Method of manufacturing a drug delivery device

Abstract

Method of production of a drug delivery device comprising - a pre-filled drug container (6), - a fluid package comprising a liquid flow system (7) providing a fluid connection from the drug container to a patient during a drug delivery action of the drug delivery device, - a control unit comprising electronic components, - a housing (2), the method comprising the steps of: a) assembling components of the fluid package to form the fluid package, b) sterilizing the fluid package, c) providing the pre-filled drug container, d) assembling the fluid package to the pre-filled drug container to form a container package system, e) assembling the container package system to the control unit and the housing (2) to form the drug delivery device, wherein steps c) and d) are performed under aseptic conditions.

Description

Technical Field

[0001] This invention relates to a method for manufacturing a drug delivery device for subcutaneous administration of liquid drugs. In particular, this invention relates to a method for manufacturing a drug delivery device in the form of a patch. Background Technology

[0002] Drug delivery devices in the form of patch devices for subcutaneous delivery of liquid medications, which are attached to a patient's skin, are known. Some devices typically contain a cartridge or have an internal reservoir filled by the patient / healthcare professional. In this case, the medication is drawn from the vial using a syringe and transferred to the internal reservoir. Because cartridges are common and their disposal is very easy, it is advantageous to provide a device that can be used with standard cartridges. The liquid medication can be, for example, a biomedical product or other medication intended for single-injection administration over a relatively short period (depending on the intended use). It is known to provide drug delivery devices in the form of patch devices having a single-use, disposable component assembled to a reusable part containing drive and control electronics, or as a single disposable component.

[0003] The reliability, safety, compactness, and ease of use of patient-worn drug delivery devices are of paramount importance. For disposable components, the number of parts and consequently, the cost of disposable devices are also significant considerations.

[0004] To meet safety and reliability requirements, many traditional patch pump drug delivery devices have complex pump mechanisms and are quite large. Furthermore, long shelf lives and thorough sterilization are often difficult to achieve, increasing manufacturing costs.

[0005] We can consider various manufacturing methods for drug delivery devices. The first method would include the following steps:

[0006] a) Production of fluid packages, housings, and control units.

[0007] b) Sterilize the fluid package, outer shell, and control unit.

[0008] c) It is sent to the sterile area and assembled with the pre-filled container.

[0009] However, an important issue to consider is that the sterilization process may damage electronic components, batteries, and medications in pre-filled containers.

[0010] Drug delivery devices are typically manufactured by producing their individual components in a first step. After the individual components are produced, they are sterilized using a known type of sterilization process. Following sterilization, the components are transferred to an area with sterile conditions. In this area, the components are typically assembled. The problem with using conventional assembly processes is that these processes are not suitable for components containing electronic components, batteries, or sensitive medications within pre-filled containers. Sterilizing electronic components, batteries, or sensitive medications within pre-filled containers could destroy them, a risk that is unacceptable. Therefore, conventional manufacturing processes cannot provide functional assembly and ultimately cannot guarantee patient safety.

[0011] The second method may include the following steps:

[0012] a) Manufacturing / installing fluid packages, housings, and control units under aseptic conditions;

[0013] b) Assemble with a pre-filled container.

[0014] An important issue to consider is that this process limits the available manufacturing methods because welding, bonding, subtractive processes, and other processes that produce particles are not suitable for aseptic conditions. This also means introducing many components into the aseptic room, increasing the risk of contaminating the aseptic environment.

[0015] Since these methods are unsuitable, the current methods typically employ the following:

[0016] - The medication delivery device is not delivered with the pre-filled medication container; the patient must place the pre-filled container themselves. The disadvantage is that this requires additional user steps and carries the risk of not inserting the medication container correctly or not closing the cap properly.

[0017] or

[0018] - The drug container is assembled under normal cleanroom conditions, with an ultraviolet (UV) light source added to areas requiring sterility. The UV light source sterilizes critical parts of the container and its septum before piercing the needle. A drawback of this method is the difficulty in demonstrating evidence of UV sterilization, as normal cleanroom conditions may allow a variety of bacteria whose response to UV light remains to be confirmed. Summary of the Invention

[0019] In view of the foregoing, one object of the present invention is to provide a safe, reliable and compact method for manufacturing a drug delivery device for applying liquid drugs, which is in the form of a patch device having a disposable unit, or is intended to be a completely disposable device.

[0020] Advantageously, a method for producing a drug delivery device that can be used to administer a liquid drug disposed in a drug container having a plunger is provided.

[0021] Advantageously, it provides a method for producing an easy-to-use drug delivery device, particularly reducing the number of steps required by the patient.

[0022] Advantageously, it provides a method for producing economically viable drug delivery devices.

[0023] Therefore, it is important to avoid the need to establish expensive production lines in a sterile environment (Level 5 or lower according to ISO 14644-1 standard).

[0024] Advantageously, a method for producing a drug delivery device with a long shelf life is provided.

[0025] The object of the present invention has been achieved by providing a method for manufacturing a drug delivery device according to this application. Various advantageous embodiments are described in this application.

[0026] According to a first aspect of the present invention, a method for manufacturing a drug delivery device is disclosed herein, the drug delivery device comprising:

[0027] - A pre-filled drug container, wherein the drug container includes a cylindrical portion and a plunger slidably mounted within the cylindrical portion and sealing the drug within the container.

[0028] - A fluid package, including a liquid flow system, provides a fluid connection from the drug container to the patient during drug delivery operations of the drug delivery device.

[0029] - Including control or drive units for electronic components, and

[0030] - Outer shell,

[0031] The method includes the following steps:

[0032] a) Assemble the components of the fluid package to form the fluid package.

[0033] b) Sterilize the fluid package.

[0034] c) Provide the pre-filled drug container,

[0035] d) After sterilization, assemble the fluid package into a pre-filled drug container to form a container package system.

[0036] e) Assemble the container system to the control unit and housing (2) to form a drug delivery device.

[0037] Steps c) and d) are performed under aseptic conditions.

[0038] In an advantageous embodiment, the drug container includes a cylindrical portion and a plunger slidably mounted within the cylindrical portion and sealing the drug within the container.

[0039] Step a) involves assembling the fluid pack of the drug delivery device. The fluid pack includes at least a fluid flow system that provides a fluid connection from the pre-filled drug container to the patient's body during drug delivery operations of the drug delivery device. The fluid flow system typically includes different components made of different materials. For example, the patient-side cannula may include metal, while the fluid path is typically made of or formed from plastic parts, forming a hose or channel.

[0040] Step b) involves the sterilization of the fluid pack. Since assembled fluid packs are typically not manufactured under aseptic conditions, they must be sterilized to ensure that the patient cannula, needle, and the entire fluid pathway remain uncontaminated. Common sterilization methods for achieving component sterility depend on the combination of different materials and the product design (e.g., grooves). Common sterilization methods for fluid packs include gamma ray sterilization, ethylene oxide (ETO) sterilization, nitrogen dioxide (NO2) sterilization, steam sterilization, vaporized hydrogen peroxide (VHP) sterilization, X-ray sterilization, or electron beam sterilization.

[0041] Step c) involves providing a pre-filled drug container. The container can be made of glass, polymer, or other materials that are inert to drug stability and preferably biocompatible. Glass is commonly used in commercially available, FDA-approved drug containers manufactured by many different companies. Therefore, there are well-established and approved procedures for the aseptic filling and storage of drugs in glass containers, which can expedite the approval process for drug pump devices that protect drugs in glass containers. Polymer containers, such as those made of COP (cyclic olefin polymers) or COC (cyclic olefin copolymers), may be suitable for certain drugs that degrade rapidly upon contact with glass, such as protein drugs. After filling, the container is sealed with a plunger, typically made of rubber. This container is filled and sealed under aseptic conditions (Level 5 or lower as specified in ISO 14644-1).

[0042] Step d) involves assembling the fluid package to a pre-filled drug container to form a container package system, which may have a fluid connection between the fluid package and the pre-filled drug container, or the connection may be established separately, for example, after manufacturing or before delivery of the drug to a patient.

[0043] Step e) involves assembling the container system to a control or drive unit and a housing to form a drug delivery device. The assembly of the control or drive unit with the user interface of the container system and the installation of the housing can be achieved through standard form-fit connections or any other conventional manufacturing method. To achieve a watertight or even airtight housing, this may also include welding or adhesive processes.

[0044] Definition of aseptic conditions: In addition to low particle counts, aseptic conditions ensure the absence of pathogens, such as bacteria, viruses, and other pathogenic microorganisms, in the filling and assembly environment. Aseptic conditions can be achieved in, for example, a Class 5 cleanroom as specified in ISO 14644-1 or a lower class cleanroom (i.e., a higher standard cleanroom).

[0045] In an advantageous embodiment of this method, step e) is not performed under aseptic conditions. Electronic components are highly sensitive to common sterilization methods, such as gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization, or electron beam sterilization. By performing step e) under non-aseptic conditions, damage to the electronic components can be avoided. Therefore, there is no risk of any component being damaged during the assembly of the drug delivery device, thus ensuring patient safety. Therefore, the manufacturing method of step e) is not limited to particle-free or low-particulate emission connection technologies.

[0046] The container package system includes a container housing that surrounds a pre-filled drug container. The container housing can be connected to a fluid package, thus easily maintaining the sterility of the pre-filled drug container. The container can be in direct fluid communication with a fluid flow system, or the fluid package can include tools for separately connecting the pre-filled drug container to the fluid flow system (e.g., after manufacturing or immediately before the drug is delivered to the patient).

[0047] The container system includes a pump system. The pump system is configured to further push a plunger into a pre-filled drug container to administer the drug. In an advantageous embodiment, the pump system performs drug delivery by drawing in ambient air and injecting it into the container housing.

[0048] The pump system includes a coupling interface of the pump system for the delivery unit, where the pump driver provides torque to the rotor of the pumping system, wherein the coupling interface is sealed by a sealing membrane to remain sterile after step b). The seal can be made of a two-component molded thermoplastic elastomer (TPE) or a single TPE or elastomer, which seals against the moving coupling interface. The seal can also be made to completely cover the coupling interface and be destroyed upon the first rotation of the coupling. In this case, it can be made of polyethylene foil (such as Tyvek). TM It is composed of foil rather than elastic material.

[0049] In an advantageous embodiment of the method, the housing includes a user interface. The user interface may include electronic components that are highly sensitive to conventional sterilization methods.

[0050] In an advantageous embodiment of the method, the sterilization method of b) is any one of gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization or electron beam sterilization.

[0051] In an advantageous embodiment of the method, the assembly step e) includes a form-fit connection. The simplicity of performing step e) by utilizing a form-fit connection allows it to be carried out in the same room (production line) as the filling and closing of the drug container. The resulting particles and equipment, produced by performing and validating this step, are small in size and therefore suitable for aseptic conditions.

[0052] In an advantageous embodiment of the method, the form-fit connection provides an airtight seal for the pre-filled drug container within the container pack system. Therefore, the pre-filled drug container is not only airtight or liquid-tight, but can also be configured to remain sterile in a simple manner throughout the entire shelf life of the device.

[0053] In an embodiment of the method, the delivery unit described herein without assembled drug containers forms the fluid package, the delivery unit with assembled drug containers forms the container package, and the drive unit described herein forms the control or drive unit including electronic components.

[0054] In embodiments of this method, the drug delivery device may have any one or more additional features of any embodiment of the device described herein.

[0055] A drug delivery device is also disclosed, comprising a delivery unit including a drug container, a liquid flow system, a pumping system, and a housing therein enclosing at least a portion of the drug container, the pumping system, and the liquid flow system. The drug container includes a cylindrical portion and a plunger slidably mounted within the cylindrical portion and sealing the drug within the container at one end of the cylindrical portion. The liquid flow system is fluidly connected to the drug container during delivery of the liquid drug. The drug container is housed within a container receiving cavity of a container housing portion of the housing, the container receiving cavity being fluidly interconnected in an airtight manner to a fluid outlet of the pumping system. The pumping system includes a fluid inlet connected to ambient air, and is configured to pump ambient air drawn in through the fluid inlet into the container receiving cavity, thereby applying pressure at the rear end of the plunger to deliver the liquid drug.

[0056] In an advantageous embodiment, the pumping system includes a pump motor, which comprises:

[0057] - Stator,

[0058] - A rotor, which is at least partially rotatably and axially slidably mounted in a stator, the rotor including a first axial extension having a first diameter and a second axial extension having a second diameter greater than the first diameter.

[0059] - A first valve, formed by a first valve seal mounted on the stator around a first axial extension and engaging with a first passage in the rotor, the first passage being configured to allow fluid communication across the first valve seal when the first valve is in the open position, and

[0060] - A second valve is formed by a second valve seal mounted on the stator about a second axial extension and combined with a second passage in the rotor, the second passage being configured to allow fluid communication across the second valve seal when the second valve is in the open position.

[0061] In an advantageous embodiment, the drug container is a cartridge.

[0062] A drug delivery device is also disclosed, comprising:

[0063] - A delivery unit, comprising a drug container including a cylindrical portion and a plunger slidably mounted within the cylindrical portion and hermetically sealing the inner surface of the cylindrical portion to contain a liquid drug within the drug container; and

[0064] - An electronic control system and a plunger sensing system including an optical sensor comprising a transmitter and a receiver, the transmitter being configured to transmit an optical signal to the rear end of the plunger and the receiver being configured to receive an optical signal reflected back from the rear end of the plunger, the plunger sensing system being connected to the electronic control system being configured to measure the time of flight of the optical signal from the transmitter to the receiver and thereby determine the position of the plunger within the cylindrical portion of the drug container.

[0065] In one embodiment, the delivery unit includes a housing comprising a container housing portion including a plunger end covering the plunger-facing end of a drug container. The plunger end includes a transparent sensor window that allows optical signals to pass through the plunger end of the container housing. An optical sensor is located above or near the sensor window. A transmitter is configured to transmit optical signals through the sensor window to the rear end of the plunger. A receiver is configured to receive optical signals reflected from the rear end of the plunger and returned through the sensor window.

[0066] In one embodiment, the plunger end of the container housing portion includes a protrusion that positions a sensor window at a distance from the rear end of the plunger end, thereby allowing optical time-of-flight measurements of the plunger in its initial position.

[0067] In one embodiment, the distance from the rear end of the plunger is in the range of 5 mm to 20 mm.

[0068] In one embodiment, the delivery unit includes a housing comprising a container housing portion including a plunger end covering the plunger-facing end of a drug container. The plunger end includes a transparent sensor prism that allows optical signals to pass through the plunger end of the container housing. An optical sensor is positioned above or near the surface of the sensor prism. A transmitter is configured to transmit optical signals through the sensor prism to the rear end of the plunger, and a receiver is configured to receive optical signals reflected back from the rear end of the plunger and returned through the sensor prism.

[0069] In one embodiment, the face of the sensor prism on which the optical sensor is mounted is substantially orthogonal to the direction of travel of the plunger.

[0070] A drug delivery device is also disclosed, comprising a delivery unit including a drug container, a liquid flow system, a pressurized gas source, and a housing therein enclosing at least a portion of the drug container, the pressurized gas source, and the liquid flow system. The drug container includes a barrel-shaped portion and a plunger slidably mounted within the barrel-shaped portion and sealing the drug within the container at one end of the barrel-shaped portion. The drug container is housed within a container receiving cavity of a container housing portion of the housing, the container receiving cavity being fluidly interconnected in an airtight manner to a fluid outlet of the pressurized gas source. The pressurized gas source is configured to supply pressurized gas within the container receiving cavity, thereby applying pressure to the rear end of the plunger for delivery of the liquid drug. The drug delivery device also includes a pressure sensor fluidly coupled to the container housing to measure the pressure within the container housing, the pressure sensor being connected to an electronic control system configured to measure the pressure detected by the pressure sensor over time and determine the position of the plunger over time based on the pressure measurement results, including cessation of plunger movement due to obstruction of the drug delivery flow system or the end of the plunger's stroke within the container (corresponding to a container emptying position).

[0071] In an advantageous embodiment, the pressurized gas source includes a pumping system configured to pump gas into the container receiving chamber, thereby applying pressure at the rear end of the plunger.

[0072] In an advantageous embodiment, the pumping system is configured to pump ambient air into the container receiving chamber, thereby applying pressure to the rear end of the plunger.

[0073] A drug delivery device including a delivery unit is also disclosed. The delivery unit includes a drug container in the form of a cartridge containing a liquid drug, a liquid flow system, a pumping system, and a housing. At least a portion of the drug container, the pumping system, and the liquid flow system are installed within the housing. The drug container includes a diaphragm sealing the ends of the drug container. The liquid flow system includes an injection delivery system including an injection needle configured for injecting a drug in an actuated state of the drug delivery device. The liquid flow system also includes a container fluid connection system including a diaphragm needle mounted on a movable diaphragm needle support, a spring pressing the diaphragm needle support against the diaphragm of the drug container, and a blocking mechanism movable from a blocking position to an actuated position. In the blocking position, the diaphragm needle support is held in a retracted position where the diaphragm needle does not contact the diaphragm. In the actuated position, the diaphragm needle support is released and allowed to travel toward the diaphragm of the drug container, such that the diaphragm needle punctures the diaphragm under the action of the spring force.

[0074] In an advantageous embodiment, the blocking mechanism includes a rotatable support ring and a blocking finger that extends from the support ring and is rotatably moved together with the support ring from a position where the blocking finger engages with the diaphragm needle support and holds it in a retracted position to an actuated position where the blocking finger disengages from the diaphragm needle support to allow it to travel to an actuated position where the diaphragm needle pierces the diaphragm.

[0075] In an advantageous embodiment, the diaphragm needle support includes a flange portion and a gap between the flange portions, and the blocking finger engages the flange portion during the blocking position when the diaphragm needle support is retracted.

[0076] In an advantageous embodiment, the diaphragm needle support includes a guide in a relative position that engages a complementary guide portion in the housing for slidably guiding the diaphragm needle support from a retracted position to a diaphragm puncture position.

[0077] In one advantageous embodiment, the injection delivery system includes a needle actuation mechanism configured to move an injection needle from a retracted position within the housing of the drug delivery device to an extended delivery position, in which the injection needle protrudes through the bottom wall of the housing. The needle actuation mechanism includes a rotary actuation disk configured to engage with an actuation rod coupled to a slidable diaphragm needle support for transfer between the retracted and extended delivery positions.

[0078] In an advantageous embodiment, the actuating disc is directly coupled to or integrally formed with the rotor of the pump motor of the pumping system.

[0079] In an advantageous embodiment, the actuating rod is coupled to the blocking mechanism to move it from the locked position to the unlocked position.

[0080] In an advantageous embodiment, the actuating rod includes a support ring mounted around a protective portion of the housing that surrounds a cavity in which a diaphragm end of a drug container is received.

[0081] In an advantageous embodiment, the actuating rod includes a lever arm extending from a rotatable support ring, the lever arm being configured to engage a recess in the actuating disc upon initial actuation of the drug delivery device.

[0082] A drug delivery device is also disclosed, comprising a housing, a delivery unit including a drug container, and a control unit mounted within the housing. The control unit includes a body sensing system comprising electrodes connected to an electronic control system for measuring capacitance values. These electrodes are configured to detect whether the drug delivery device is positioned against a patient's skin. The housing has an inner side facing the interior of the housing where the delivery unit and control unit are mounted, and an outer mounting side facing the exterior of the housing and intended for placement against the patient's skin. The electrodes include a metal layer mounted directly against the inner side of the skin contact wall.

[0083] In an advantageous embodiment, the metal layer of the electrode consists of a metal layer deposited directly on the inner surface of the skin contact wall.

[0084] In an advantageous embodiment, the directly deposited metal layer is an electroplated layer.

[0085] In an advantageous embodiment, the body sensing system further includes a protective portion in the form of a conductor surrounding the electrodes.

[0086] In an advantageous embodiment, the body sensing system is configured to measure the capacitance between the electrode and ground.

[0087] In an advantageous embodiment, the body sensing system includes a second electrode that is insulated and separated from the electrode constituting the first electrode, and measures the potential between the first electrode and the second electrode to determine a capacitance value.

[0088] In an advantageous embodiment, the second electrode is formed as a metal layer directly on the inside of the mounting wall.

[0089] In an advantageous embodiment, the second electrode is formed as a metal layer in the same manner as the first electrode.

[0090] In an advantageous embodiment, the second electrode and the first electrode have interleaved portions.

[0091] In various embodiments, the drug container may include a diaphragm at one end of the drug container, which is fluidly connected to a diaphragm needle perforation of the injection needle during actuation of the drug delivery device.

[0092] In various embodiments, the drug delivery device may include an injection needle mounted on a movable needle support configured to move the needle from a retracted position, which is fully within the housing, to an actuated position, in which the needle tip protrudes beyond the skin contact wall of the housing to inject and deliver a liquid drug.

[0093] In various embodiments, the liquid flow system may include an injection delivery system comprising an injection needle mounted on a movable needle support, the injection needle being connected via a conduit to a container fluid connection system including a diaphragm needle.

[0094] In various embodiments, the drug delivery device may also include a drive unit comprising a pump driver having a coupling interface coupled to a drive coupling interface of a pumping system of the delivery unit, the pump driver providing torque to the rotor of the pumping system.

[0095] In various embodiments, the drug delivery device may include a housing, a delivery unit and a drive unit assembled within the housing, the housing including a skin contact wall for mounting against a patient's skin, the skin contact wall including an adhesive patch with a protective film.

[0096] In various implementations, for certain medical applications, the drug delivery device may be configured as a single-use, disposable device, and in particular, may be configured for liquid drugs contained in a single-dose administration container.

[0097] Further objects and advantageous features of the invention will become apparent from this document, wherein: Attached Figure Description

[0098] Figure 1a This is a perspective view of a drug delivery device according to an embodiment of the present invention;

[0099] Figure 1b yes Figure 1a A perspective view of the device, in which the cover and the adhesive with the protective film have been disassembled;

[0100] Figure 2 yes Figure 1b An exploded view of the embodiment, in which the cover and adhesive with a protective film have been removed, showing the housing base, conveying unit and drive unit;

[0101] Figure 3a This is according to an embodiment of the present invention. Figure 2 An exploded view of the drive unit shows the drug container within the drive delivery unit;

[0102] Figure 3b and Figure 3c This is a perspective sectional view of the conveying unit according to an embodiment of the present invention;

[0103] Figure 4a This is a perspective view of the pump and liquid flow system of the delivery unit of the drug delivery device according to an embodiment of the present invention.

[0104] Figure 4b and 4c yes Figure 4a Exploded perspective view of a liquid flow pumping system;

[0105] Figures 5a to 5e This is a cross-sectional view of the liquid flow and pumping system of a drug delivery device according to an embodiment of the present invention, showing different steps of actuating the needle of the percutaneous delivery system and the needle of the container fluid connection system when the drug delivery device is actuated.

[0106] Figure 6a yes Figure 5a The device in corresponding Figure 5a A perspective view of the initial position (with the outer shell portion removed to better see the interior);

[0107] Figure 6b It is similar to Figure 6a The view shows the corresponding Figure 5c The middle actuation position;

[0108] Figure 6c Is with Figure 6b A similar view, in which a portion of the shell is added to the cross-section, shows a view similar to... Figure 5e The corresponding position is the endpoint where both needles are fully inserted;

[0109] Figure 6d It is from the opposite side. Figure 6a A perspective view of the device;

[0110] Figure 6e It is similar to Figure 6d The view shows the intermediate actuation position of the diaphragm needle as it is about to be released;

[0111] Figure 6e It is similar to Figure 6d and 6f The view shows the endpoint where both needles are fully inserted;

[0112] Figure 7a It is along Figure 5a Perspective section view of line 7a-7a;

[0113] Figure 7b It is along Figure 5e Sectional view of line 7b-7b;

[0114] Figure 8a It is along Figure 7a A sectional view of line 8a-8a;

[0115] Figure 8b It is along Figure 7a The sectional view of line 8b-8b;

[0116] Figure 9a It is along Figure 5a A sectional view of line 9a-9a;

[0117] Figure 9b It is along Figure 5e Sectional view of line 9b-9b;

[0118] Figure 10a This is an exploded perspective view of the drive unit of a drug delivery device according to an embodiment of the present invention.

[0119] Figure 10b This is a cross-sectional view of a portion of a drug delivery device according to an embodiment of the present invention, showing a drive unit in an uncoupled state from the delivery unit of the drug delivery device according to an embodiment of the present invention.

[0120] Figure 10c It is similar to Figure 10b The view shows the coupling state;

[0121] Figure 11a This is a perspective view of a drug delivery device according to an embodiment of the present invention, wherein the housing has been removed, showing the assembled delivery unit and drive unit, together schematically illustrating a plunger sensing system according to a first variant;

[0122] Figure 11b It is along Figure 11a A sectional view of line 11b-11b;

[0123] Figure 12a yes Figure 11a A perspective view of a variant of the device;

[0124] Figure 12b It is along Figure 12a A sectional view of line 12b-12b;

[0125] Figure 13 This is a cross-sectional view of the liquid flow and pumping system of a drug delivery device according to an embodiment of the present invention, showing the air flow system of the pneumatic actuator.

[0126] Figure 14a It shows the coverage Figure 13 A partial cross-sectional view of the sealing membrane at the pump-engine coupling interface of the device;

[0127] Figure 14b This is a perspective view of the first embodiment of the sealed interface;

[0128] Figure 14c This is a perspective view of a second embodiment of the sealed interface;

[0129] Figure 15a This is a schematic diagram of a drug container in a liquid flow pumping system of a drug delivery device according to an embodiment of the present invention, showing a pneumatic actuator and a pneumatic plunger sensing system.

[0130] Figure 15b It is a schematic diagram of the pressure change over time of the pneumatic plunger system according to an embodiment of the present invention;

[0131] Figure 15c This is a schematic diagram of a curve showing the change of drug flow rate over time as measured by a pneumatic plunger sensing system according to an embodiment of the present invention.

[0132] Figure 15d It is a graph showing the change in air pressure inside the container holder of a drug delivery device over time;

[0133] Figure 16a This is a perspective view of a drug delivery device according to an embodiment of the present invention;

[0134] Figure 16b yes Figure 16a A perspective view of a drug delivery device, in which the drug container is removed or before being inserted into the drug delivery device;

[0135] Figure 16c It is used for insertion Figure 16b A perspective view of a drug container and a closed cap mounted on a plunger in a drug delivery device.

[0136] Figure 16d yes Figure 16c A cross-sectional view of the lid of a medicine container;

[0137] Figure 16e yes Figure 16a A cross-sectional view of the implementation method;

[0138] Figure 17a This is a partial cross-sectional perspective view of a drug delivery device according to yet another embodiment of the present invention, in which certain components have been removed.

[0139] Figure 17b It is similar to Figure 17a The view shows the component in a cross-sectional plan view;

[0140] Figure 18a This is a schematic diagram of the body sensing system of a drug delivery device according to an embodiment of the present invention;

[0141] Figure 18bThis is a perspective view of a delivery unit coupled to a drive unit of a drug delivery device according to an embodiment of the present invention, showing components of the body sensing system;

[0142] Figure 18c This is a perspective view of the housing cover of a drug delivery device, showing components of a body sensing system according to an embodiment of the present invention;

[0143] Figure 18d This is a schematic diagram of an on-body sensing system for a drug delivery device with two electrodes according to an embodiment of the present invention.

[0144] Figures 19a to 19d These are schematic diagrams illustrating various embodiments of the assembly and sterilization steps of a drug delivery device according to various embodiments of the present invention. Detailed Implementation

[0145] Referring to the accompanying drawings, the drug delivery device 1 according to an embodiment of the present invention includes a housing 2, a delivery unit 3, and a control or drive unit 4, wherein the delivery unit 3 and the control or drive unit 4 are assembled within the housing 2. The housing 2 may be made of two or more components, thereby allowing the delivery unit, drive unit, and any other components to be assembled within the housing.

[0146] In the illustrated embodiment, the drug delivery device 1 is a single-use, disposable unit for subcutaneous administration of a liquid drug (medication). Administration can be performed in a single dose over a short period (typically less than one hour, e.g., about 30 minutes or less). The single-use, disposable drug delivery device can also be used for subcutaneous injection of liquid drugs over longer periods ranging from several hours to several days or even up to one to three weeks. Depending on the volume of the drug to be injected, the drug delivery device can also be configured to inject the liquid drug within minutes.

[0147] There are various applications, one of the advantages of which is providing a drug delivery device to a patient who needs medication, which the patient can wear on their body, or which allows the patient to apply the device directly to their skin before use, to inject medication outside of a hospital or medical facility (e.g., at home). For some medical applications, it may also be necessary to deliver liquid medication for a period of time following an event (e.g., once the patient returns home) after an event has occurred (e.g., surgical intervention, or other forms of treatment in a hospital or clinic). There may also be applications where, advantageously, a drug delivery device is provided to the patient for injecting medication at specific times (e.g., weekly or monthly, or various other intervals depending on the medication and treatment), without requiring the patient to be administered medication by a healthcare professional in a clinical setting, thus allowing, for example, treatment at the patient's residence.

[0148] Although the embodiments shown in the accompanying drawings relate to single-use, disposable drug delivery devices, within the scope of the invention described herein for various purposes, drug delivery devices having disposable components that can be assembled into reusable portions comprising a drive unit, electronics, and a power supply can also be used. The delivery unit 3 can be mounted in the housing of the drug delivery device, while the drive unit 4 can be mounted in a detachable housing portion, allowing the drive unit 4 to be reused with subsequent delivery units. An example of a drug delivery device having both single-use, disposable components and reusable components is described, for instance, in WO 2020109409.

[0149] The drug delivery device includes a user interface 55, which may include one or more buttons for actuating the drug delivery device, light and / or sound status indicators, and optionally a screen or other display for presenting information to the operator of the device.

[0150] The drug delivery device according to an embodiment of the invention can be advantageously configured as a patch device for application to a patient's skin. An adhesive layer (not shown) may be disposed on the outer surface of the skin contact wall 81 of the housing 2 (e.g., on the surface of the cover 2b), which is covered by a protective film that can be peeled off from the adhesive layer before it is placed on the patient's skin injection site. The needle hole 10 through the skin contact wall 81 is covered by the protective film 11 before use, and allows the percutaneous injection needle 15 to extend through it and pierce the patient's skin when the drug delivery device 1 is actuated.

[0151] The delivery unit 3 includes a drug container 6 (e.g., a cartridge) containing a liquid drug 78, a fluid flow system 7 for subcutaneously guiding the liquid drug to the patient, a pumping system 8, and a housing 9 for accommodating the drug container, the fluid flow system 7, and the pumping system 8.

[0152] In one embodiment, the housing 9 may be configured to airtightly seal the drug container, thereby generating air pressure within the housing portion surrounding the drug container to enable the pumping action of the drug, which will be described in more detail herein.

[0153] The drug container 6 can be a conventional type of cartridge comprising a container having a cylindrical portion 6a, a neck portion 6b having an open end closed by a diaphragm 6c, and a plunger 12 closing the open end of the cylindrical portion 6a. The liquid medication 78 to be administered to the patient is sealed within the cylindrical portion 6a between the plunger and the diaphragm. Such drug containers 6 are well-known in the pharmaceutical industry and can be used to aseptically contain many different types of liquid medications. Such medications can also be provided in different sizes (volumes), and it should be understood that the drug delivery device according to embodiments of the invention can be dimensionally adjusted to accommodate different types of drug containers depending on the medical application. Embodiments of the invention can also be used with non-standard drug containers.

[0154] While some aspects of the invention disclosed herein require drug containers including sliding plungers, it should be noted that other aspects of the invention disclosed herein are not limited to drug containers with plungers and can be used with other forms of drug containers without plungers. For example, as will be further described, the in vivo sensing system is independent of the type of drug container used in the drug delivery device. Furthermore, for example, as will be further described, the container fluid connection system 17 requires a drug container with a puncture-resistant sterile barrier, but does not necessarily require a drug container with a plunger. Additionally, as will be further described, the method of manufacturing the drug delivery device is independent of the type of drug container used in the drug delivery device.

[0155] Delivery unit 3 is integrated with pumping system 8, which pumps liquid from the container to the injection needle 15 once the drug delivery device is activated. The pumping system includes a drive coupling interface 33, which is coupled to the coupling interface 54 of the pump driver 52 of drive unit 4. Therefore, the drive unit provides mechanical power to drive the pumping system 8 via couplings 54 and 33.

[0156] The pump engine 28 may advantageously include a design and construction similar to those described in WO 2007074363 or WO 2015015379, wherein the rotor 32 is mounted within the stator 29 and is rotatably and axially movable within the stator to pump fluid from the fluid inlet 30 to the fluid outlet 31. As is known from the aforementioned publications, the rotor 32 has a pump shaft 36 having a first diameter and a second diameter surrounded by seals, which open and close the fluid passage between the inlet and outlet as the stator rotates and axially displaces due to a cam mechanism between the stator and the rotor, thereby performing the pumping action during the opening and closing of valves between the fluid inlet and the pumping chamber, and between the pumping chamber and the outlet, respectively.

[0157] In summary, the pump engine 28 according to the preferred embodiment includes:

[0158] - Stator 29,

[0159] - A rotor 32, which is at least partially slidably and rotatably mounted in a stator, the rotor including a first axial extension having a first diameter and a second axial extension having a second diameter greater than the first diameter.

[0160] - A first valve, which is formed by a first valve seal mounted on the stator around a first axial extension and engaging with a first passage in the rotor, the first passage being configured to allow fluid communication across the first valve seal when the first valve is in the open position.

[0161] - A second valve is formed by a second valve seal mounted on the stator around a second axial extension and combined with a second passage in the rotor, the second passage being configured to allow fluid communication across the second valve seal when the second valve is in the open position.

[0162] Although the general design of the pump motor and the principle of pumping operation can be understood by referring to the aforementioned publications, in embodiments of the invention, the pumping system is not fluidly connected to the liquid to be applied. Instead, in embodiments of the invention, the pump motor can advantageously be used to pump air, which exerts pressure on the container plunger to move the plunger and force liquid out of the container when the diaphragm is punctured.

[0163] In advantageous embodiments of the invention, particularly for single use and single injection of the contents of the drug container (e.g., over a period spanning several minutes to 60 minutes), a pump motor can be used to pump air that pressures the plunger 12 to push the plunger toward the diaphragm and to propel the liquid 78 within the container through the injection needle 15 of the subcutaneous delivery system 13 via the liquid flow system 7. In these embodiments, the pumping system 8 thus acts as a pneumatic actuator, generating air pressure within at least a portion of the housing 9 behind the plunger 12, such as... Figure 13 As shown in the best example.

[0164] In this embodiment of the drug delivery device, a key advantage of using this pump motor is that there is no direct fluid connection between the inlet and outlet at any position of the rotor, and no valves need to be actuated, ensuring particularly reliable and leak-free gas pumping in an easy-to-operate arrangement. The pump motor 28 is very compact and can be directly driven by the rotary motor 53 of the pump driver 52 in the drive unit 4 without a transmission. In fact, due to the differential pumping volume displacement defined by the axial displacement of the rotor and the difference between the first and second diameters of the pump shaft, the pumping volume displacement rotation can be easily configured to achieve optimal operation using a given type of electric motor rotating at a constant speed. Furthermore, the pump motor components can be made entirely of polymer materials, and the rotor can be easily coupled to the pump driver, ensuring a sterile barrier between the fluid portion of the pump motor and the coupling interface.

[0165] It can be noted that certain aspects of the embodiments of the invention described herein do not necessarily rely on pneumatic actuators to achieve their functions. For example, the body sensing system 5 and the plunger sensing system 70 using the optical sensor 71 do not necessarily require pneumatic actuators and can also be implemented in drug delivery devices, where the pump motor acts directly on the liquid drug in a conventional manner or using other pump systems known in the art for directly drawing liquid from the container (e.g., as described in WO2015015379). Moreover, the container fluid connection system 17 (described in more detail below) can also be implemented with different pumping systems, such as pneumatic actuators, or actuators known per se that mechanically press against the plunger, or by drawing liquid using the motor described in WO 2015015379.

[0166] The drive unit 4 is primarily configured to drive the pumping system 8 of the delivery unit 3, but may also have additional functions, such as processing sensing signals and sending and receiving data from external devices via a wireless communication link (e.g., using Bluetooth).

[0167] The drive unit 4 includes an electronic control system 47, which may include a circuit board 48 on which electronic components including at least one microprocessor 49 and an optional wireless connectivity module are mounted. The electronic control system also includes a power source 50, for example in the form of a battery, and a pump driver 52 including an electric motor 53.

[0168] The shaft of the motor 53 can be coupled to a coupling interface 54, which is configured to engage a complementary coupling interface 33 of the pump motor rotor 32 on the delivery unit 3. If the pump motor 28 is configured with a rotatable and axially movable rotor as discussed above, in a preferred embodiment, the drive coupling interface 54 can slide axially relative to the motor output shaft and be biased by a spring 69, which presses the motor drive coupling interface 54 against the coupling interface 33 of the pump motor rotor 32. Figures 10a to 10c As shown in the best example.

[0169] The drive unit may also include a plunger sensing system 70 for sensing the position of the container plunger. The plunger sensing system is used to determine the correct operation of the drug delivery device and to identify, for example, blockages in the liquid flow system, or to identify the end of the plunger's stroke when the drug container is empty at the end of the drug administration process. Embodiments of the plunger sensing system 70 will be described in further detail.

[0170] It can be noted that the plunger sensing system 70 for sensing plunger position according to an embodiment of the present invention can be implemented on various drug delivery systems having a drug container including a plunger, such as on syringe devices, autoinjectors, pen injection systems (like insulin pens), or any other plunger movement in the primary packaging of liquid drugs.

[0171] The drive unit may also include a body sensing system 5 for detecting whether the drug delivery device is in contact with the patient's skin for positioning. If the drug delivery device is not in contact with the patient's skin for positioning, the body sensing system will prevent the operation of the drug delivery device, and may also detect whether the drug delivery device has been removed before complete drug delivery. Implementations of the body sensing system 5 will be described in further detail.

[0172] The liquid flow system 7 includes a subcutaneous delivery system 13 and a container fluid connection system 17. The subcutaneous delivery system 13 includes an injection needle 15 for piercing the patient's skin, and the container fluid connection system 17 includes a diaphragm needle 18 for piercing the diaphragm 6c of the container 6 when the drug delivery device is actuated. The subcutaneous delivery system includes a needle support 16 slidably mounted within the housing 2 along a housing slide 67. The needle is mounted on the needle support and can be fully retracted from the housing 9 of the delivery unit 3 together with the needle support 16 to a fully retracted position (e.g., ...). Figure 6a , Figure 6d and Figure 9a (As shown) Move to the full extension position during drug administration (e.g.) Figure 6c , Figure 6f and Figure 9b (As shown).

[0173] The fluid passage within the needle and needle support is connected to a conduit 14, which may advantageously be in the form of a flexible tube, allowing the needle support to slide from a retracted position to an extended position, the other end of which is connected to a container fluid connection system 17.

[0174] The container fluid connection system 17 includes a diaphragm needle support 19, on which diaphragm needles 18 are mounted. The diaphragm needle support 19 is slidably mounted within a housing and configured to... Figure 6a , 6d The retraction positions shown in 7a and 8a are moved to, for example, as shown in 7a and 8a. Figure 6c , 6f The extended positions are shown in 7b and 8b. In the retracted position, the diaphragm needle 18 is not in contact with the drug 78 inside the drug container. In the extended position, the diaphragm needle has pierced the sealing member 27 (sterile barrier) and diaphragm 6c of the drug container and is in contact with the liquid 78 inside the container.

[0175] In an advantageous embodiment, the container fluid connection system 17 can be actuated simultaneously with the subcutaneous delivery system 13. However, it can be noted that, within the scope of the invention, the container fluid connection system 17 can be actuated, for example, sequentially before actuating the subcutaneous delivery system 13. The step of first connecting the diaphragm needle 18 to the drug fluid before piercing the patient's skin with the injection needle 15 allows the fluid connection including the catheter 14 to be filled with drug before injection, so as to remove air from the fluid channel prior to injection.

[0176] In an advantageous embodiment, the container fluid system 17 includes a slidable needle support 19 having a flange portion 20, the flange portion 20 having a guide 22 at its outer end, the guide 22 being slidably engaged in a complementary guide in the outer shell portion of the housing 9. The container fluid connection system 17 also includes a blocking mechanism 24 having a blocking finger 26. Figure 6a , 6d The diaphragm needle support 19 shown in Figures 7a and 8a is in a locked position in the retracted position, with the blocking finger 26 blocking the diaphragm needle support in the retracted position by pressing against at least one flange portion 20. A spring 23, for example in the form of a conical helical spring, is pressed against the rear side of the diaphragm needle support by the spring force of the sealing member 27 (sterile barrier) and the diaphragm 6c, configured to move the diaphragm needle support toward the drug container. Other forms of springs may be provided within the scope of the invention. The blocking finger 26 can move out of engagement with the diaphragm needle support, for example by moving in the gap between the flange portions 20, such that the spring 23 pushes the diaphragm needle support toward the sealing member 27 and the diaphragm 6c, causing the diaphragm needle 18 to pierce the sealing member and the diaphragm.

[0177] In an advantageous embodiment, the blocking mechanism 24 may include a rotatable support ring 25 from which blocking fingers 26 protrude. The rotatable support ring 25 may be mounted, for example, around a shroud forming a cavity into which a container cap having a diaphragm 6c is inserted.

[0178] The blocking mechanism can be actuated to release the diaphragm needle support, thereby allowing it to travel from the retracted position to the extended position by rotation of the blocking mechanism 24.

[0179] In an advantageous embodiment, the movement of the blocking finger 26 and its release from the diaphragm needle support 19 can be performed by actuation of the pump motor 28 of the pumping system 8. The subcutaneous delivery system 13 can also be simultaneously actuated by the initial rotation of the rotor 32 of the pump motor 28.

[0180] In this invention, the subcutaneous delivery system may include a configuration similar to that described in WO 2015015379, which is incorporated herein by reference. In this configuration, the rotor 32 of the pump motor 28 includes an actuation disc 34 coupled to the pump shaft 36, the actuation disc including a recess 35 that engages the tip of a lever arm 65 connected to a support ring 66 of the actuation rod 64. (See reference...) Figures 5a to 6c as well as Figure 4b and Figure 4c As best shown, the support ring 66 of the actuator rod 64 is rotatably mounted around a shroud forming a cavity that accommodates the container lid, while the lever arm 65 extends to a tip configured to engage in a notch 35 of the actuator disc 34 when the rotor 32 is rotated by the pump driver 52 of the drive unit 4.

[0181] like Figure 5a and Figure 6a As shown, the initial position before the drug delivery device is used for the first time is illustrated, with the tip of the lever arm 65 abutting against the outer peripheral surface of the actuation disk 34. When the drug delivery device is actuated, the pumping operation begins, at which point the actuation disk 34 rotates (counterclockwise in the figure), causing the tip of the lever arm 65 to engage in the notch 35, as shown. Figure 5b As shown in the diagram. Subsequently, the continued rotation of the rotor causes the actuator rod 64 to pivot (clockwise as shown in the diagram, as...). Figure 5c , 5d (as shown in 6b) until Figure 5e The fully actuated position is shown, in which the injection needle 15 is fully extended. The actuating rod 64 is also coupled to the support ring 25 of the blocking mechanism 24 via a pin, protrusion, or other mechanism (not visible in the figure), and rotates it (to...). Figures 5b to 5d (as shown in the clockwise direction), causing its blocking finger 26 to disengage from the diaphragm needle support 19.

[0182] Therefore, in the advantageous embodiment described above, the actuation of the pump driver automatically and simultaneously actuates the subcutaneous delivery system 13 and the container fluid connection system 17 to administer the drug. This simultaneous actuation upon startup of the pump system ensures that the drug is sealed within the container until it is administered to the patient, thereby improving sterility and shelf life.

[0183] like Figure 7a and Figure 3c In the best visible position, a sealing member 27 can be provided to cover the central opening in front of the retracted diaphragm needle before the diaphragm needle 18 pierces the container diaphragm.

[0184] The injection needle 15 extends through the orifice 68 in the housing 9 (see Figure 9a , 9b It may also include a sealing member that is punctured during needle actuation.

[0185] At the end of the injection cycle, the rotor 32 of the pump motor 28 can be reversed to pivot the actuator rod 64 and lever arm 65 in the opposite direction, thereby moving the needle support 16 upward and retracting the injection needle 15 into the housing 9. The patient can then safely remove the drug delivery device without any risk of being pricked by the injection needle 15.

[0186] In a variant (not shown), actuation of the container fluid connection system can be performed by a different mechanism, such as a manual actuation button on the housing, pressing the blocking finger 26 to disengage it from the diaphragm needle support 19. In this configuration, sensors can be provided to prevent actuation of the subcutaneous delivery system 13 and the pumping system 8 until the container fluid connection system 17 has been actuated.

[0187] In embodiments including a pneumatic actuator, housing 9 includes a container housing 38 having a container receiving cavity 75 that surrounds the drug container 6 and is hermetically connected to a portion of a pump and needle system housing 37 surrounding a diaphragm needle outlet orifice. The interior of the container housing 38 is fluidly connected via a fluid passage 74 to the outlet 31 of the pump motor 28, such as... Figure 13 The pneumatic flow system 74 is isolated from the volume within the pump and needle system housing 37 surrounding the pump motor 8, and the inlet 30 on the stator 29 of the pump motor 28 is located within this volume to draw air into the pump motor. Therefore, the housing 9 may be provided with a valve inlet or a filter inlet (not shown) to allow air to be drawn into the volume surrounding the pump motor.

[0188] Advantageously, in the pneumatic actuator configuration of this embodiment, the pumping system 8 is actuated to generate gas pressure within the container housing 38, which in turn applies pressure to the rear end 73 of the plunger 12. This configuration allows for a very compact delivery unit, and therefore a very compact drug delivery device 1, because very little space is required behind the plunger due to the absence of a mechanical actuator that directly pushes the plunger. Moreover, the use of a pump motor 28, known per se for pumping liquids, is particularly advantageous in pneumatic actuator applications, considering its very compact size and ability to pump gas without the need for additional valves. Furthermore, the pump can be driven by an electric motor without the need for a transmission device. Sterilization of the delivery unit 3 before assembly with the drug container 6 can also be easily performed using gamma radiation as a substantially closed unit.

[0189] Reference Figures 15a to 15d A drug delivery device having a pneumatic flow system and a pneumatic actuator may include a pressure sensor 80 that measures the pressure in the pneumatic flow system 71. For example... Figure 15b As shown, the pressure measured over time in the pneumatic flow system represents the displacement of plunger 12. Blockage of the plunger due to obstruction in the liquid flow system can be detected by the increase in the rate of pressure increase over time. Furthermore, the end of the plunger's stroke, i.e., the emptying of the drug container, can also be detected, for example, by... Figure 15b The increase in the rate of pressure increase identified in part E is easily detected.

[0190] like Figure 15b As shown, if the pneumatic pump system described above is used, the air pumping action is preferably transmitted in a pulse manner, thus creating a pumping phase followed by a non-operating phase in which the pump is stopped, resulting in a change in air pressure, producing... Figure 15b and 15d The serrated features are shown. Each active pumping phase can be achieved through a single rotation cycle (360° rotation) of the pump motor rotor 32 or through multiple predefined rotation cycles. The inactive phase where the pump is stopped can be of a predetermined duration, depending on the desired drug delivery rate.

[0191] Pressure sensors are very economical and easy to integrate. Therefore, the advantages of this pneumatic plunger position sensing system are its very low cost and ease of integration, and it is particularly suitable for applications requiring control of average flow rates (e.g., as...). Figure 15c (As shown) and a single injection cycle should determine the final position of the plunger in the container. In this case, precise verification of the plunger position is not required.

[0192] The plunger position can also be determined by other sensing devices, and in another embodiment, the plunger sensing system 70 includes an optical sensor 71 mounted on the rear end of the container facing the plunger 12 at the end 73. The container housing portion 38 of the housing 9 includes a sensor window 43 or a sensor prism 43' mounted on the end 42 of the container housing 38 facing the plunger 12.

[0193] An optical sensor 71 can be positioned on the outer surface of a sensor window 43 or a sensor prism 43', which is made of a transparent material for transmitting optical signals to the optical sensor 71. The optical sensor system can advantageously include a transmitter 71a and a receiver 71b, measuring the distance from the sensor window to the plunger rear end 73 via time-of-flight (TOF) measurement. Advantageously, such a time-of-flight optical sensor is particularly economical and easy to implement. To obtain an actual measurement, the window 43 can be positioned on the protruding plunger end 42 to have a minimum distance from 3 mm to up to 30 mm (e.g., between 5 and 20 mm) at the initial position of the plunger 12 when the container is full, so that the initial position of the plunger can be more easily detected by optical time-of-flight measurement.

[0194] The optical sensor 71 can be mounted on a circuit board 72 protruding from the drive unit 4, such as... Figure 11a , 11b And 12a, 12b are shown schematically. In Figure 12a , 12b In the variant shown, the optical sensor can be positioned such that light is guided orthogonally to the direction of travel of the plunger. The light is reflected by prism 43', which, as is known in the field of optics, has an internal reflecting surface for total internal reflection. The prism also serves to increase the initial path of both transmitted and reflected light, allowing for meaningful measurement of the initial position of the plunger when the container is full.

[0195] As the plunger moves toward the emptied position of the container, the accuracy of the time-of-flight measurement increases, thus allowing for higher accuracy when the container reaches the emptied position.

[0196] Optical sensors can be used with pneumatic actuators as described above, but can also be used in drug delivery systems with other pumping technologies, such as pump motors that draw liquid directly from the drug container and displace the plunger 12 within the container by suction (reduced pressure).

[0197] Therefore, the plunger sensing system 70 with an optical sensor 71 based on a transparent window at the rear end of the container housing 38 is particularly cost-effective and easy to deploy in a very compact arrangement.

[0198] Reference Figures 16a to 16eAnother embodiment of the drug delivery device 1 is shown, which has a different arrangement of the housing 2. In this embodiment, instead of providing a container housing 38 extending the entire length of the container 6, a cover 44 is provided, forming the plunger end 42 of the container housing, which is configured to close the container receiving cavity 75 within the housing 2. A sealing ring 41 may be provided between the cover and the cavity wall to seal the container 6 within the housing 2. An optical sensor 71 of the plunger sensing system 70 may be incorporated within the cover 44, which is also positioned on the transparent sensor window 43. The optical sensor 71 may be mounted on a circuit board 72 electrically interconnected to contacts 45 protruding from the outer surface of the cover for electrical connection with complementary contacts 45 on the housing 2. In this embodiment, the container 6 can therefore be installed within the housing after the drive unit 4 and delivery unit 3 are assembled, for example, to allow the container 6 to be inserted by a patient or healthcare practitioner, rather than factory-installed.

[0199] Reference Figure 17a and Figure 17b Another embodiment of the drug delivery device is disclosed, which is consistent with... Figures 16a to 16d Similar to the implementation method, this embodiment also allows the medication container 6 to be inserted by a healthcare practitioner or user after the housing, drive unit, and delivery unit have been assembled in the factory. In this embodiment, the rear open end of the container housing 38 is closed by a cap 2c, which is hingedly coupled to the base 2a of the housing 2 via a hinge coupling 46 and includes a container sealing ring 77. Once the container is inserted, the container sealing ring 77 is inserted and hermetically seals the rear open end of the container housing portion 38. It can be noted that in Figure 17a and Figure 17b The drive unit is not shown in the diagram to increase the clarity of the illustration of other components.

[0200] Now refer to Figures 18a to 18d The drug delivery device according to an embodiment of the invention advantageously includes a body sensing system 5 electrically connected to an electronic control system 47 of a drive unit 4. The body sensing system 5 is based on capacitance measurement of the presence of body tissue near a capacitive sensor. Capacitive sensors for measuring the proximity of a medical device to the skin of a sensor are known in themselves; however, conventional sensors are either not particularly reliable or expensive to integrate into a drug delivery device. In this invention, the body sensing system 5 includes an electrode 56 comprising a metal layer formed directly on the inner surface of a contact wall 81 of a housing, the outer surface of which is configured to rest against the patient's skin.

[0201] Electrode 56 can be advantageously formed by depositing a metal layer (e.g., electroplating) on ​​the inner surface of the housing cover 56. The electroplating process can be an electroplating process, but other metal deposition techniques for directly forming a metallized layer on the inner surface of the skin contact wall 81 can be utilized within the scope of this invention. The housing can be made of a thermoplastic or thermosetting polymer, and is therefore an insulating material. Electrode 56 can be connected to the electronic control system 47 of the drive unit 4 via interconnecting terminals 61.

[0202] Interconnect terminal 61 can be connected to circuit board 48 of electronic control system 47 at circuit board connection terminal 62 (e.g., via circuit traces soldered to the circuit board) and extends to electrode connection terminal 63 that contacts metal electrode layer 56. Electrode connection terminal 63 can be elastically supported, for example by being provided at the end of a spring beam configured to press against the metal layer of electrode 56 when drive unit 4 is assembled within housing 2.

[0203] Electronic components such as the microprocessor 49 of the electronic control system 47 can be connected to electrodes to measure capacitance values ​​and changes in capacitance values ​​for detecting when the drug delivery device is placed against the patient's skin.

[0204] The activation of the drug delivery device can be configured in the electronic control system 47 to be possible only when the body sensing system detects that the drug delivery device is in the correct position on the patient's skin.

[0205] In a first embodiment, the bulk sensing system includes a sensor electrode implemented as a single electrode, wherein the capacitance between the measuring electrode and a reference potential is measured.

[0206] In a second embodiment, the sensor electrodes can also be implemented as a pair of electrodes 56a, 56b, wherein the capacitance between them is measured. The advantage of this is that it reduces false detections caused by external factors affecting capacitance measurement (such as moisture (sweat) at the contact interface), which the measurement system will reject.

[0207] The advantage of the metal layer on the inner surface of the outer casing 2 is its large surface area, which the electrodes can cover to reliably read capacitance values ​​that take into account changes in capacitance coupling with the patient's skin.

[0208] In a variant, the body sensing system may further include a conductive protective frame 57 surrounding the electrodes, which provides some protection against interference from external fields. The protection may also be connected to a circuit board 48 of the electronic control system via contacts similar to those described above for connecting to the electrode layer. Instead of using a metal layer deposited directly on the inner surface of the housing wall that is mounted against the patient's skin, the electrodes may also comprise a stamped metal sheet or a foil of conductive material bonded or fixed directly against the inner surface of the housing, instead of a deposited metal layer. The conductive foil may be bonded to the inner surface of the housing wall 81, for example, by adhesive or solder, to form a stable electrode.

[0209] Reference Figures 19a to 19d This describes an advantageous assembly method for a drug delivery device according to an embodiment of the present invention. First, refer to... Figure 19a The production of components for a drug delivery device that must be sterilized in a highly reliable manner is disclosed. As shown, individual components for a fluid package are manufactured and assembled, which corresponds to the liquid flow system 7 and pumping system 8 in the housing 9 of the above embodiment. Figure 19a The container housing shown corresponds to container housing 38 and is assembled to other housing components once the drug container 6 has been inserted therein. The drug container components are manufactured separately, and the drug container is assembled to the fluid package within the container housing under aseptic conditions (according to ISO Standard 5 in the current example). Both the container housing and the fluid package, i.e., the liquid flow system 7, the pumping system 8, and the housing 9, can be sterilized using gamma sterilization, which is highly reliable for killing all pathogens. Other sterilization methods can be employed within the scope of this invention, including chemical and thermal sterilization methods, including NO2 (nitrogen dioxide), VHP (vaporized hydrogen peroxide), ETO (ethylene oxide), and steam sterilization methods. Therefore, the container package formed by the assembly of these components corresponds to the delivery unit 3 containing all components, which requires a very high degree of sterilization.

[0210] As noted regarding the previously described embodiments, all outlets of the delivery unit 3 are provided with seals, particularly a sealing membrane 27 covering the container fluid connection system 17, a sealing ring 41 between the container housing 38 and the pump and needle housing 37, and a seal 79 covering the interface between the pumping system rotor and the drive coupling interface 33. The sealing membrane 79 can completely cover the drive coupling interface 33 (e.g., Figure 14c (As shown), or it may only cover the gap between the rotor and stator. The sealing membrane 79 may be interfacing bonded or welded to form an airtight seal, and may be, for example, fragile, such that the seal breaks or ruptures when the drive unit is assembled to the delivery unit and when the device is actuated. Thus, the delivery unit remains sterile and has a long shelf life until the drug delivery device is used.

[0211] Fluid packages, container caps, and drug containers can be manufactured in a single manufacturing facility and assembled within the same facility, such as... Figure 19a As shown.

[0212] In a variant, such as Figure 19b As shown, the fluid cap and container cap can be manufactured in the first manufacturing facility, and preferably using materials as specified in the diagram. Figure 19a The drug is sterilized using gamma sterilization in the method, and then supplied to a second facility, for example, located in a pharmaceutical company, where the drug containers are manufactured and filled. As mentioned above, other sterilization methods, including chemical and thermal sterilization methods (e.g., NO2, VHP, ETO, and steam sterilization methods), can be employed within the scope of this invention. Therefore, the components for forming the drug containers and fluid packs, as well as the container caps, of the delivery unit 3 can be formed within a second manufacturing location where the container packs are produced.

[0213] like Figure 19c and Figure 19d As shown, the sterile container package representing delivery unit 3 in this embodiment can then be assembled with electronics (representing drive unit 4 in this embodiment) and optionally other non-sterile components to finally assemble the drug delivery device under controlled conditions, such as ISO 9 standards.

[0214] like Figure 19d As shown, various configurations for manufacturing and assembly can be performed at different locations. For example, the drug container components can be supplied to the drug manufacturer performing the filling process, while the fluid pack and container cap can be supplied to the pharmaceutical company at a second location for assembling the container to the fluid pack and container cap to form a cartridge (i.e., delivery unit 3 corresponding to the embodiment described herein). The cartridge can then be assembled to electronic components (i.e., drive unit 4 corresponding to the embodiment described herein) and other components can be assembled to the cartridge at the pharmaceutical company location to form a drug delivery device.

[0215] Advantageously, the construction of the delivery unit, which has a housing 9 containing the liquid flow system 7 and the pumping system 8, can be sterilized by gamma sterilization and then assembled to the drug container 6 to form a sealed, sterile delivery unit, which can then be assembled to non-sterile components (e.g., the electronics of the drive unit 4 and the housing component 2). This assembly process provides an efficient manufacturing process and also ensures the sterility and safety of the drug delivery device when needed.

[0216] In summary, a method for manufacturing a drug delivery device includes:

[0217] - A pre-filled drug container, wherein the drug container includes a cylindrical portion and a plunger slidably mounted within the cylindrical portion and sealing the drug within the container.

[0218] - A fluid package, including a liquid flow system, provides a fluid connection from the drug container to the patient during drug delivery operations of the drug delivery device.

[0219] - Including control units with electronic components, and

[0220] - Outer shell,

[0221] According to an embodiment of the present invention, the method includes the following steps:

[0222] a) Assemble the components of the fluid package to form the fluid package.

[0223] b) Sterilize the fluid package.

[0224] c) Provide the pre-filled drug container,

[0225] e) Assemble the fluid package into a pre-filled drug container to form a container package system.

[0226] f) Assemble the container system to the control unit and housing (2) to form a drug delivery device.

[0227] Steps c) and e) are performed under aseptic conditions.

[0228] In an advantageous embodiment, the drug container includes a cylindrical portion and a plunger slidably mounted within the cylindrical portion and sealing the drug within the container.

[0229] Step a) involves the assembly of the fluid pack of the drug delivery device. The fluid pack includes at least a fluid flow system that provides a fluid connection from the pre-filled drug container to the patient's body during drug delivery operations of the drug delivery device. The fluid flow system typically consists of different components made of different materials. For example, the patient-side cannula may be made of metal, while the fluid path may typically be formed by tubing or channels made of plastic parts.

[0230] Step b) involves the sterilization of the fluid pack. Since assembled fluid packs are typically not manufactured under aseptic conditions, they must be sterilized to ensure that the patient cannula, needle, and the entire fluid pathway remain uncontaminated. Common sterilization methods for achieving component sterility depend on the combination of different materials and the product design (e.g., grooves). Common sterilization methods for fluid packs include gamma radiation, ethylene oxide (ETO) sterilization, nitrogen dioxide (NO2) sterilization, steam sterilization, vaporized hydrogen peroxide (VHP) sterilization, X-ray sterilization, or electron beam sterilization.

[0231] Step c) involves providing a pre-filled drug container. The container can be made of glass, polymer, or other materials that are inert to drug stability and preferably biocompatible. Glass is commonly used in commercially available, FDA-approved drug containers manufactured by many different companies. Therefore, there are well-established and approved procedures for the aseptic filling and storage of drugs in glass containers, which can expedite the approval process for drug pump devices that protect drugs in glass containers. Polymer containers, such as those made of COP (cyclic olefin polymers) or COC (cyclic olefin copolymers), may be suitable for certain drugs that degrade rapidly upon contact with glass, such as protein drugs. After filling, the container is sealed with a plunger, typically made of rubber. This container is filled and sealed under aseptic conditions (Level 5 or lower as specified in ISO 14644-1).

[0232] Step d) involves assembling the fluid pack to a pre-filled drug container to form a container pack system, which may have a fluid connection between the fluid pack and the pre-filled drug container, or the connection may be established separately, for example, after production or immediately before delivery of the drug to the patient.

[0233] Step e) involves assembling the container system to the control unit and housing (2) to form a drug delivery device. The assembly of the control unit with the user interface of the container system and the installation of the housing can be achieved through standard molding connections or any other conventional manufacturing method. This may also include welding or adhesive processes to achieve a watertight or even airtight housing.

[0234] Definition of aseptic conditions: In addition to low particle count, aseptic conditions ensure that the filling and assembly environment is free of pathogens, such as bacteria, viruses and other pathogenic microorganisms.

[0235] Aseptic conditions can be achieved in, for example, a Class 5 cleanroom as specified in ISO 14644-1 or a lower class cleanroom (i.e., a higher standard cleanroom).

[0236] Another definition of aseptic conditions can also be found in the United States Pharmacopeia (USP) section [number missing]. <1116> It was found in the chapter "Microbial Control and Monitoring of Aseptic Processing Environments".

[0237] Another definition of aseptic conditions can be found in "DIN EN ISO 13408-1, Aseptic processing of health care products - Part 1: General requirements".

[0238] In an advantageous embodiment of this method, step f) is not performed under aseptic conditions. Electronic components are highly sensitive to common sterilization methods, such as gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization, or electron beam sterilization. By performing step e) under non-aseptic conditions, damage to the electronic components can be avoided. Therefore, there is no risk of any component being damaged during the assembly of the drug delivery device, thus ensuring patient safety. Therefore, the manufacturing method of step e) is not limited to particle-free or low-particulate emission connection technologies.

[0239] In an advantageous embodiment of the method, the container package system includes a container housing surrounding a pre-filled drug container. The container housing can be connected to a fluid package, thus easily maintaining the sterility of the pre-filled drug container. The container can be in direct fluid communication with a fluid flow system, or the fluid package can include a tool for separately (e.g., after manufacturing or immediately before the drug is to be delivered to the patient) connecting the pre-filled drug container to the fluid flow system.

[0240] In an advantageous embodiment of the method, the container system includes a pump system. The pump system is configured to further push a plunger into the pre-filled drug container to administer the drug. In an advantageous embodiment, the pump system performs drug delivery by drawing in ambient air and injecting it into the container housing.

[0241] In an advantageous embodiment of the method, the pump system includes a pump system coupling interface of the delivery unit, the pump driver providing torque to the rotor of the pumping system, wherein the coupling interface is sealed by a sealing membrane to remain sterile after step b). The seal can be made of a two-component molded thermoplastic elastomer (TPE) or a single TPE or elastomer, which seals over the moving coupling interface. The seal can also be made to completely cover the coupling interface and be destroyed upon the first rotation of the coupling. In this case, it can be made of polyethylene foil (such as Tyvek). TM It is composed of foil rather than elastic material.

[0242] In an advantageous embodiment of the method, the housing includes a user interface. The user interface may include electronic components that are highly sensitive to conventional sterilization methods.

[0243] In an advantageous embodiment of the method, the sterilization method of b) is any one of gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization or electron beam sterilization.

[0244] Feature list

[0245] Drug 78

[0246] Drug delivery device 1

[0247] Outer shell 2

[0248] Base 2a

[0249] Lid 2b

[0250] Skin contact wall 81

[0251] 10 pinholes

[0252] Adhesive layer

[0253] Protective film 11

[0254] Cover 2c

[0255] Container sealing ring 77

[0256] Hinge Coupler 46

[0257] Conveying Unit 3

[0258] Drug container 6

[0259] cylindrical part 6a

[0260] Neck section 6b

[0261] Diaphragm 6c

[0262] Piston 12

[0263] 73 at the rear end of the plunger

[0264] Liquid Flow System 7

[0265] Subcutaneous delivery system 13

[0266] Catheter 14

[0267] Injection needle 15

[0268] Needle support (sliding) 16

[0269] 67-inch outer casing slide

[0270] Container fluid connection system 17

[0271] Diaphragm needle 18

[0272] Diaphragm needle support 19

[0273] Flange portion 20

[0274] Gap / Cavity (used to block finger release) 21

[0275] Guide component 22

[0276] Spring 23

[0277] Conical spring

[0278] Blocking mechanism 24

[0279] Support ring (rotatable) 25

[0280] Blocking refers to 26

[0281] Sealing film 27

[0282] Actuator 64

[0283] Support ring 66

[0284] Lever arm 65

[0285] Pumping system 8

[0286] Pump engine 28

[0287] Stator 29

[0288] Fluid inlet 30

[0289] Fluid outlet 31

[0290] Rotor 32

[0291] Drive coupling interface 33

[0292] Actuator 34

[0293] Notch 35

[0294] Pump shaft 36

[0295] Seals

[0296] Pneumatic flow system 74

[0297] Casing 9

[0298] Pump and needle system housing 37

[0299] Needle exit hole 68

[0300] Container shell 38

[0301] Container receiving cavity 75

[0302] tubular portion 39

[0303] diaphragm end 40

[0304] Sealing ring 41

[0305] plunger end 42

[0306] Sensor window 43

[0307] Sensor prism 43'

[0308] Cover 44

[0309] Electrical contact interface 45

[0310] Control unit or drive unit 4

[0311] Electronic control system 47

[0312] Circuit board 48

[0313] Microprocessor 49

[0314] Wireless connection module

[0315] Power source (battery) 50

[0316] Pump driver 52

[0317] Electric motor 53

[0318] Coupling interface 54

[0319] Spring 69

[0320] User Interface 55

[0321] Piston Sensing System 70

[0322] Circuit board 72

[0323] Optical sensor 71

[0324] Launcher 71

[0325] Receiver 71b

[0326] Prism 43', Window 43

[0327] Electrical contact interface 45

[0328] Body sensing system 5

[0329] Electrode 56

[0330] Metallization layer

[0331] Protection Department 57

[0332] Processing circuit 58

[0333] Circuit board 59

[0334] Microprocessor 60

[0335] Interconnection terminal 61

[0336] Circuit board connection terminal 62

[0337] Electrode connection terminal 63

[0338] Spring beam.

Claims

1. A method for manufacturing a drug delivery device, the drug delivery device including... - Pre-filled drug container (6). - A fluid package, including a liquid flow system (7), provides a fluid connection from the drug container to the patient during drug delivery operations of the drug delivery device. - Drive unit, which includes electronic components and pump driver (52). - Outer shell (2), The method includes the following steps: a) Assemble the components of the fluid package to form the fluid package. b) Sterilize the fluid package. c) Provide the pre-filled drug container, d) After sterilization, assemble the fluid package into a pre-filled drug container to form a container package system. e) Assemble the container system to the drive unit and housing (2) to form a drug delivery device. The fluid package is characterized by comprising a container housing (9) for receiving a pre-filled drug container (6) therein, and a pump motor (28) having a rotor (32) including a coupling interface (33) adapted to be coupled to a pump driver (52) for providing torque to the rotor, wherein the coupling interface is sealed by a sealing membrane (79) to remain sterile after step b), and Steps c) and d) are performed under aseptic conditions.

2. The method according to claim 1, wherein step e) is not performed under aseptic conditions.

3. The method according to claim 1, wherein the drug container comprises a cylindrical portion (6a) and a plunger (12) slidably mounted within the cylindrical portion and sealing the drug (78) within the container.

4. The method of claim 1, wherein the sealing film may be made of a two-component molded thermoplastic elastomer (TPE) together with the housing or as a separately assembled component.

5. The method of claim 1, wherein the sealing film is made of polyethylene foil covering the coupling interface.

6. The method of claim 1, wherein the sealing membrane is configured to rupture upon pump driver startup.

7. The method of claim 1, wherein the housing includes a user interface (55).

8. The method according to claim 1, wherein the sterilization method of b) is any one of gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization or electron beam sterilization.

9. The method according to claim 1, wherein the assembly step d) includes a shape-fit connection.

10. The method of claim 9, wherein the shape-fit connection provides an airtight seal for the pre-filled drug container within the container pack system.

11. The method according to claim 1, wherein the drug delivery device: - Delivery unit (3), the delivery unit includes a drug container (6), a liquid flow system (7), a pumping system (8) including a pump motor (28), and a housing (9) therein enclosing the drug container, the pumping system and the liquid flow system. - Drive unit (4); - and housing (2), in which a conveying unit and a drive unit are installed, in, The fluid package is formed by a delivery unit without assembled drug containers, and the container package is formed by a delivery unit with assembled drug containers, wherein the drive unit includes an electronic control system (47) and a power supply (50).

12. The method of claim 11, wherein the drug container is housed within a container receiving cavity (75) of a container housing portion (38) of a housing (9), the container receiving cavity being fluidly interconnected in an airtight manner to a fluid outlet (31) of a pumping system (8), the pumping system including a fluid inlet (30) connected to ambient air, the pumping system being configured to pump ambient air drawn in through the fluid inlet (30) into the container receiving cavity (75), thereby applying pressure to the rear end (73) of the plunger to deliver the liquid drug.

13. The method of claim 11, wherein the liquid flow system (7) of the delivery unit comprises a container fluid connection system (17) comprising a diaphragm needle (18) mounted on a movable diaphragm needle support (19), a spring (23) pressing the diaphragm needle support against the diaphragm of the drug container, and a blocking mechanism (24) movable from a blocking position to an actuated position, wherein the diaphragm needle support (19) is held in a retracted position where the diaphragm needle (18) is not in contact with the diaphragm (6c) and is behind the sterile barrier seal member (27) of the housing (9), and wherein the actuated position is released and allowed to travel toward the diaphragm of the drug container such that the diaphragm needle (18) pierces the sterile barrier seal member (27) and the diaphragm (6c) under the force of the spring (23).

14. The method according to claim 3 or 11, wherein the drive unit comprises an electronic control system (47) and a plunger sensing system (70) comprising an optical sensor (71) comprising a transmitter (71a) and a receiver (71b), the transmitter being configured to transmit an optical signal to the rear end (73) of the plunger (12) and the receiver being configured to receive an optical signal reflected back from the rear end (73) of the plunger, the plunger sensing system being connected to the electronic control system (47) being configured to measure the time of flight of the optical signal from the transmitter to the receiver and thereby determine the position of the plunger within the cylindrical portion of the drug container.

15. The method of claim 11, wherein the driving unit includes a body sensing system (5) including electrodes (56) for measuring capacitance values ​​connected to an electronic control system (47) of the driving unit, configured to detect whether the drug delivery device is positioned against the patient's skin, the skin contact wall (81) of the housing (2) having an inner side facing the interior of the housing on which the delivery unit and the driving unit are mounted and an outer mounting side facing the exterior of the housing and intended to be placed against the patient's skin, wherein the electrodes (56) include a metal layer mounted directly against the inner side of the skin contact wall.

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