate it to the stopper position in the cartridge 600.

[0091] FIG. 7A to FIG. 7D The schematic diagram shown in illustrative figures depicts the position and orientation of various electronic components relative to the plug 702 . Fig. 7A 7 is a schematic diagram of a distributed electronic system 700 for a medical cartridge 600, wherein a wireless transceiver 704, an energy source 706, and a sensor 708 are disposed within a stopper 702. In this embodiment, the stopper includes three embedded electronic devices, and the cartridge 600 does not include external electronic devices that communicate with the embedded electronic devices. When external electronic devices are not required, space can be saved in the cartridge and / or the need for external devices coupled to the syringe pen can be eliminated, thereby simplifying assembly. In addition, when all necessary electronic components are included in the stopper, the cartridge is easier to assemble.

[0092] Figure 7B700 is a schematic diagram of a distributed electronic system 700 for a medical cartridge 600, wherein a sensor 708 is disposed within a plug 702 and connected to an external energy source 706 via at least one connector 710. In this embodiment, the sensor 708 must be electrically connected to the energy source 706 so that the energy source 706 can provide power to the sensor 708. In this embodiment, the electrical connection is achieved by wiring the sensor and the energy source to each other using the connector 710. These wires can be embedded in the core or shell of the plug 702 ( Figure 2A ). This embodiment allows the stopper to be heat sterilized, but allows the use of an energy source 706 that may not be able to withstand the heat sterilization process of the stopper.

[0093] Figure 7C 7 is a schematic diagram of a distributed electronic system 700 for a medical cartridge 600, wherein a wireless transceiver 704, an energy source 706, and a sensor 708 are disposed outside of a plug 702. In this embodiment, the electronic devices 704, 706, and 708 are disposed in the cartridge 600 outside of the plug 702, and may be located, for example, in a threaded rod portion of the cartridge assembly ( Fig. 8A and Figure 8B ). In this embodiment, the sensor signal output by the sensor 708 must be able to travel through the plug 702 and return to the sensor 708 to collect data regarding the positioning of the plug 702. This embodiment allows the plug to be heat sterilized, but allows the use of electronic components that may not be able to withstand the heat sterilization process of the plug.

[0094] Fig.7D 7 is a schematic diagram of a distributed electronic system 700 for a medical cartridge 600, wherein a wireless transceiver 704 and a sensor 708 are disposed within a plug 702 and an energy source 706 is disposed outside the plug 702. In this embodiment, the electronics (e.g., the energy source) disposed in the cartridge outside the plug can be located, for example, in a threaded rod portion of the cartridge assembly. Fig. 8A and Figure 8B An embodiment of the electronics located in the threaded rod portion is shown. This embodiment allows the stopper to be heat sterilized, but allows the use of an energy source 706 that may not withstand the heat sterilization process of the stopper. Electronic components that can withstand the heat sterilization process (here, wireless transceiver 704 and sensor 708) are embedded in the stopper to save space and / or provide a favorable arrangement for position-based measurements.

[0095] Fig. 8A and Figure 8Bis a cross-sectional view of a disposable syringe 800 having electronics 862 embedded in 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 rod 860 to the stopper 802. As detailed above, the stopper 802 is sealingly engaged to a cartridge, shown here as a housing 801 of the syringe, using a plurality of sealing members 808 arranged around the periphery of the stopper 802. In operation, the distal end 861 of the plunger 860 moves (e.g., arrow 897) to contact the stopper 802 and rotates (e.g., arrow 898) to threadably engage the stopper 802, as shown in FIG. Figure 8B In this configuration, the electronic device 806 is disposed in the stopper 802 and is arranged to emit a sensing signal 870 to determine the position of the stopper 802 within the housing 801 of the syringe 800 in some embodiments, or to determine whether an injection operation has occurred.

[0096] like Figure 8B As shown, force 899 is applied to plunger 860 (e.g., by a patient or clinician injecting syringe 800 ), and plunger 860 drives stopper 802 in housing 801 of syringe 800 to expel at least a portion of medication 80 from syringe 800 . Fig. 8A and Figure 8B One advantage of the configuration of the disposable syringe 800 is the ability to heat sterilize the syringe housing 801 and the stopper 802 prior to introducing the plunger 860 into the stopper 802, thereby eliminating the need to heat sterilize the electronic device 806 included in the distal end 861 of the plunger 860.

[0097] exist Fig. 8A and Figure 8B In the illustrated embodiment, one or more electronic devices may be embedded in the plug 802. The one or more embedded electronic devices may communicate with the electronic device 806 disposed in the threaded distal end 861 of the plunger 860. The plug having at least one embedded electronic device may include a rigid housing, or may be as described with respect to Figure 2A Another advantage of this implementation is that the electronic device 806 is outside the sterilization process. It can be manufactured more easily and cheaply in a typical manufacturing process. From a logistics point of view, the introduction of the electronic device 806 can be done in a subsequent manufacturing step and provides advantages regarding battery life because storage time can be optimized.

[0098] Fig. 9 900 is a flow chart depicting a process for manufacturing a medical cartridge having distributed electronic components. The process includes embedding 902 at least one electronic device in the core of the plug. Figure 2A Describes the types of electronic devices and their characteristics. Figure 2A Materials for making the core of the plug are discussed. The process also includes coupling the core to a housing 904, the housing providing heat resistance to at least one electronic device embedded in the core. Coupling the core to the housing may include forming a Figure 2A and Figure 3A The substantially inseparable one-piece plug described herein may include inserting a preformed core into the shell to create a substantially non-separable one-piece plug as described herein. Figure 4 and Figure 5 The process also includes sterilizing the plug via heat sterilization 906. In an exemplary heat sterilization protocol, the plug is sterilized at a temperature of at least 120 degrees Celsius for twenty to thirty minutes. The process also includes assembling 908 the plug into the cartridge. Assembling the plug into the cartridge creates a sealing interface to seal the medicament in the cavity of the cartridge. Additionally, when assembling the plug with the cartridge, other electronic components that are not embedded in the core of the plug can be assembled into the cartridge.

[0099] Fig.10 is a cross-sectional view of a plug placed inside a cartridge and powered by a wireless system. An example of an energy harvesting system is Fig.10 Shown in. Fig.10 A cartridge 1000 is shown that includes a plug 1002 disposed in a housing 1001 of the cartridge 1000. The plug 1002 and the sealing element 1008 together contain a medicament 1011 in the housing 1001, and the plug 1002 includes a plurality of sealing elements 1008 arranged around the periphery of the plug 1002 and sealingly engaged to the inner surface of the housing 1001. The plug 1002 also includes a cap 1010 that closes the opening of the plug 1002, and the electronic components 1071, 1078, 1079 have been inserted into the cap. In operation, the electronic components 1071, 1078, 1079 are integrated with or carried by the cap 1010 in some embodiments, whereby securing the cap 1010 to the plug 1002 includes inserting the electronic components 1071, 1078, 1079 into the cavity of the plug 1002. The electronic components 1071 , 1078 , 1079 include a sensing device (S) 1079 , a wireless device (WL) 1078 , and a capacitive device (CE) 1071 .

[0100] In operation, the sensing device 1079 is configured to sense the position of the plug 1002 within the housing 1001, and the wireless device 1078 is configured to communicate with an external electronic device (not shown) to transmit 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 from a wireless signal 1081 located near the cartridge 1000 by way of wireless inductive charging. In some embodiments, the capacitive device 1071 includes a capacitive circuit configured to receive power wirelessly from, for example, a smartphone 1080 via a near field communication protocol (NFC) signal 1081, or by a typical wireless charging device with other inductive load means, so as to provide sufficient energy for initiating and performing measurements using the sensing device 1079 in the cartridge 1000 and transmitting the results back using the wireless device 1078.

[0101] Fig.11A and Fig. 11B is a cross-sectional view of a stopper disposed within a cartridge and powered by a piezoelectric system. Another example of an energy harvesting system is to use piezoelectric technology to harvest energy from a stopper between a stopper and a plunger (or, for example, Fig.11A and Fig. 11B Energy is collected from the mechanical forces generated by the cartridge stopper threaded rod system) to provide sufficient energy to initiate and perform the measurement in the cartridge and transmit back the results. Fig.11A A cartridge 1100 is shown having a plug 1102 disposed in a housing 1101 of the cartridge 1100 and a plunger 1160 that is advanced (e.g., along arrow 1197) to contact a cap 1110 of the plug 1102. The plug 1101 and the sealing elements 1108 together contain a medicament 1111 in the housing 1101, and the plug 1102 includes a plurality of sealing elements 1108 disposed around the periphery of the plug 1102 and sealingly engaged to an inner surface of the housing 1101. The cap 1110 closes an opening of the plug 1102 into which electronic components 1172, 1178, 1179 have been inserted, and the cap 1110 is configured to at least partially deflect under the force of the plunger 1160 or otherwise be capable of transmitting force from the plunger to a portion of the electronic components 1172, 1178, 1179. In operation, the electronic components 1172, 1178, 1179 are integrated with or carried by the cap 1110 in some embodiments, whereby securing the cap 1110 to the plug 1102 includes inserting the electronic components 1172, 1178, 1179 into a cavity of the plug 1102. The electronic components 1172, 1178, 1179 include a sensing device (S) 1179, a wireless device (WL) 1178, and a piezoelectric element (PE) 1172.

[0102] In operation, the sensor device 1179 is configured to sense the position of the plug 1102 within the housing 1101, and the wireless device 1178 is configured to communicate with an external electronic device (not shown) to transmit information from the sensor device 1179. The piezoelectric element 1172 is configured to provide power to the sensor device 1179 and the wireless device 1178 by converting a portion of the force applied to the plug 1102 into electrical energy. Fig. 11B As shown, by the force applied by the plunger 1160 to the cap 1110 (during the movement indicated by the arrow 1197), the piezoelectric element 1172 is moved from Fig. 8A The position 1198 is converted into Figure 8B deflected position 1199. The transition of piezoelectric element 1172 from position 1198 to deflected position 1199 absorbs energy and converts a portion of it into electrical energy.

[0103] Fig. 12A and Fig. 12B is a cross-sectional view of a plug disposed within a cartridge and comprising a Peltier thermoelectric device. Another example of an integrated energy harvesting device is to include a thermoelectric element (TE), such as a Peltier element, to convert the temperature difference between the cooling of the pen or syringe during storage and its heating into electrical energy to provide sufficient energy for initiating and performing a measurement in the cartridge of the syringe / pen and transmitting back the result. Fig. 12A A cartridge 1200 is shown, which is stored in a low temperature environment (e.g., 4° C.) and has a plug 1202 disposed in a housing 1201 of the cartridge 1200 and a plunger 1120 positioned against a cap 1210 of the plug 1202. The plug 1202 and the sealing element 1208 together contain a medicament 1211 in the housing 1201, and the plug 1202 includes a plurality of sealing elements 1208 disposed around the periphery of the plug 1202 and sealingly engaged to the inner surface of the housing 1201. The cap 1210 closes the opening of the plug 1202, into which the electronic components 1273, 1278, 1279 have been inserted, and the cap 1210 or the plug 1202 is configured to transfer thermal energy at least partially to the electronic components 1273, 1278, 1279. In operation, the electronic components 1273, 1278, 1279 are in some embodiments integrated with or carried by the cap 1210, whereby securing the cap 1210 to the plug 1202 includes inserting the electronic components 1273, 1278, 1279 into a cavity of the plug 1202. The electronic components 1273, 1178, 1179 include a sensing device (S) 1279, a wireless device (WL) 1278, and a thermoelectric element (TE) 1273.

[0104] In operation, the sensor device 1279 is configured to sense the position of the plug 1202 within the housing 1201, and the wireless device 1278 is configured to communicate with an external electronic device (not shown) to transmit information from the sensor device 1279. The thermoelectric element 1273 is configured to provide power to the sensor device 1279 and the wireless device 1278 by generating energy when the temperature of the thermoelectric element changes. Fig. 12B As shown, the cartridge 1200 is moved to a relatively high temperature environment (e.g., 20° C.), and (during the temperature transition indicated by arrow 1299) the thermoelectric element 1273 is heated by absorbing thermal energy from the environment outside the cartridge 1200. The thermal energy absorbed by the thermoelectric element 1273 generates electrical energy to power, for example, the sensing device 1279 and the wireless device 1278. The described features can be implemented in digital electronic circuits, or in computer hardware, firmware, software, or a combination thereof. The apparatus can be implemented in a computer program product tangibly embodied in an information carrier (e.g., in a machine-readable storage device) for execution by a programmable processor; and the method steps can be performed by a programmable processor executing an instruction program to perform the functions of the described implementation by operating on input data and generating output. The described features can be advantageously implemented in one or more computer programs that can be executed on a programmable system including at least one programmable processor, the at least one programmable processor being coupled to receive data and instructions from a data storage system, at least one input device, and at least one output device, and to transmit data and instructions to it. A computer program is a set of instructions that can be used, directly or indirectly, in a computer to perform a certain activity or cause a certain result. Computer programs may be written in any form of programming language, including compiled or interpreted languages, and computer programs may be deployed in any form, including as a stand-alone program or as a module, component, subroutine or other unit suitable for use in a computing environment.

[0105] Above relative to Figure 2A Various materials that can be used to make the shell and the core are described, as well as various electronic devices that can be embedded in the core. In addition, the material used for the shell can be medical grade, wherein the plug is configured to contact the medicament.

[0106] The term "drug" or "medicament" is used herein to describe one or more pharmaceutically active compounds. As described below, a drug or medicament may include at least one small molecule or macromolecule or a combination thereof in various types of formulations for treating one or more diseases. Exemplary pharmaceutically active compounds may 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 may be incorporated into molecular delivery systems (such as vectors, plasmids or liposomes). Mixtures of one or more of these drugs may also be envisioned.

[0107] The term "drug delivery device" should encompass any type of device or system that is configured to distribute a drug amount into a human or animal body. The drug amount can typically be about 0.5 ml to about 10 ml. In a non-limiting manner, a drug delivery device can include a syringe, a needle safety system, a pen injector, an automatic injector, a large volume device (LVD), a pump, an infusion system, or other devices configured for subcutaneous, intramuscular, or intravascular delivery of a drug. Such devices typically include a needle, wherein the needle can include a small gauge needle (e.g., greater than about 24 gauges, and including 27, 29, or 31 gauges).

[0108] In combination with a particular drug, the presently described devices may also be customized to operate within desired parameters, for example, within a certain time period (e.g., about 3 seconds to about 20 seconds for a syringe, about 5 minutes to about 60 minutes for a LVD), with a low or minimal level of discomfort, or within certain conditions related to human factors, shelf life, expiration date, biocompatibility, environmental factors, etc. These modifications may result from various factors such as, for example, the viscosity of the drug ranges from about 3 cP to about 50 cP.

[0109] The drug or medicament can be contained in a primary package or "drug container" adapted for use with a drug delivery device. The drug container can be, for example, a cartridge, a syringe, a reservoir or other vessel, which is configured to provide a suitable chamber for storing (e.g., short-term or long-term storage) one or more pharmaceutically active compounds. For example, in some embodiments, the chamber can be designed to store the drug for at least one day (e.g., 1 day to at least 30 days). In some embodiments, the chamber can be designed to store the drug for about 1 month to about 2 years. Storage can occur at room temperature (e.g., about 20°C) or refrigerated temperature (e.g., from about -4°C to about 4°C). In some embodiments, the drug container can be or can include a dual-chamber cartridge, which is 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 of which is stored in each chamber. In such an embodiment, the two chambers of the dual-chamber cartridge can be configured to allow mixing between two or more components of the drug or medicament before and / or during distribution to the human or animal body. For example, the two chambers may be configured so that they are in fluid communication with each other (e.g., via a conduit between the two chambers) and allow the user to mix the two components if desired prior to dispensing. Alternatively or additionally, the two chambers may be configured to allow mixing when dispensing the components into a human or animal body.

[0110] Drug delivery devices and drugs described herein can be used to treat and / or prevent many different types of disorders. Exemplary disorders include, for example, diabetes or complications associated with diabetes (such as diabetic retinopathy), thromboembolic disorders (such as deep vein or pulmonary thromboembolism). Other exemplary disorders are acute coronary syndrome (ACS), angina pectoris, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and / or rheumatoid arthritis.

[0111] Exemplary drugs for treating and / or preventing diabetes or complications associated with diabetes include insulin (e.g., human insulin, or human insulin analogs or derivatives); glucagon-like peptide (GLP-1), GLP-1 analogs or GLP-1 receptor agonists, or analogs or derivatives thereof; dipeptidyl peptidase-4 (DPP4) inhibitors, or pharmaceutically acceptable salts or solvates thereof; or any mixture thereof. As used herein, the term "derivative" refers to any substance that is sufficiently similar in structure to the original substance so as to have substantially similar function or activity (e.g., therapeutic effectiveness).

[0112] Exemplary insulin analogs are Gly(A21), Arg(B31), Arg(B32) human 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 which the Lys at position B29 may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.

[0113] Exemplary insulin derivatives are, 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-myristoylLysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-Thr B29LysB30 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 are, for example: lixisenatide / AVE0010 / ZP10 / Lyxumia, exenatide / Exendin-4 / Byetta / Bydureon / ITCA 650 / AC-2993 (a 39 amino acid peptide derived from Gila lizard monster), Liraglutide / Victoza, Semaglutide, Taspoglutide, Syncria / Albiglutide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide / HM-11260C, CM-3, GLP-1Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, 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, Exenatide-XTEN, and Glucagon-Xten.

[0114] An exemplary oligonucleotide is, for example, mipomersen / Kynamro, a cholesterol-reducing antisense therapeutic used to treat familial hypercholesterolemia.

[0115] Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.

[0116] Exemplary hormones include pituitary hormones or hypothalamic hormones or regulatory activity peptides and their antagonists, such as gonadotropins (follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin, tocopherol), growth hormone (somatropin), desmopressin, terlipressin, gonadorelin, triptorelin, leuprorelin, buserelin, nafarelin and goserelin.

[0117] Exemplary polysaccharides include glucosaminoglycanes, hyaluronic acid, heparin, low molecular weight heparin or ultra-low molecular weight heparin or derivatives thereof, or sulfated polysaccharides (e.g., polysulfated forms of the above-mentioned polysaccharides), and / or pharmaceutically acceptable salts thereof. The example of a pharmaceutically acceptable salt of polysulfated low molecular weight heparin is enoxaparin sodium. The example of a hyaluronic acid derivative is Hylan G-F20 / Synvisc, which is a sodium hyaluronate.

[0118] As used herein, the term "antibody" 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, which retain the ability to bind to antigens. The antibody can be a polyclonal antibody, a monoclonal antibody, a recombinant antibody, a chimeric antibody, a deimmunized or humanized antibody, a fully human antibody, a non-human (e.g., murine) antibody, or a single-chain antibody. In some embodiments, the antibody has effector functions and can repair complement. In some embodiments, the antibody has reduced or no ability to bind to Fc receptors. For example, the antibody can be an isotype or subtype, an antibody fragment or a mutant that does not support binding to Fc receptors, for example, it has a mutagenic or missing Fc receptor binding region.

[0119] The term "fragment" or "antibody fragment" refers to a polypeptide derived from an antibody polypeptide molecule (e.g., an antibody heavy chain and / or light chain polypeptide) that does not contain a full-length antibody polypeptide, but still contains at least a portion of a full-length antibody polypeptide that can bind to an antigen. An antibody fragment may include a cleavage portion of a full-length antibody polypeptide, although the term is not limited to such cleavage fragments. Antibody fragments that can be used 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., double-chain antibodies, three-chain antibodies, four-chain antibodies)), mini antibodies, chelated recombinant antibodies, three antibodies or double antibodies, intracellular antibodies, nano antibodies, small modular immunopharmaceuticals (SMIPs), binding domain immunoglobulin fusion proteins, camelized antibodies, and antibodies containing VHH. Additional examples of antigen-binding antibody fragments are known in the art.

[0120] The term "complementarity determining region" or "CDR" refers to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. The term "framework region" refers to amino acid sequences within the variable region of both heavy and light chain polypeptides that are not CDR sequences and are primarily responsible for maintaining the correct positioning of the CDR sequences to allow antigen binding. Although the framework region itself is typically not directly involved in antigen binding, as known in the art, certain residues within the framework region of certain antibodies may be directly involved in antigen binding or may affect the ability of one or more amino acids in the CDR to interact with the antigen.

[0121] Exemplary antibodies are anti-PCSK-9 mAb (eg, Alirocumab), anti-IL-6 mAb (eg, Sarilumab), and anti-IL-4 mAb (eg, Dupilumab).

[0122] The compounds described herein can be used in pharmaceutical formulations comprising (a) one or more compounds or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds can also be used in pharmaceutical formulations including one or more other active pharmaceutical ingredients or in pharmaceutical formulations in which the compounds of the present invention or pharmaceutically acceptable salts thereof are the sole active ingredients. Therefore, the pharmaceutical formulations of the present disclosure encompass any formulation prepared by mixing the compounds described herein and a pharmaceutically acceptable carrier.

[0123] Pharmaceutically acceptable salts of any drug described herein are also intended for use in drug delivery devices. Pharmaceutically acceptable salts are, for example, acid addition salts and basic salts. Acid addition salts are, for example, HCl or HBr salts. Basic salts are, for example, salts with cations selected from: alkali metals or alkaline earth metals, for example, Na+, or K+, or Ca2+, or ammonium ions N+(R1)(R2)(R3)(R4), wherein R1 to R4 represent, independently of one another: hydrogen, optionally substituted C1-C6-alkyl groups, optionally substituted C2-C6-alkenyl groups, optionally substituted C6-C10-aryl groups, or optionally substituted C6-C10-heteroaryl groups. Other examples of pharmaceutically acceptable salts are known to those skilled in the art.

[0124] Pharmaceutically acceptable solvates are, for example, hydrates or alkanolates, such as methanolate or ethanolate.

[0125] Those skilled in the art will appreciate that modifications (such as, for example, adjustments, additions, or removals) may be made to the various components / components of the materials, formulations, apparatuses, methods, systems, devices, and embodiments described herein without departing from the overall scope and spirit of the inventive concept, and that the present invention covers such modifications and any equivalents thereof.

[0126] Many embodiments of the present disclosure have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the present disclosure. Therefore, other embodiments are also within the scope of the appended claims.

[0127] This application further includes the following:

[0128] 1. An injection device (100), comprising:

[0129] Housing (110);

[0130] a drug container (800) disposed in the housing (110), the drug container (800) allowing a needle (115) to be attached to a distal end of the drug container (800);

[0131] a stopper (802) disposed in the drug container (800);

[0132] a plunger (860) configured to contact the stopper (802) and drive the stopper (802) into the drug container (800) to inject the medicament (80) into a patient;

[0133] an electronic device (806) disposed in the stopper (802), the electronic device (806) being configured to determine a state of the drug container (800) via receiving a signal (870) passing through a portion of the stopper (802) when the plunger (860) is in contact with the stopper (802);

[0134] an energy source (706) configured to provide power to the electronic device (806); and

[0135] A cap (116; 117; 118) configured to cover the needle (115) when the needle (115) is attached to the distal end of the drug container (800).

[0136] 2. An injection device according to claim 1, wherein the state of the drug container (800) includes a position of the stopper (802) within the drug container (800).

[0137] 3. An injection device according to item 1, wherein the state of the drug container (800) comprises a filling level of the drug container (800).

[0138] 4. An injection device according to claim 1, wherein the status of the drug container (800) includes a measurement of an injected dose of the medicament (80).

[0139] 5. An injection device according to item 1, wherein the status of the drug container (800) includes a determination of whether an injection operation has occurred.

[0140] 6. An injection device according to any one of items 1 to 5, wherein the electronic device (806) is arranged in the plunger (860) and is arranged in the stopper (802) when the plunger (860) is in contact with the stopper (802).

[0141] 7. An injection device according to claim 6, wherein the plunger (860) includes one or more threads (862), and the stopper includes one or more corresponding threads (852), and the one or more corresponding threads (852) are configured to engage with one or more threads (862) of the plunger (860) when the plunger (860) contacts the stopper (802).

[0142] 8. An injection device according to any one of items 1 to 5, wherein the energy source (706) is located outside the stopper (802).

[0143] 9. An injection device according to any one of items 1 to 5, wherein the energy source (706) is connected to the electronic device (806) via at least one connector (710).

[0144] 10. An injection device according to any one of items 1 to 5, wherein the stopper (802) has been exposed to a temperature of at least 120 degrees Celsius.

[0145] 11. The injection device according to any one of items 1 to 5, wherein the drug container (800) is a cartridge.

[0146] 12. An injection device according to any one of items 1-5, wherein the electronic device (806) includes a wireless transceiver (704), and the wireless transceiver (704) is configured to transmit data to a device outside the stopper (802), and the data includes a determined state of the drug container (800).

[0147] 13. An injection device (100), comprising:

[0148] Housing (110);

[0149] a drug container (800) arranged in the housing (110);

[0150] a stopper (802) disposed in the drug container (800);

[0151] a plunger (860) configured to be inserted into the stopper (802) and to drive the stopper (802) into the drug container (800) to expel the medicine (80) from the drug container (800);

[0152] an electronic device (806) disposed in the plunger (860), the electronic device (806) being configured to determine the status of the drug container (800) via receiving a signal (870) passing through a portion of the stopper (802) when the plunger (860) is inserted into the stopper (802); and

[0153] An energy source (706) is configured to provide power to the electronic device (806).

[0154] 14. An injection device according to item 13, wherein the state of the drug container (800) comprises a position of the stopper (802) within the drug container (800).

[0155] 15. Injection device according to item 13, wherein the state of the drug container (800) comprises a filling level of the drug container (800).

[0156] 16. An injection device according to item 13, wherein the status of the drug container (800) includes a measurement of an injected dose of the medicament (80).

[0157] 17. An injection device according to clause 13, wherein the status of the drug container (800) includes a determination of whether an injection operation has occurred.

[0158] 18. An injection device according to any one of items 13-17, wherein the plunger (860) includes one or more threads (862), and the stopper includes one or more corresponding threads (852), and the one or more corresponding threads (852) are configured to engage with the one or more threads (862) of the plunger (860) when the plunger (860) contacts the stopper (802).

[0159] 19. An injection device according to any one of items 13 to 17, wherein the energy source (706) is located outside the stopper (802).

[0160] 20. Injection device according to item 19, wherein the energy source (706) is connected to the electronic device (806) via at least one connector (710).

[0161] 21. An injection device according to any one of items 13-17, wherein the stopper (802) has been exposed to a temperature of at least 120 degrees Celsius.

[0162] 22. An injection device according to any one of items 13-17, wherein the electronic device (806) includes a wireless transceiver (704), and the wireless transceiver (704) is configured to transmit data to a device outside the stopper (802), and the data includes a determined state of the drug container (800).

[0163] 23. An injection device according to any one of items 13 to 17, comprising a needle (115) attached to the distal end of the drug container (800).

[0164] 24. Injection device according to item 23, comprising a cap (116; 117; 118) configured to cover the needle (115).

[0165] 25. Injection device according to any one of items 13-17, wherein the drug container (800) is a cartridge.

[0166] 26. An injection device (100), comprising:

[0167] Housing (110);

[0168] a drug container (114; 600; 800) arranged in the housing;

[0169] a stopper (200; 300; 802) arranged in the drug container;

[0170] a plunger (860) configured to drive the stopper (802) into the drug container (800) to discharge the drug (80) from the drug container (800);

[0171] electronic means (206; 306; 806) disposed within the stopper, the electronic means being configured to determine a position of the stopper (802) within the drug container via receiving a signal (870) passing through a portion of the stopper; and

[0172] An energy source (706) is configured to provide power to the electronic device.

[0173] 27. An injection device according to clause 26, wherein the electronic device is configured to determine a fill level of the drug container based on the determined position of the stopper.

[0174] 28. An injection device according to item 26, wherein the electronic device is configured to determine an injected dose of the medicament based on the determined position of the stopper.

[0175] 29. An injection device according to item 26, wherein the electronic device is configured to determine whether an injection operation has occurred based on the determined position of the stopper.

[0176] 30. An injection device according to any one of items 26-29, wherein the energy source is positioned outside the stopper.

[0177] 31. Injection device according to item 30, wherein the energy source is connected to the electronic device via at least one connector (710).

[0178] 32. Injection device according to any of items 26-29, wherein the drug container (800) is a cartridge.

[0179] 33. An injection device according to any one of items 26-29, wherein the stopper has been exposed to a temperature of at least 120 degrees Celsius.

[0180] 34. An injection device according to clause 33, wherein the plug is thermally insulated to allow the electronic device to be arranged in the plug when the plug is exposed to a temperature of at least 120 degrees Celsius.

[0181] 35. An injection device according to any one of items 26 to 29, wherein the stopper is thermally insulated to allow the electronic device to be arranged in the stopper during heat sterilization of the stopper.

[0182] 36. An injection device according to any one of items 26-29, wherein the electronic device includes a wireless transceiver (704), which is configured to send data to a device outside the stopper, the data including the determined status of the drug container (114, 600).

[0183] 37. An injection device according to any one of items 26 to 29, wherein the stopper comprises a shell (202) and a core (204), the core being arranged in the shell.

[0184] Reference numerals

[0185] 80 Pharmacy

[0186] 100 Injection device

[0187] 104 Cartridge housing

[0188] 106 Driving mechanism

[0189] 108 plug

[0190] 109 needles

[0191] 110 Housing

[0192] 111 Injection button

[0193] 112 Dosage knob

[0194] 113 Dosage Window

[0195] 114 Cartridge

[0196] 115 Needle Assembly

[0197] 116 Inner needle cap

[0198] 117 outer needle cap

[0199] 118 Hat

[0200] 122 Electronic components

[0201] 124 Electronic components

[0202] 200 Stopper

[0203] 202 Rigid Shell

[0204] 204 cores

[0205] 206a Electronic Devices

[0206] 206b Electronic Devices

[0207] 206c Electronic Devices

[0208] 208 Sealing element

[0209] 300 Stopper

[0210] 302 soft shell

[0211] 304 Rigid Core

[0212] 306a Electronic devices

[0213] 306b Electronic Devices

[0214] 306c Electronic Devices

[0215] 308 Sealing element

[0216] 400 Plug

[0217] 402 Rigid Shell

[0218] 404 core

[0219] 406a Embedded Electronics

[0220] 406b Embedded Electronics

[0221] 406c Embedded Electronics

[0222] 408 Sealing element

[0223] 410 Hood

[0224] 500 Stopper

[0225] 502 Soft Shell

[0226] 504 can be inserted into the rigid core

[0227] 506a Embedded Electronics

[0228] 506b Embedded Electronics

[0229] 506c Embedded Electronics

[0230] 508 Sealing element

[0231] 600 Cartridges

[0232] 602 Cartridge Shell

[0233] 604 Cap

[0234] 700 Distributed Electronic Systems

[0235] 702 Plug

[0236] 704 Wireless Transceiver

[0237] 706 Energy Source

[0238] 708 Sensor

[0239] 710 Connector

[0240] 800 Disposable Syringes

[0241] 801 Housing

[0242] 802 plug

[0243] 806 Electronic Devices

[0244] 808 Sealing components

[0245] 852 Thread Features

[0246] 859 Central cavity

[0247] 860 Plunger

[0248] 861 Remote

[0249] 862 Corresponding thread features

[0250] 870 Sensor signal

[0251] 897 Arrow

[0252] 898 Arrow

[0253] 899 Strength

[0254] 900 Process

[0255] 902 Embedded Electronics

[0256] 904 Coupling the core to the housing

[0257] 906 Sterilize the stopper

[0258] 908 Assembling the stopper into the cartridge

[0259] 1000 Cartridges

[0260] 1001 Housing

[0261] 1002 Plug

[0262] 1008 Sealing element

[0263] 1010 Hat

[0264] 1011 Pharmacy

[0265] 1071 Capacitive Devices (CE)

[0266] 1078 Wireless Device (WL)

[0267] 1079 Sensor(S)

[0268] 1081 Wireless Signal

[0269] 1080 Smartphone

[0270] 1100 Cartridge

[0271] 1101 Housing

[0272] 1102 Plug

[0273] 1108 Sealing element

[0274] 1110 Cap

[0275] 1111 Pharmacy

[0276] 1160 Plunger

[0277] 1172 Piezoelectric element (PE)

[0278] 1178 Wireless Device (WL)

[0279] 1179 Sensor(S)

[0280] 1197 Arrow

[0281] 1198 Location

[0282] 1199 Deflection position

[0283] 1200 Cartridges

[0284] 1201 Housing

[0285] 1202 Plug

[0286] 1208 Sealing element

[0287] 1210 Hat

[0288] 1211 Pharmacy

[0289] 1260 Plunger

[0290] 1273 Thermoelectric element (TE)

[0291] 1278 Wireless Device (WL)

[0292] 1279 Sensor(S)

[0293] 1299 Arrow

Claims

1. An injection device (100), comprising: Housing (110); a drug container (800) disposed in the housing (110), the drug container (800) allowing a needle (115) to be attached to a distal end of the drug container (800); a stopper (802) disposed in the drug container (800); a plunger (860) configured to contact the stopper (802) and drive the stopper (802) into the drug container (800) to inject the medicament (80) into a patient; an electronic device (806) disposed in the stopper (802), the electronic device (806) being configured to determine a state of the drug container (800) via receiving a signal (870) passing through a portion of the stopper (802) when the plunger (860) is in contact with the stopper (802); an energy source (706) configured to provide power to the electronic device (806); and A cap (116; 117; 118) configured to cover the needle (115) when the needle (115) is attached to the distal end of the drug container (800).

2. The injection device according to claim 1, wherein the state of the drug container (800) comprises a position of the stopper (802) within the drug container (800).

3. The injection device according to claim 1, wherein the state of the drug container (800) comprises a filling level of the drug container (800).

4. The injection device according to claim 1, wherein the status of the drug container (800) includes a measurement of an injected dose of the medicament (80).

5. The injection device of claim 1, wherein the status of the drug container (800) includes a determination of whether an injection operation has occurred.

6. The injection device according to any one of claims 1 to 5, wherein the electronic device (806) is arranged in the plunger (860) and is arranged in the stopper (802) when the plunger (860) is in contact with the stopper (802).

7. An injection device according to claim 6, wherein the plunger (860) includes one or more threads (862), and the stopper includes one or more corresponding threads (852), and the one or more corresponding threads (852) are configured to engage with the one or more threads (862) of the plunger (860) when the plunger (860) contacts the stopper (802).

8. The injection device according to any one of claims 1 to 5, wherein the energy source (706) is located outside the stopper (802).

9. The injection device according to any one of claims 1 to 5, wherein the energy source (706) is connected to the electronic device (806) via at least one connector (710).

10. The injection device according to any one of claims 1-5, wherein the stopper (802) has been exposed to a temperature of at least 120 degrees Celsius.

Images