Manufacturing two-piece resilient plunger

Abstract

The invention relates to manufacturing a two-piece resilient plunger. A technique for manufacturing a resilient container closure or plunger having an embedded functional component to avoid thermal damage to the component includes molding a drug contact from a first material at a first temperature and within a first length of time defining a first thermal exposure. After molding the drug contact, an auxiliary component is inserted into the drug contact, where an operating thermal budget of the auxiliary component is less than the first thermal exposure. Next, the drug-contacting portion and the auxiliary component are overmolded with a second material at a second temperature for a second length of time to form a non-drug-contacting portion, and mechanically connecting the non-drug contact portion and the drug contact portion to form the resilient container closure and seal the auxiliary component inside the resilient container closure. The overmolding defines a thermal exposure that is less than the working thermal budget of the auxiliary component.

Description

[0001] This invention application is a divisional application based on an invention patent application with application date of December 14, 2018, application number 201880081257.0 (international application number PCT / EP2018 / 084869) and name “Manufacturing a Two-Piece Elastic Plunger”. Technical Field

[0002] The present description relates to the manufacture of a resilient plunger with internal electronic components for use in a cartridge or syringe of an injection device configured to expel a medicament using the plunger. Background Art

[0003] There are a variety of existing diseases that need to be treated by injection of medicaments. This injection can be performed by using an injection device, which is used by medical personnel or the patient himself. For example, type 1 and type 2 diabetes can be treated by the patient himself by injecting insulin dosage, such as once or several times a day. For example, a pre-filled disposable insulin pen or an automatic injector can be used as an injection device. Alternatively, a reusable pen or automatic injector can be used. A reusable pen or automatic injector allows an empty medicament cartridge to be replaced with a new medicament cartridge. Each of these devices usually adopts an elastic plunger or a stopper to drive medicine from a cartridge or a syringe in the device, and some devices include one or more electronic devices embedded in the plunger. Summary of the invention

[0004] An exemplary implementation is a method of manufacturing an elastic container closure having an embedded functional component. The method includes molding a drug contact portion of the elastic container closure from a first material at a first temperature and for a first length of time, exposing the drug contact portion to the first temperature for the first length of time to define a first thermal exposure. After molding the drug contact portion, inserting an auxiliary component into the drug contact portion, the auxiliary component having an operating thermal budget less than the first thermal exposure, and overmolding the drug contact portion and the inserted auxiliary component with a second material at a second temperature for a second length of time to form a non-drug contact portion and mechanically connecting the non-drug contact portion and the drug contact portion to form the elastic container closure and sealing the auxiliary component inside the elastic container closure. The second thermal exposure defined by the overmolding is less than the operating thermal budget of the auxiliary component.

[0005] In some examples, the auxiliary component is configured to operate after being exposed to a temperature lower than the first temperature of the first material during the molding step.

[0006] In some examples, the second temperature is lower than the first temperature, and wherein the auxiliary component is configured to operate after exposure to the second temperature of the second material during the overmolding step.

[0007] In some examples, the auxiliary component is incompatible with the first temperature of the molding of the drug contact portion.

[0008] In some examples, the auxiliary components include functional electronic components.

[0009] In some examples, the overmolding includes a UV curing process of the second material.

[0010] In some examples, the first temperature is 150°C-180°C.

[0011] In some examples, the second temperature is 150°C-120°C.

[0012] In some examples, the second temperature is below 120°C.

[0013] In some examples, the second temperature is below 80°C.

[0014] In some examples, the second temperature is below 45°C.

[0015] In some examples, the first material includes a butyl halide.

[0016] In some examples, the method includes, prior to inserting the auxiliary component, laminating the drug contact portion with a fluoropolymer film prior to inserting the auxiliary component.

[0017] In some examples, the first material comprises a pharmaceutical grade thermoset material selected from the group consisting of halobutyl, polyisoprene, and styrene-butadiene, and the molding of the drug contact portion comprises compression molding.

[0018] In some examples, the first material comprises a thermoplastic elastomer, and the molding of the drug contact portion comprises injection molding.

[0019] In some examples, the second material includes silicone rubber.

[0020] In some examples, the second material includes at least one of liquid silicone rubber and high consistency silicone rubber.

[0021] In some examples, the first material is air-impermeable.

[0022] In some examples, the method includes trimming the molded drug contact portion after inserting the auxiliary component.

[0023] In some examples, the method includes trimming the molded drug contact portion prior to inserting the auxiliary component.

[0024] In some examples, the resilient container closure defines a plunger or stopper configured to be inserted into a syringe housing, a cartridge housing, or a medicament container.

[0025] In some examples, the method includes sterilizing the resilient container closure after closure using a sterilization process having a thermal budget that is less than the thermal budget of the auxiliary component.

[0026] In some examples, the molding includes molding the drug contact portion in a first mold, and wherein the overmolding includes overmolding the drug contact portion and the auxiliary component in a second mold, and the method includes removing the drug contact portion from the first mold and disposing the drug contact portion in the second mold.

[0027] In some examples, the auxiliary component is inserted into the drug contact portion before removing the drug contact portion from the first mold.

[0028] In some examples, the auxiliary component is inserted into the drug contact portion after the drug contact portion is disposed in the second mold.

[0029] In some examples, the auxiliary component includes a battery.

[0030] In some instances, the drug contact portion defines a receptacle for receiving the auxiliary component.

[0031] In some examples, the drug contact portion defines a protrusion configured to extend into the overmolded non-drug contact portion to increase mechanical adhesion between the drug contact portion and the non-drug contact portion after the non-drug contact portion is overmolded around the protrusion.

[0032] In some examples, the protrusion defines one or more of: threads, flanges, and embossings.

[0033] In some examples, the flange is configured to increase mechanical adhesion of the drug contact portion to the overmolded non-drug contact portion.

[0034] Another example of the present disclosure is a resilient container closure manufactured according to the above method by molding a drug contact portion of the resilient container closure from a first material at a first temperature and for a first length of time, exposing the drug contact portion to the first temperature for the first length of time to define a first thermal exposure. After molding the drug contact portion, inserting an auxiliary component into the drug contact portion, the auxiliary component having an operating thermal budget less than the first thermal exposure, and overmolding the drug contact portion and the inserted auxiliary component with a second material at a second temperature for a second length of time to form a non-drug contact portion and mechanically connecting the non-drug contact portion and the drug contact portion to form the resilient container closure and sealing the auxiliary component inside the resilient container closure. The second thermal exposure defined by the overmolding is less than the operating thermal budget of the auxiliary component.

[0035] Yet another example is a drug delivery device including a resilient container closure manufactured according to the methods described herein.

[0036] In some examples, the drug delivery device includes a container having an open end sealed by the resilient container closure, and the container includes a medicament.

[0037] In some examples, the agent includes a pharmaceutically active compound.

[0038] In general, the examples described herein relate to a technique for manufacturing a pharmaceutical elastic closure component with an embedded functional component. The techniques and related components described herein constitute an effective way to manufacture a container closure component (i.e., a pharmaceutical rubber proven plunger) with an embedded component that enhances functionality beyond mere containment. In some instances, the embedded component is an electronic active component for sensing and monitoring, or a passive component for tracking and tracing the operation of the device and / or the administration of drugs from the device.

[0039] Specifically, the present invention relates to the following:

[0040] 1. A method of manufacturing a closure for a flexible container (108, 200, 440) having an embedded functional component, the method comprising:

[0041] molding a drug contacting portion (405) of the elastomeric container closure (108, 200, 440) from a first material (401) at a first temperature and for a first length of time, exposing the first temperature for the first length of time to define a first thermal exposure;

[0042] After molding the drug contact portion (405), inserting an auxiliary component (420) into the drug contact portion (405), the auxiliary component (420) having an operating thermal budget less than the first thermal exposure; and

[0043] A second material is deposited on the drug contact portion (405) and the inserted auxiliary component (420) to form the elastic container closure (108, 200, 440), wherein forming the elastic container closure (108, 200, 440) includes overmolding a non-drug contact portion (441) around the drug contact portion (405) with the second material at a second temperature for a second time period, the second time period defining a second thermal exposure less than the operating thermal budget of the auxiliary component (420) to seal the auxiliary component (420) within the elastic container closure (108, 200, 440).

[0044] 2. A method according to item 1, wherein the auxiliary component (420) is configured to operate after being exposed to a temperature lower than the first temperature of the first material (401) during the molding step.

[0045] 3. A method according to item 2, wherein the second temperature is lower than the first temperature, and wherein the auxiliary component (420) is configured to operate after exposure to the second temperature of the second material during the overmolding step.

[0046] 4. A method according to item 3, wherein the auxiliary component (420) is incompatible with the first temperature of the molding of the drug contact portion (405).

[0047] 5. A method according to any one of items 1 to 4, wherein the first material (401) comprises a halogenated butyl group.

[0048] 6. A method according to any one of items 1 to 5, wherein the second material comprises silicone rubber.

[0049] 7. A method according to any one of items 1 to 6, wherein molding the drug contact portion (405) includes molding the drug contact portion (405) in a first mold (404), and wherein overmolding includes overmolding the non-drug contact portion (420) with the second material around the drug contact portion (405) and the auxiliary component (420) in a second mold (433).

[0050] 8. A method according to item 7, comprising removing the drug contact portion (405) from the first mould (404) and arranging the drug contact portion (405) into the second mould (433) prior to the overmoulding.

[0051] 9. A method according to any one of items 1 to 8, wherein molding the drug contact portion (405) includes compressing the drug contact portion (405) so that the shape of the drug contact portion (405) includes a peripheral flange (415), which is configured to increase the mechanical adhesion of the drug contact portion (405) to the overmolded non-drug contact portion (420).

[0052] 10. The method according to any one of items 1 to 9, wherein the deposition process comprises a UV curing process of the second material.

[0053] 11. The method according to any one of items 1 to 10, wherein the second temperature is between 60°C and 120°C.

[0054] 12. An elastic container closure (108, 200, 440) manufactured according to the method of any one of items 1 to 11.

[0055] 13. A drug delivery device (100) comprising the resilient container closure (108, 200, 440) according to item 12.

[0056] 14. A drug delivery device (100) according to claim 12, comprising a container (104, 390), the open end of which is sealed by the elastic container closure (108, 200, 440), and the container comprises a medicament (60).

[0057] 15. A drug delivery device according to claim 13, wherein the medicament (60) comprises a pharmaceutically active compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 is an exploded view of the injection device.

[0059] Figure 2A is a cross-sectional view of a plunger configured to be disposed in an injection device, the plunger having a drug contact portion and a non-drug contact portion, wherein an electronic device is embedded in the non-drug contact portion.

[0060] Figure 2B yes Figure 2A Top view of the plunger.

[0061] Figure 3A is a cross-sectional view of a plunger configured to be disposed in an injection device, the plunger having a drug contact portion and a non-drug contact portion, wherein an electronic device is embedded in the non-drug contact portion.

[0062] Figure 3B yes Figure 3A Top view of the plunger.

[0063] Figure 3C yes Figure 3A and 3B A cross-sectional view of a plunger disposed in a cartridge.

[0064] Figures 4A-4I is an illustration of a technique for making a two-piece plunger with embedded electronics.

[0065] Figure 5 is a flow chart of a two-piece process for molding a plunger with embedded auxiliary components using two different materials.

[0066] Fig. 6A Before being driven by the plunger Fig. 4I A cross-sectional view of a plunger including a removable insert.

[0067] Figure 6B During the sensing operation during or after the plunger is driven into the cartridge Fig. 4I Cross-sectional view of the plunger.

[0068] Figure 7 is a cross-sectional view of a plunger disposed within a cartridge and powered by a wireless system.

[0069] Fig. 8A and 8B is a cross-sectional view of a plunger disposed within a cartridge and powered by a piezoelectric system.

[0070] Fig. 9A and 9B is a cross-sectional view of a plunger disposed within a cartridge and powered by a thermoelectric system. DETAILED DESCRIPTION

[0071] Some cartridge-based injection and medical syringe systems are difficult to manufacture if the electronics contained in the replaceable part of the device (e.g., the cartridge stopper or the cartridge housing) may not withstand the heating of the molding process of the cartridge plunger. In some examples, the cartridge plunger (e.g., the stopper or the stopper) can be manufactured using a two-step process, in which the drug contact portion of the plunger is molded before some auxiliary electronic components are inserted into the drug contact portion, after which a second molding around the drug contact portion and the auxiliary components completes the plunger. For example, a first molding process of the drug contact portion of the plunger is performed using a first material suitable for sealing the drug inside the cartridge, but under heat exposure (i.e., the length of time the first material is exposed to a certain temperature during molding), which may damage or destroy a set of auxiliary electronic components included in the complete stopper. Next, after the molding of the drug contact portion is completed, the auxiliary electronic components are inserted into the drug contact portion, and a second overmolding of the two parts is performed using a second material to form the non-drug contact portion of the plunger. The second material is overmolded over the auxiliary electronic component under thermal exposure that the auxiliary electronic component can withstand, which is done by performing at a temperature below the maximum temperature limit of the auxiliary electronic component or by exposing the auxiliary electronic component to a temperature exceeding its maximum temperature limit but for a time long enough to keep the auxiliary electronic component below its thermal budget (i.e., a function of temperature and time).

[0072] Also in some examples, the drug contacting portion of the plunger or stopper is structured to seal against the cartridge wall with a soft O-ring seal so that the second material of the non-drug contacting portion does not contact the sterilizing liquid inside the cartridge. In this way, the drug contacting portion of the plunger seals the cartridge, and the non-drug contacting portion of the plunger can accommodate the plunger rod to drive the plunger into the cartridge.

[0073] In general, the examples described herein relate to a technique for manufacturing a pharmaceutical elastic closure component with an embedded functional component. The techniques and related components described herein constitute an effective way to manufacture a container closure component (i.e., a pharmaceutical rubber proven plunger) with an embedded component that enhances functionality beyond mere containment. In some instances, the embedded component is an electronic active component for sensing and monitoring, or a passive component for tracking and tracing the operation of the device and / or the administration of drugs from the device.

[0074] Conventional high volume rubber pharmaceutical closures are manufactured using single material compression molding of thermosetting elastomers or injection molding of thermoplastic or thermosetting elastomers. Typically, the thermal budget (i.e., heat exposure) associated with those processes is incompatible with auxiliary components that may be embedded in the plunger to achieve additional functionality of the plunger.

[0075] The presently described example of a two-step manufacturing process enables the embedding of ancillary components into a container plunger, where the ancillary components cannot withstand the molding process that would expose them to the drug-contacting portion of the plunger.

[0076] Figure 1 is an exploded view of the injection device 100. The injection device 100 comprises a housing 110 and has therein a cartridge 114 with a cartridge housing 104, 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 or drug to be expelled from the injection device 100 is selected by turning a dose knob 112, and the selected dose is displayed via a dose window or display 113, for example in multiples of so-called international units (IU), where for example one IU is biologically equivalent to approximately 45.5 micrograms of pure crystalline insulin (1 / 22 mg). An example of a selected dose displayed in the dose window or display 113 could be, for example, 30 IU, such as Figure 1 The selected dose may equally well be displayed in a different manner, for example by an electronic display. The dose window 113 relates to a section of the injection device through or on which the selected dose is visible.

[0077] As described further below, the injection device 100 may include one or more auxiliary electronic components 122 , 124 , some of which may be included in the plunger 108 , for example.

[0078] Rotating 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, which is contained in the housing 110 and mechanically interacts with the piston in the cartridge 114. When the needle 115 is inserted into the skin portion of the patient and then the injection button 111 is pushed, the drug dose (e.g., insulin) displayed in the dose window 113 will be discharged from the injection device 100. During injection, the drive mechanism 106 (which is shown as the profile of the plunger arm) drives the stopper (also interchangeably referred to as a plunger herein) 108 into the cartridge (e.g., cartridge 114). When the needle 115 of the injection device 100 is retained in the skin portion for a certain time after pushing the injection button 111, most of the dose is actually injected into the patient. The discharge of the insulin dose can also cause a mechanical click, but it is different from the sound produced when the dose knob 112 is used.

[0079] The injection device 100 may be used for several injection procedures until the insulin cartridge 114 is empty or the injection device 100 reaches its expiration date (eg, 28 days after first use).

[0080] Furthermore, before using the injection device 100 for the first time, it may be advantageous to perform a so-called "prime shot" to remove air from the insulin cartridge 114 and needle 109, for example by selecting 2 units of insulin and depressing the injection button 111 while holding the needle 109 of the injection device 100 pointing upwards.

[0081] For simplicity of representation, it will be assumed hereinafter that the expelled dose substantially corresponds to the injected dose, so that, for example, when a dose to be injected next is suggested, this dose is equal to the dose that must be expelled by the injection device. However, it may of course be necessary to take into account differences (e.g. losses) between the expelled dose and the injected dose.

[0082] Figure 2A is a cross-sectional view of an implementation of a plunger 200 configured to be disposed in an injection device (e.g., injection device 100), the plunger 200 having a drug contact portion 202 and a non-drug contact portion 204, wherein an electronic device is embedded in the non-drug contact portion 204. In some examples, the electronic device is sealed in the plunger 200 through the non-drug contact portion 204. Figure 2A A plunger 200 is shown that includes a drug contact portion 202 and a non-drug contact portion 204 that includes electronic devices 206a, 206b, and 206c, which, in some examples, are sealed against the non-drug contact portion 204 by the material of the non-drug contact portion 204 during an overmolding process after molding the drug contact portion 202. In this implementation, the non-drug contact portion 204 is configured to be overmolded around the drug contact portion 202 during manufacture of the electronic devices 206a, 206b, and 206c and after insertion. In some examples, the drug contact portion 202 is manufactured using a first molding step, and the electronic devices 206a, 206b, and 206c are inserted into the drug contact portion 202 after the first molding step. Subsequently, in a second molding step, the non-drug contact portion 204 is molded over the drug contact portion 202 to seal the electronic devices 206a, 206b, and 206c into the plunger 200. The drug contact portion 202 and the non-drug contact portion 204 together seal the embedded electronic devices 206a, 206b, and 206c into the plunger 200. In some examples, the electronic devices 206a, 206b, and 206c are held in place (e.g., inserted into the cavity) by the drug contact portion 202 before the second molding of the non-drug contact portion 204. In some examples, the drug contact portion 202 includes a sealing element 208 (e.g., an O-ring) that is arranged to provide a sealing interface with the inner surface of the cartridge 114 when the drug contact portion 202 is inserted into the cartridge 104. In some examples, the sealing element 208 is integrated into the drug contact portion 202 as a sealing protrusion.

[0083] The material is selected based on the hardness, elasticity, and heat resistance or insulation performance of the drug contact part 202 and the non-drug contact part 204. In some instances, the non-drug contact part is made of a material selected to be molded at a temperature lower than the maximum exposure temperature of the embedded electronic device 206a, 206b and 206c or a material that can be molded for a certain temperature and time so as to be able to keep the embedded electronic device 206a, 206b and 206c lower than the minimum thermal budget of the electronic device 206a, 206b and 206c. In some implementations, the drug contact part 202 and the non-drug contact part 204 are made of a polymer material with a variable elastic property. In some implementations, a heat-resistant coating can also be applied to the non-drug contact part 204 or the drug contact part 202 to increase heat resistance, such as, for example, a polytetrafluoroethylene (PTFE) coating. In some cases, drug contact portion 202 is made of a material selected to be compatible with the agent, such as PP, PE, COC, OCP, PTFE, or butyl rubber at surface 203 that contacts the agent.

[0084] Embedded electronic devices 206a, 206b and 206c may include, for example, sensors, energy sources, microcontrollers and wireless transceivers. In some instances, the sensor may be a sensor / transmitter device, such as, for example, a piezoelectric device, an acoustic sensor or an electromagnetic sensor. The sensor / transmitter may transmit a signal, such as, for example, ultrasound, sound, light or other signal, through the plunger 200, and measure a response, which in some instances may be used to determine the position of the plunger 200 in the cartridge 114 or determine whether an injection of a syringe has occurred. In some instances, the response received by the sensor 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 114. In some instances, the state of the cartridge 114 may correspond to the filling level of the medicament in the cartridge 114 or the position of the plunger 200. In some instances, the state of the cartridge 114 enables measurement of the injected dose of the medicament.

[0085] In some examples, the energy source may be a battery that can charge a capacitor or a solar energy source through any energy harvesting technology. The wireless transceiver can communicate with the external electronic device and with the sensor and energy source. The external electronic device (which may be a controller) can transmit 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.

[0086] Figure 2B yes Figure 2A200. The drug contact portion 202 surrounds the non-drug contact portion 204 and interfaces with a sealing element 208, which forms a sealing interface with the cartridge 114 when the plunger 200 is introduced into the cartridge 114. The sealing interface can form at least a portion of a sterile barrier within the cartridge 114, which is necessary to maintain the sterility of the medicament to be delivered by the injection device.

[0087] Figure 3A 1 is a cross-sectional view of a plunger 300 configured to be disposed in an injection device 100, the plunger 300 having a drug contact portion 302 and a non-drug contact portion 304, the non-drug contact portion having embedded electronic devices 306a, 306b, 306c. In some examples, the drug contact portion 302 and the non-drug contact portion 304 are substantially inseparable after the non-drug contact portion is overmolded. For example, the non-drug contact portion 304 can be molded around a protrusion of the drug contact portion 302, or fixed using an adhesive to combine the non-drug contact portion 304 and the drug contact portion 302 together. The non-drug contact portion 304 includes embedded electronic devices 306a, 306b, and 306c. In one implementation, after the drug contact portion 302 is molded from the first material, the electronic devices 306a, 306b, and 306c are inserted into the drug contact portion 302, and a second material is molded around the electronic devices 306a, 306b, and 306c to form the non-drug contact portion 304. In another implementation, the electronic devices 306a, 306b, 306c can be inserted into the second material while the second material is in a non-cured, soft state before the second material solidifies to form the non-drug contact portion 304. The integrated sealing element 308 is configured to provide a sealing interface with the cartridge 114 when the plunger 300 is inserted into the cartridge 114.

[0088] Above about Figure 2A Various materials that can be used to make the drug contact portion 302 and the non-drug contact portion 304 and various electronic devices that can be embedded in the non-drug contact portion are described. In addition, the material used for the drug contact portion 302 can be medical grade, wherein the plunger drug contact portion 302 is configured to contact the drug.

[0089] Figure 3B yes Figure 3A The drug contact portion 302 surrounds the non-drug contact portion 304 and includes an integrated sealing element 308 that forms a sealing interface with the cartridge 114 when the plunger 300 is introduced into the cartridge 114. The sealing interface can form at least a portion of a sterile barrier within the cartridge 114 that is necessary to maintain the sterility of the medicament to be delivered by the injection device 100.

[0090] Figure 3Cis a cross-sectional view of a plunger disposed within cartridge 390. Figure 3A and Figure 3B Various features of the plunger shown are described. The plunger 300 can be replaced by any plunger in the previous figures, which will dock with the cartridge 390 in a manner almost identical to that described herein for the plunger 300. The cartridge 390 includes a housing 392 that docks with a sealing element 308 of the plunger 300 to seal the open end of the cartridge 390. In some instances, a medicament (e.g., a medical fluid or drug) is disposed in a space between the cap 394 of the cartridge 600 and the drug contact portion 302 of the plunger 300. In some instances, the embedded electronic devices 306a, 306b, and 306c include sensors that are configured to send and receive signals to sense the position of the plunger 300 in the cartridge 390.

[0091] The sensor 310 may be a sensor / transmitter device, such as, for example, a piezoelectric device. The sensor / transmitter may transmit a sensing signal (such as, for example, ultrasound, sound, light, or other signal) through the plunger 300 and measure a response. 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 390. The state of the cartridge 390 may correspond to, for example, a fill level of a medicament in the cartridge 390 or a position of the plunger 300. The state of the cartridge may allow for measurement of an injected dose of the medicament.

[0092] For example, the non-drug contact portion may be sterilized by using a heat sterilization process after overmolding the non-drug contact portion. Figure 2A , 2B , 3A, 3B and 3C. In an exemplary heat sterilization process, the complete plunger including the auxiliary electronic components will be sterilized at a temperature of about 80 degrees Celsius to 120 degrees Celsius for about twenty to thirty minutes.

[0093] Figures 4A-4I is an illustration of a technique for making a two-piece plunger with embedded electronics. Figure 4A The rubber material 401 is shown after it has been mixed and extruded into the shape of the reading mold part. In some examples, the rubber material 401 includes a pharmaceutical grade thermoset material such as halobutyl, polyisoprene, and styrene-butadiene. Figure 4B The rubber material 401 is shown after a fluoropolymer film 402 has been applied to one side of the rubber material 401 using, for example, a film lamination process. The purpose of the film is to provide a barrier to prevent unwanted inorganic and organic substances from leaching from the plunger into the drug formulation.

[0094] Figure 4CA compression molding apparatus is shown that includes a top mold 403 and a bottom mold 404, wherein a laminated rubber material 401 is located between the top mold 403 and the bottom mold 404. In operation, the top mold 403 and the bottom mold 404 compress the laminated rubber material 401 into the desired shape of the drug contact portion 405 of the plunger, such as Figure 4D 401 as the first molding process. The first molding process involves thermal exposure of the rubber material 401, which is defined as the total energy transferred to the material, or more simply, the integral of the material temperature during the first molding period.

[0095] Figure 4E The complete drug contact portion 405 after the first molding step is shown. As described below, the drug contact portion 405 includes a protrusion 414, which forms an inner cavity 411 and a peripheral flange 415, which is configured to increase the mechanical adhesion of the drug contact portion 405 to the overmolded portion. The drug contact portion 405 also defines: a bottom surface, which is configured to face the interior of the drug cartridge; and two peripheral sealing edges 412, which are configured to sealably dock with the inner surface of the drug cartridge when inserted. In some instances, the protrusion 414 includes geometric features to allow the auxiliary component to be positioned in the cavity 411. In some instances, the protrusion 414 includes geometric features to enhance the mechanical stability of the portion molded above the protrusion 414.

[0096] Figure 4F 4 is a diagram showing the auxiliary component 420 being inserted into the cavity 411 of the drug contact portion 405 . Figure 4G The drug contact portion 405 and the auxiliary component 420 are shown placed in an injection mold including a top mold 433 and a bottom mold 404. In some examples, the bottom mold 404 is the same bottom mold 404 as the first compression molding step, and in other examples, the bottom is the same as the bottom mold 404 of the first compression molding step, but the drug contact portion 405 is removed from the first bottom mold 404 and placed into a new bottom mold of the injection molding machine. Figure 4H The drug contact portion 405 is shown in the injection mold 404, 433 immediately before injecting material into the cavity 435 of the injection mold 404, 433. In some examples, the injected material is silicone rubber, which can be, for example, liquid silicone rubber or high consistency silicone rubber. Fig. 4IA complete plunger 440 is shown, which includes a drug contact portion 405 defining the lower half of the plunger 440, wherein an injection molded non-drug contact portion 441 surrounds the auxiliary component 420 and defines the complete upper half of the plunger 440. The auxiliary component 420 is sealed within the plunger 440 between the drug contact portion 405 and the non-drug contact portion 441. The non-drug contact portion includes a top surface 444, which is configured to be contacted by the head of the plunger rod to drive the plunger 440 into the cartridge. The non-drug contact portion 441 also includes a peripheral sealing edge 442 that forms a third sealing edge of the plunger 440.

[0097] In operation, the thermal budget of auxiliary component 420 may be lower than Figure 4D In some examples, during the compression molding step, the curing temperature of the drug contact portion 405 is between 150°C and 180°C. In some examples, the maximum heat exposure temperature limit of the auxiliary component is less than 150°C. In some examples, Figure 4H Injection molding includes curing the injected material between 150° C. and 120° C. In some examples, the curing temperature of the injected material is below 120° C. In some examples, the injected material is below 80° C. In some examples, the injected material is below 45° C. In some examples, ultraviolet exposure can be used to cure the injected material.

[0098] In some examples, the maximum thermal exposure limit of the auxiliary component 420 is between the temperature of the rubber material 401 during compression molding and the temperature of the injected material during injection molding. In some examples, the auxiliary component 420 has a thermal budget that defines the maximum thermal energy that can be transferred to the auxiliary component 420 before degradation becomes a problem. In some examples, the temperature of the injected material is higher than the maximum thermal exposure temperature of the auxiliary component 420, but the total thermal exposure of the injection molding process is less than the thermal budget of the auxiliary component 420. That is, the temperature of the injected material is higher than the maximum temperature threshold of the auxiliary component 420, but the total thermal energy transferred to the auxiliary component 420 during the injection molding process is less than the thermal budget of the auxiliary component 420, so the auxiliary component never reaches its maximum thermal exposure temperature, or if the auxiliary component 420 reaches its maximum thermal exposure temperature, the temperature of the auxiliary component 420 stays above the maximum temperature for a time that does not last long enough for thermal degradation to affect the function of the auxiliary component 420.

[0099] In some examples, the inner cavity 411 of the drug contact portion 405 is sized so that the non-drug contact portion 441 can be formed in the inner cavity 411 without forming a portion around the drug contact portion 405. In this way, the inner cavity 411 is sized to completely accept the auxiliary electronic device 420, and the second material is filled into the inner cavity 411 and completely surrounds the auxiliary electronic device 420, thereby sealing the auxiliary electronic device 420 into the drug contact portion 405 and using the inner cavity 411 as a mold for the second material instead of the top mold 433 to form the non-drug contact portion 441 inside the inner cavity 411. In some examples, forming the non-drug contact portion 441 includes a deposition process that places the second material on, in, or around the drug contact portion 405 in a mold-free process.

[0100] Figure 5 is a flow chart of a two-piece process for molding a plunger with an embedded auxiliary component using two different materials and different thermal exposures. The multi-step manufacturing process 500 includes molding 510 a drug contact portion of a container closure (i.e., a plunger) with a first material at a first temperature and for a time length defining a first thermal exposure. This can be accomplished using a proven drug contact material (e.g., halogenated butyl rubber), potentially using fluoropolymer film lamination as well as conventional high-volume compression molding techniques. Next, the auxiliary component is inserted 520 into the molded drug contact portion. In some instances, this is accomplished using high-speed pick-and-place techniques, and the insertion 520 can be performed before or after trimming the drug contact portion. After the auxiliary component is inserted, the drug contact portion and the auxiliary component are molded 530 with a second material at a second temperature and for a time length defining a second thermal exposure that is less than the thermal budget of the auxiliary component to form a non-drug contact portion of the container closure. In some instances, the second material is a medical grade material that is compatible with the thermal budget of the auxiliary component, such as, for example, liquid silicone rubber. In addition, and as described below with respect to Figures 7 to 9B As explained in more detail, the second material should be compatible with any intended functionality of the ancillary component. Next, the complete plunger (i.e., the drug contacting and non-drug contacting portions molded with the ancillary component embedded inside) is subjected 540 to conventional closure processing, which in some instances includes cleaning and siliconization. Finally, the complete plunger (i.e., the container closure) is sterilized 550 using a technique that exposes the embedded ancillary component to a thermal exposure that is less than the thermal budget of the ancillary component when embedded in the complete plunger. In some instances, the sterilization process 550 includes steam, ethylene oxide (EtO), nitrogen oxides NO x , electron beam, or similar processes known in the art. In some examples, the thermal budget of the auxiliary components embedded in the complete plunger is higher than the thermal budget of the auxiliary components during overmolding 530, because the complete plunger can provide a certain degree of thermal insulation for the short sterilization process.

[0101] Fig. 6A 4 is a cross-sectional view of a plunger 440 disposed within a cartridge 601 and an auxiliary electronic component 420 embedded in the plunger 440 between a drug contact portion 605 and a non-drug contact portion 441. In some examples, the plunger 440 is an elastic container closure. The plunger 440 is shown as being inside the cartridge 601, wherein a plurality of sealing edges 412, 442 of the plunger 440 form a seal around a bottom surface 413 of the drug contact portion 405 to contain the medicament 60 in the cartridge 601. In some examples, the auxiliary electronic component (or electronic assembly) 420 includes one or more of the following: a sensor, a power source (e.g., a battery), a controller, a wireless communication module (e.g., IEEE 802.15, NFC, RF, IrDA), an acoustic module, a memory, an on-off switch, a thermal sensing element or a pressure sensor, etc. In some examples, the auxiliary electronic component 420 includes an on-off switch configured to be triggered by any suitable impact to the non-drug contacting portion 441 of the plunger (e.g., by a force 698 from the plunger rod 660).

[0102] Fig. 6A 601. The plunger 440 is shown before being driven into the cartridge 601 by the plunger rod 660. In some examples, the plunger rod 660 (e.g., a plunger rod and a plunger head configured to contact the plunger 440) is provided by a syringe (e.g., a syringe having a cartridge 601) Figure 1 601 is a syringe housing. In operation, the plunger rod 660 is driven (as indicated by arrow 698) against the non-drug contact portion 441, thereby applying a force to the plunger drug contact portion 605 to move the plunger 440 into the cartridge 601 so as to drive a portion of the medicament 60 from the cartridge 601.

[0103] Figure 6B During the sensing operation during or after being driven by the plunger rod 660 into the cartridge 601 Fig. 6A A cross-sectional view of the plunger 440 . Figure 6B The plunger rod 660 is shown, which contacts the non-drug contacting portion 441 of the plunger 440 and has driven the plunger 440 into the cartridge 601 (as indicated by arrow 699). In operation, the auxiliary electronic component 420 can emit a sensing signal 670, which in some examples is responsive to the position of the plunger 440 in the cartridge 601 and enables the auxiliary electronic device 420 to generate a signal indicative of the movement of the plunger 440.

[0104] Some embodiments include plungers with auxiliary electronic components inside disposable medicament syringes such as pre-filled single-chamber and dual-chamber syringes. The examples described above for integrating auxiliary components into the plunger of the cartridge can be extended from use in the cartridge to disposable pre-filled syringes. In addition, in some instances, in a dual-chamber syringe or cartridge, the various aspects detailed herein are all arranged in an intermediate plunger to sense and / or measure the state of the device (e.g., "pre-mixing", "mixed solution standby" or "injection completed" based on a sensing signal).

[0105] Described below are devices and techniques for using energy harvesting to provide energy to electronic circuits in cartridge systems, such as those disclosed herein, to provide an alternative to or in addition to standard batteries.

[0106] Aspects of the system disclosed above enable medical injectors to provide certain functionality to the cartridge of an injector device (e.g., a pen injector) using 'smart' technology by attaching embedded electronic components (e.g., RFID, sensors). When the electronics are integrated into the plunger of the cartridge, one or more components may be active (e.g., sensors for measuring certain properties of the syringe or cartridge) and require an energy source, which may typically be a battery. As described below, an alternative is to use different energy harvesting methods as an alternative to batteries.

[0107] Figure 7 is a cross-sectional view of a plunger 740 disposed within a cartridge 700 and powered by a wireless system 780. An example of an energy harvesting system is Figure 7 Shown in. Figure 7 A cartridge 700 is shown including a plunger 740 disposed in a housing 701 of the cartridge 700. The plunger 740 includes a drug contact portion 705 that seals a medicament 711 in the housing 701. The plunger 740 also includes a non-drug contact portion 741 that seals auxiliary electronic components 771, 778, 779 into the plunger 740. The auxiliary electronic components 771, 778, 779 include a sensing device (S) 779, a wireless device (WL) 778, and a capacitive device (CE) 771.

[0108] In operation, the sensing device 779 is configured to sense the position of the plunger 740 within the housing 701, and the wireless device 778 is configured to communicate with an external electronic device (not shown) to transfer information from the sensor device 779. The capacitive device 771 is configured to provide power to the sensing device 779 and the wireless device 778 from a wireless signal 781 located near the cartridge 700 by way of wireless inductive charging. In some examples, the capacitive device 771 includes a capacitive circuit configured to wirelessly receive power from, for example, a wireless system 780 (e.g., a smartphone) via a near field communication protocol (NFC) signal 781, or by a typical wireless charging device with other inductive load means to provide sufficient energy for initiating and performing measurements using the sensing device 779 in the cartridge 700 and transmitting the results back using the wireless device 778.

[0109] Fig. 8A and 8B is a cross-sectional view of a plunger disposed within a cartridge and powered by a piezoelectric system. Another example of an energy harvesting system is the use of piezoelectric technology to harvest energy from the mechanical forces occurring between the plunger rod and the plunger, such as during syringe handling or injection operations, to provide sufficient energy for initiating and performing measurements in the cartridge and transmitting back the results. Fig. 8A A cartridge 800 is shown having a plunger 840 disposed in a housing 801 of the cartridge 800 and a plunger rod 860 that advances (e.g., along arrow 897) to contact a non-drug contact portion 810 of the plunger 840. The drug contact portion 805 of the plunger 840 seals a medicament 811 in the housing 801 by sealingly engaging the inner surface of the housing 801. The non-drug contact portion 810 is molded over auxiliary electronic components 872, 878, 879 inserted into the drug contact portion 805 of the plunger, and the non-drug contact portion 810 is configured to at least partially deflect under the force of the plunger rod 860 or otherwise be able to transfer force from the plunger to a portion of the auxiliary electronic components 872, 878, 879. The auxiliary electronic components 872, 878, 879 include a sensing device (S) 879, a wireless device (WL) 878, and a piezoelectric element (PE) 872.

[0110] In operation, the sensing device 879 is configured to sense the position of the plunger 840 within the housing 801, and the wireless device 878 is configured to communicate with an external electronic device (not shown) to transmit information from the sensor device 879. The piezoelectric element 872 is configured to provide power to the sensing device 879 and the wireless device 878 by converting a portion of the force applied to the plunger 802 into electrical energy. Figure 8B As shown in FIG. 8 , the piezoelectric element 872 is moved from the non-drug contact portion 810 by the force applied by the plunger rod 860 to the non-drug contact portion 810 (during the movement indicated by arrow 897). Fig. 8A The position 898 is converted into Figure 8B deflected position 899. The transition of piezoelectric element 872 from position 898 to deflected position 899 absorbs energy and converts part of it into electrical energy.

[0111] Fig. 9A and 9B is a cross-sectional view of a plunger disposed within a cartridge and including a Peltier thermoelectric device. Another example of an integrated energy harvesting device is to include a Peltier element (PE) to convert the temperature difference between cooling (of the pen or syringe during storage) and heating (e.g., exposure to room temperature) into electrical energy to provide sufficient energy for initiating and performing measurements in the cartridge of the syringe / pen and transmitting back the results. Fig. 9A A cartridge 900 is shown, which is stored in a low temperature environment (e.g., 4° C.) and has a plunger 940 disposed in a housing 901 of the cartridge 900 and a plunger rod 860 positioned against a non-drug contact portion 941 of the plunger 940. The drug contact portion 405 of the plunger 940 seals the medicament 911 in the housing 901 by sealingly engaging the inner surface of the housing 901. The non-drug contact portion 941 surrounds the embedded auxiliary electronic components 973, 978, 979, and the non-drug contact portion 941 or the plunger 902 is configured to at least partially transfer thermal energy to the auxiliary electronic components 973, 978, 979. The auxiliary electronic components 973, 978, 979 include a sensing device (S) 979, a wireless device (WL) 978, and a thermoelectric element (TE) 973.

[0112] In operation, in some examples, the sensing device 979 is configured to sense the position of the plunger 940 within the housing 901, and the wireless device 978 is configured to communicate with an external electronic device (not shown) to transmit information from the sensor device 979. The thermoelectric element 973 is configured to provide power to the sensing device 979 and the wireless device 978 by generating energy when the temperature of the thermoelectric element changes. Fig. 9B As shown, the cartridge 900 is moved to a relatively high temperature environment (e.g., 20° C.), and the thermoelectric element 973 is heated (during the temperature transition indicated by arrow 999) by absorbing thermal energy from the environment outside the cartridge 900. The thermal energy absorbed by the thermoelectric element 973 generates electrical energy to power, for example, the sensing device 979 and the wireless device 978.

[0113] Some of the features described may be implemented in digital electronic circuit systems, or in computer hardware, firmware, software, or a combination thereof. The apparatus may 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 may be performed by a programmable processor executing a program of instructions to perform the functions of the described implementation by operating on input data and generating output. The features described may be advantageously implemented in one or more computer programs that may be executed 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 may be used directly or indirectly in a computer to perform an activity or cause a result. A computer program may be written in any form of programming language, including compiled or interpreted languages, and 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.

[0114] 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.

[0115] The term "drug delivery device" should encompass any type of device or system that is configured to distribute the amount of drug to the human or animal body. The amount of drug can typically be about 0.5 ml to about 10 ml. In a non-limiting manner, the drug delivery device can include a syringe, a needle safety system, a pen injector, an automatic injector, a large capacity 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).

[0116] 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 and 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.

[0117] The drug or medicament can be contained in a primary package or "drug container" suitable for use with a drug delivery device. The drug container can be, for example, a cartridge, a syringe, a reservoir or other vessel, and the other vessel 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 cases, 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 cases, 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 cases, 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 examples, 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 can be configured so that they are in fluid communication with each other (e.g., through a conduit between the two chambers) and allow the user to mix the two components if necessary before dispensing. Alternatively or additionally, the two chambers can be configured to allow mixing when the components are dispensed into the human or animal body.

[0118] 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 (e.g., diabetic retinopathy), thromboembolic disorders (e.g., 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.

[0119] 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).

[0120] 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.

[0121] 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.

[0122] An exemplary oligonucleotide is, for example, mipomersen / Kynamro, a cholesterol-reducing antisense therapeutic used to treat familial hypercholesterolemia.

[0123] Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.

[0124] 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.

[0125] 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.

[0126] 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, and the antibody does not support binding to Fc receptors, for example, it has a mutagenic or missing Fc receptor binding region.

[0127] 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. Antibody fragments can include cleavage portions of full-length antibody polypeptides, 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.

[0128] 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.

[0129] 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).

[0130] 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.

[0131] 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.

[0132] Pharmaceutically acceptable solvates are, for example, hydrates or alkanolates, such as methanolate or ethanolate.

[0133] 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.

[0134] Many implementations of the present disclosure have been described. However, it should be understood that various modifications may be made without departing from the spirit and scope of the present disclosure. Therefore, other implementations are within the scope of the following claims.

[0135] Many implementations of the present disclosure have been described. However, it should be understood that various modifications may be made without departing from the spirit and scope of the present disclosure. Therefore, other implementations are within the scope of the following claims.

[0136] The present invention also relates to the following items:

[0137] 1. An injection device (100), comprising:

[0138] Housing (110);

[0139] a container (114), the container (114) being attached to the housing (110) and being used for containing a drug (M);

[0140] a plunger rod (660), the plunger rod (660) being slidably disposed in the injection device (100);

[0141] A plunger (440) slidably disposed in the container (114) and comprising:

[0142] a first portion (405), the first portion (405) having an axial end surface (413), the axial end surface (413) being configured to contact the drug (M) in the container (114);

[0143] an electronic device (420), the electronic device (420) being disposed in the cavity (411) of the first portion (405); and

[0144] a second portion (441), the second portion (441) being overmolded on the electronic device (420) so that the second portion (441) surrounds at least a portion of the electronic device (420), the second portion (441) having an axial end surface (444), the axial end surface (444) being configured to contact the plunger rod (660),

[0145] The injection device (100) is configured such that forward movement of the plunger rod (660) relative to the container (114) causes the plunger (440) to move forward within the container (114) to dispense the drug (M) from the injection device (100).

[0146] 2. The injection device (100) according to item 1, wherein the first portion (405) is formed of a first material (401), and the second portion (441) is formed of a second material different from the first material (401).

[0147] 3. An injection device (100) according to claim 2, wherein the first material (401) has a first molding temperature that exceeds the upper temperature limit of the electronic device (420), and the second material has a second molding temperature that is lower than the upper temperature limit of the electronic device (420).

[0148] 4. An injection device (100) according to claim 3, wherein the first part (405) has been molded at the first molding temperature, and the second part (441) has been overmolded onto the first part (405) at the second molding temperature.

[0149] 5. An injection device (100) according to any one of items 1 to 4, wherein one or more axially extending protrusions (405) extend within the plunger (440), and the electronic device (420) is arranged between the one or more axially extending protrusions (405).

[0150] 6. An injection device (100) according to any one of items 1 to 4, wherein the first part (405) includes an axially extending protrusion (414) that defines the cavity (411), and the axially extending protrusion (414) is positioned inwardly on the outer surface of the first part (405), and the outer surface is configured to engage with the inner surface of the container (114) to at least partially seal the drug (M) in the container (114).

[0151] 7. An injection device (100) according to item 6, wherein the second portion (441) surrounds the axially extending protrusion (414) of the first portion (405).

[0152] 8. An injection device (100) according to claim 6, wherein the axially extending protrusion (414) includes an outward protrusion (415), and the outward protrusion (415) is configured to at least partially retain the second part (441) on the first part (405).

[0153] 9. An injection device (100) according to any one of items 1-4, wherein the outer surface of the first part (405) and the outer surface of the second part (441) are configured to engage the inner surface of the container (114) to at least partially seal the opening of the container (114).

[0154] 10. An injection device (100) according to claim 9, wherein the outer surface of the first part (405) includes a curved portion having a radius that varies along the axial direction of the plunger (440), and the outer surface of the overmolded second part (441) includes a curved portion having a radius that varies along the axial direction of the plunger (440).

[0155] 11. An injection device (100) according to item 9, wherein an outer surface of the first part (405) and an axial end surface of the first part (405) comprise a layer of a membrane (402).

[0156] 12. An injection device (100) according to any one of items 1-4, wherein the container (114) includes the drug (M) and the electronic device (420) is configured to determine the position of the plunger (440) relative to the container (114).

[0157] 13. A plunger (440) for an injection device (100), the plunger (440) comprising:

[0158] a first portion (405), the first portion (405) having an axial end surface (413), the axial end surface (413) being configured to contact a drug (M) within a container (110) of the injection device (100);

[0159] an electronic device (420), the electronic device (420) being disposed in the cavity of the first portion (405); and

[0160] A second portion (441), the second portion (441) is overmolded on the electronic device (420) so that the second portion (441) surrounds at least a portion of the electronic device (420), the second portion (441) having an axial end surface (444), and the axial end surface (444) is configured to contact the plunger rod (660) of the injection device (100).

[0161] 14. The plunger (440) of item 13, wherein the first portion (405) is molded from a first material (401) and the second portion (441) is molded from a second material.

[0162] 15. The plunger (440) of clause 13, wherein the first portion (405) is molded at a first temperature that exceeds an upper temperature limit of the electronic device (420).

[0163] 16. The plunger (440) of clause 15, wherein the second portion (441) is overmolded at a second temperature that is lower than an upper temperature limit of the electronic device (420).

[0164] 17. A plunger (440) according to any one of items 13-16, wherein the first portion (405) includes an axially extending protrusion (414) that defines the cavity (411), the axially extending protrusion (414) being positioned inwardly on an outer surface of the first portion (405), and the outer surface being configured to engage with an inner surface of the container (114) to at least partially seal the drug (M) within the container (114).

[0165] 18. The plunger (440) of claim 17, wherein the second portion (441) surrounds the axially extending protrusion (414) of the first portion (405).

[0166] 19. A plunger (440) according to claim 17, wherein the axially extending protrusion (414) includes an outward protrusion (415), and the outward protrusion (415) is configured to at least partially retain the overmolded second portion (441) above the first portion (405).

[0167] 20. A plunger (440) according to any one of items 13-16, wherein the first portion (405) and the second portion surround an axially extending protrusion (414) positioned inwardly on an outer surface of the first portion (405), and the outer surface is configured to engage with an inner surface of the container (114) to at least partially seal the drug (M) within the container (114).

[0168] 21. The plunger (440) of any one of items 13-16, wherein the electronic device (420) is configured to determine a position of the plunger (440) relative to the container (114).

[0169] 22. A method comprising:

[0170] a first portion (405) of a plunger (440) of a molded injection device (100), the molded first portion (405) having an axial end surface (413), the axial end surface (413) being configured to contact a drug (M) in a container (114) of the injection device (100),

[0171] inserting an electronic device (420) into the cavity (411) of the molded first part (405); and

[0172] After the electronic device (420) is inserted into the cavity (411), the second portion (441) of the plunger (440) is overmolded onto the electronic device (420) so that the second portion (441) surrounds at least a portion of the electronic device (420), and the overmolded second portion (441) has an axial end surface (444), and the axial end surface (444) is configured to contact the plunger rod (660) of the injection device (100).

[0173] 23. A method according to item 22, wherein the moulded first portion (405) is moulded from a first material (401) and the overmoulded second portion (441) is overmoulded from a second material.

[0174] 24. A method according to item 23, wherein the first material (401) has a layer of a film (402) before the moulded first part (405) is moulded.

[0175] 25. The method according to any one of items 22 to 24, wherein the molded first portion (405) is molded at a first temperature that exceeds an upper temperature limit of the electronic device (420).

[0176] 26. A method according to clause 25, wherein the overmolded second portion (441) is overmolded at a second temperature that is lower than an upper temperature limit of the electronic device (420).

[0177] 27. A method according to any one of items 22-24, comprising determining the position of the plunger (440) relative to the container (114) by means of the electronic device (440) after overmolding the second portion (441) of the plunger (440) onto the electronic device (420).

Claims

1. An injection device (100), comprising: Housing (110); a container (114), the container (114) being attached to the housing (110) and being used for containing a drug (M); a plunger rod (660), the plunger rod (660) being slidably disposed in the injection device (100); A plunger (440) slidably disposed in the container (114) and comprising: a first portion (405), the first portion (405) having an axial end surface (413), the axial end surface (413) being configured to contact the drug (M) in the container (114); an electronic device (420), the electronic device (420) being disposed in the cavity (411) of the first portion (405); and a second portion (441), the second portion (441) being overmolded on the electronic device (420) so that the second portion (441) surrounds at least a portion of the electronic device (420), the second portion (441) having an axial end surface (444), the axial end surface (444) being configured to contact the plunger rod (660), The injection device (100) is configured such that forward movement of the plunger rod (660) relative to the container (114) causes the plunger (440) to move forward within the container (114) to dispense the drug (M) from the injection device (100).

2. The injection device (100) according to claim 1, wherein the first portion (405) is formed of a first material (401), and the second portion (441) is formed of a second material different from the first material (401).

3. The injection device (100) according to claim 2, wherein the first material (401) has a first molding temperature exceeding an upper temperature limit of the electronic device (420), and the second material has a second molding temperature lower than the upper temperature limit of the electronic device (420).

4. The injection device (100) according to claim 3, wherein the first part (405) has been molded at the first molding temperature, and the second part (441) has been overmolded onto the first part (405) at the second molding temperature.

5. An injection device (100) according to any one of claims 1-4, wherein one or more axially extending protrusions (405) extend within the plunger (440), and the electronic device (420) is arranged between the one or more axially extending protrusions (405).

6. An injection device (100) according to any one of claims 1-4, wherein the first part (405) includes an axially extending protrusion (414) defining the cavity (411), and the axially extending protrusion (414) is positioned inwardly on the outer surface of the first part (405), and the outer surface is configured to engage with the inner surface of the container (114) to at least partially seal the drug (M) in the container (114).

7. The injection device (100) according to claim 6, wherein the second portion (441) surrounds the axially extending protrusion (414) of the first portion (405).

8. The injection device (100) according to claim 6, wherein the axially extending protrusion (414) includes an outward protrusion (415), and the outward protrusion (415) is configured to at least partially retain the second part (441) on the first part (405).

9. The injection device (100) according to any one of claims 1-4, wherein the outer surface of the first part (405) and the outer surface of the second part (441) are configured to engage the inner surface of the container (114) to at least partially seal the opening of the container (114).

10. An injection device (100) according to claim 9, wherein the outer surface of the first part (405) includes a curved portion having a radius that varies along the axial direction of the plunger (440), and the outer surface of the overmolded second part (441) includes a curved portion having a radius that varies along the axial direction of the plunger (440).

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