Title
Electronic system
Background
The present disclosure relates to an electronic system for a drug delivery device.
Hand-held drug delivery devices, such as injection pens, are used on a massive scale in medicine, and the demand for these devices is increasing rapidly. With the increasing complexity of the drug delivery devices used and the associated increased manufacturing costs, it is desirable to use the respective device, or at least components thereof, several times. In order to achieve sustainable use of these drug delivery devices, it is particularly desirable not to accidentally throw away reusable devices or at least components thereof.
Summary
An aim of the present disclosure is to enable improvements in relation to drug delivery devices, in particular in relation to the prevention of unintentional discarding of reusable drug delivery devices or components thereof.
This aim is achieved by the disclosed subject-matter, for example by the subject-matter defined in the appended independent claims. Advantageous refinements and developments are subject to dependent claims and/or set forth in the description below.
One aspect of the present disclosure relates to an electronic system. The electronic system may be configured for measuring injected doses and/or other parameters of a drug delivery device. The parameters may comprise the expiry date of the medication, the set dose for a scheduled injection, the type of medication, and/or the temperature of the medication. The electronic system may comprises a sensing unit configured to provide information about a change in the spatial position of the electronic system. The spatial position may be the absolute spatial position of the electric system. The information may, inter alia, include acceleration, velocity and/or vibration values detected by the sensing unit. The change in the spatial position may be a change in the position of the electronic system relative to a drug delivery device. The change in the spatial position may be a falling movement of the electronic system. The change in the spatial position may be a falling movement of the electronic system in the direction of the gravitational force of the earth. The electronic system may further comprises a localization unit for assisting the localization of the electronic system and a processor unit operatively connected to the sensing and localization unit. The processor unit may be configured, based on a comparison of the information provided by the sensing unit about the change in spatial position of the electronic system with a predefined criterion, to cause the localization unit to switch to a condition in which a user is informed on the location of the electronic system, e.g. by the localization unit, when the information about the change in the spatial position provided by the sensing unit meets the predefined criterion. The change in spatial position can give an indication that the electronic system is being thrown in the trash. The electronic system thus assists the user in finding the electronic system if it has been accidentally discarded.
In an embodiment the comparison of the information provided by the sensing unit about the change in spatial position of the electronic system with the predefined criterion can be carried out by the processor unit.
In an embodiment the comparison of the information provided by the sensing unit about the change in spatial position of the electronic system with the predefined criterion can be carried out by a processor different from the processor unit. The processor different from the processor unit may not be part of the electronic system. The processor different from the processor unit may be part of an external device. The external device may be one of a smartphone a smartwatch and/or a tablet computer.
In an embodiment the electronic system is a reusable add-on device that can be repeatedly detachably attached to a drug delivery device.
In an embodiment the electronic system comprises an electronic system housing, wherein the electronic system housing encloses the sensing unit, localization unit and the processor unit. The electronic system housing may be the housing of the add-on device. The electronic system housing may be different from a drug delivery device housing.
In an embodiment the sensing unit is configured to provide information about a change in the spatial position of the electronic system housing. The sensing unit may be configured to provide information about a change in the spatial position of an outer surface of the electronic system housing. The outer surface of the electronic system housing may have a touchable surface that is touchable by the user. The sensing unit may be configured to provide information about a change in the spatial position of the touchable surface. The touchable surface may be the surface that needs to be touched by the user to trigger the dispensing process of a drug delivery device. The term spatial position refers to the location or placement of the electronic system in a three- dimensional space. It describes where the electronic system is in relation to its coordinates or its relationship to other objects. The spatial position can be defined by specifying length, width, and height coordinates, distances from reference points, or other suitable methods.
In an embodiment the sensing unit comprises an inertial sensor or is configured to use inertial sensor technology.
In an embodiment the sensing unit is configured to provide the information about the change in the spatial position of the electronic system by measuring acceleration values of the electronic system. The sensing unit may comprise an accelerometer.
In an embodiment the sensing unit is configured to provide the information about the change in the spatial position of the electronic system by measuring angular velocity values of the electronic system. The sensing unit may comprise a gyroscope sensor.
In an embodiment the predefined criterion comprises information indicative of a predefined kinematic event of the electronic system. The term kinematic event may represent information related to the motion and position of the electronic system, whether it is, inter alia, vectors, acceleration values or velocity values.
In an embodiment the predefined criterion comprises information indicative of a predefined kinematic event about the electronic system. Optionally, the predefined criterion additionally comprises an expiration of a predefined time after the predefined kinematic event.
In an embodiment the electronic system comprises a timer. The processor unit may be operatively connected to the timer. The timer may be configured to assist the processor unit in detecting the expiration of the predefined time.
In an embodiment the predefined criterion comprises information indicative of a first predefined kinematic event about the electronic system, an expiration of the predefined time after the first predefined kinematic event has been detected, and the absence of an information indicative of a second predefined kinematic event within the predefined time that is different from the first predefined kinematic event.
In this way it may be prevented that the switch to the condition in which the user is informed about the position of the localization unit, and thus the position of the electronic system, takes place too early in cases where the user has already realized that he should not have thrown away the electronic system.
In an embodiment the information indicative of the predefined kinematic event, the first predefined kinematic event and/or the second predefined kinematic event is the detection of an acceleration value by the sensing unit. The acceleration value may be greater than or equal to the acceleration due to gravity of the earth, i.e. 9.81 m/s2. The acceleration value may be greater than or equal to 5, 6, 7, 8 or 9 m/s2. The information indicative of the predefined kinematic event may be the detection of the exceeding of an acceleration value.
In an embodiment the information indicative of the predefined kinematic event, the first predefined kinematic event and/or the second predefined kinematic event is the detection of an angular velocity value by the sensing unit. The angular velocity value may be greater than or equal to 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 7s (degrees per second). The information indicative of the predefined kinematic event may be the detection of the exceeding of an angular velocity value.
In an embodiment the predefined time is the average time taken to pick up a drug delivery device or add-on device after it has fallen down or into a bin. The predefined time may be more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 seconds.
In an embodiment the predefined kinematic event and/or the first predefined kinematic event may be the average velocity or acceleration that is achieved when a drug delivery device or add-on device is thrown into a bin. The predefined kinematic event or first predefined kinematic event may be an acceleration in the direction of the earth's gravitational force. The second predefined kinematic event may be an acceleration in the direction opposite to the earth's gravitational force.
In an embodiment the localization unit is configured to be visible, audible, tactile and/or electronically detectable in the condition in which the user is informed about the position of the electronic system, e.g. by the localization unit. The localization unit may be configured to be not visible, audible, tactile and/or electronically detectable before the localization unit switches to the condition in which the user is informed about the position of the electronic system.
In an embodiment, optionally, in order to support the detectability of the localization unit, the localization unit comprises a transmitter, a receiver and/ or a transceiver. Alternatively or additionally, the localization unit may comprise a light, a loudspeaker and/or a vibration element. In an embodiment the localization unit is configured to be physically perceptible after switching to the condition in which the user is informed about the position of the electronic system. The localization unit may be configured to be not physically perceptible before switching to the condition in which the user is informed about the position of the electronic system. The localization unit may be configured to light up, to vibrate and/or to emit audible signals after switching to the condition in which the user is informed about the position of the electronic system. The localization unit may be configured not to light up, to vibrate and/or to emit audible signals before switching to the condition in which the user is informed about the position of the electronic system.
In an embodiment the localization unit is configured to be not physically perceptible after switching to the condition in which the user is informed about the position of the electronic system. The localization unit may be configured to transmit and/or receive a signal after switching to the condition in which the user is informed about the position of the electronic system. The localization unit may be configured not to transmit and/or receive a signal before switching to the condition in which the user is informed about the position of the electronic system. The signal may be configured to be detectable and/or be sent by an external device. The signal may be wireless signal. The signal may be a Bluetooth signal. The signal may be a WLAN (Wi-Fi) signal. The external device may be one of a smartphone a smartwatch and/or a tablet.
In an embodiment, the electronic system comprises an interface configured to detect the presence of the drug delivery device. The interface may be a presence sensor. The presence sensor may be configured to detect if the electronic system is attached to a drug delivery device.
In an embodiment the electronic system is configured to have a first state and a second state, wherein in the first state the sensing unit, the processor unit, and the localization unit are not operating, and in the second state the sensing unit, the processor, and the localization unit are operating. The electronic system may be configured such that the electronic system changes from the first state to the second state when the electronic system is attached to the drug delivery device. The electronic system may be configured such that the electronic system remains in the second state when the electronic system is detached from the drug delivery device.
In an embodiment the electronic system is configured such that the electronic system changes from the first state to the second state when the interface detects one or more movements of components of the drug delivery device relative to each other or relative to the electronic system. The one or more movements may include the following movements:
- the movement of a plunger,
- the movement of a needle shroud,
- the movement of a dose dial,
- the movement of a medicament container, wherein the medicament container may be a syringe,
- the movement of a stopper in the medicament container,
- the movement of a needle,
- the movement of a cap and/or
- the movement of an energy storage unit, such as a drive spring.
In an embodiment the electronic system is configured to output a warning signal if the electronic system is detached from the drug delivery device. The localization unit may be configured to output the warning signal. Alternatively, the electronic system may comprise a warning unit, configured to output the warning signal, wherein the warning unit and the localization unit are different units.
In an embodiment the electronic system is configured such that the electronic system outputs the warning signal if the electronic system is detached from the drug delivery device and when a predefined time is exceeded after the electronic system is detached from the drug delivery device. The predefined time may be more than 5 seconds. The predefined time may be more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 seconds. The electronic system may be configured such that the electronic system outputs the warning signal if the electronic system is detached from the drug delivery device and if the electronic system is not reattached to the drug delivery device within the predefined time.
Another aspect of the present disclosure relates a drug delivery device comprising the electronic system described above. The drug delivery device may be configured to retain a drug container with a drug or may comprise a drug container with a drug. The drug delivery device may be a fully functional drug delivery device. The drug may be a medicament. The drug delivery device may be an autoinjector. In an autoinjector, the energy for the drug delivery operation may be prestored in an energy storage member. That is to say, the user does not have to provide the energy for the drug delivery operation, e.g. when preparing the drug delivery device for use. Rather, this energy may be preloaded into the drug delivery device by the manufacturer. For example, a drive spring, e.g. a spiral spring or flat spiral spring, may be pre-stressed or prebiased to provide the energy for the drug delivery operation. Alternatively, the drug delivery device may not be an auto-injector, meaning that the user must apply force to push the drug out of the container.
Another aspect of the present disclosure relates to a method for assisting the localization of the electronic system. The method may be a computer-implemented method. The method may comprise the providing of information about the change in the spatial position of the electronic system, the comparing of the information about the change in the spatial position of the electronic system with the predefined criterion and causing the electronic system to switch to the condition in which the user is informed about the position of the electronic system, when the change in the spatial position meets the predefined criterion. The method may comprise comparing of the information about the change in the spatial position of the electronic system with the predefined criterion and causing the localization unit not to switch to the condition in which the user is informed about the position of the electronic system, when the change in the spatial position does not meet the predefined criterion. The process step of switching the electronic system to the condition in which the user is informed about the position of the electronic system, may be performed by switching the localization unit to the condition in which the user is informed about the position of the electronic system as described above.
Another aspect of the present disclosure relates to a computer program product, e.g. a computer program or a computer readable storage medium, comprising instruction which when carried out by a processor cause the electronic system to perform the method. The computer readable storage medium may be hardware memory component. The processor may be different from the processor unit. Contrary to the processor unit, the processor may not be part of the electronic system. Alternatively the processor may be the processor unit.
In the present invention, singular expressions such as "a sensing unit", "a localization unit", etc. are used for ease of reading the description and claims. Since the assembly according to the invention "comprises" or "has" components or features, respectively, however, such a singular expression does not limit the number of components or features concerned. Rather, such a singular expression is intended to be understood as "at least one sensing unit", "at least one localization unit", etc., unless the context indicates otherwise
A particularly advantageous embodiment refers to an electronic system for measuring parameters of a drug delivery device, wherein the electronic system comprises a sensing unit configured to provide information about a change in the spatial position of the electronic system, a localization unit for assisting the localization of the electronic system and a processor unit operatively connected to the sensing and localization unit, wherein the processor unit is configured, based on a comparison of the information provided by the sensing unit with a predefined criterion, to cause the localization unit to switch to a condition in which a user is informed on the location of the electronic system, when the information about the change in the spatial position provided by the sensing unit meets the predefined criterion.
Another particularly advantageous embodiment refers to a drug delivery device comprising the electronic system.
A particularly advantageous method refers to a method for assisting the localization of an electronic system comprising the following steps:
- providing information about a change in the spatial position of the electronic system,
- comparing the information about the change in the spatial position of the electronic system with a predefined criterion,
- causing the electronic system to switch to a condition in which a user is informed about the position of the electronic system, when the change in the spatial position meets the predefined criterion.
We note that features described above and below in conjunction with different embodiments or aspects can be combined with one another, even if such a combination is not explicitly disclosed herein above or below. Further features, advantages and expediencies of the disclosure and, particularly, of the proposed concepts will become apparent from the following description of the exemplary embodiments in conjunction with the drawings.
Brief description of the drawings
Figure 1 illustrates an exploded view of a drug delivery device for use with an electronic system according to an embodiment of the invention;
Figure 2 illustrates the electronic system attached to the drug delivery device of Figure 1;
Figure 3 illustrates a block diagram of the electronic system shown in Figure 2 and an external device;
Figure 4 illustrates a perspective view of a portion of the drug delivery device of Figure 1 ;
Figure 5 illustrates a perspective view of a movable dosage programming component of the drug delivery device of Figure 1 ; Figure 6 illustrates a cross-sectional view of portions of the electronic system of Figure 3 and the drug delivery device of Figure 1 when attached together;
Figure 7 illustrates a graph showing an intensity of light received by a sensor arrangement in the electronic system of Figure 3;
Figure 8 illustrates a graph showing an output of the sensor arrangement based on the received light intensities shown in Figure 7; and
Figure 9 illustrates a system in which data from the electronic system of Figure 3 is transmitted to another device.
Description of the exemplary embodiments
In the following, embodiments of the present invention will be described with reference to an insulin drug delivery device. The present invention is however not limited to such application and may equally well be deployed with drug delivery devices that eject other medicaments.
Identical elements, elements of the same kind and identically or similarly acting elements may be provided with the same reference numerals in the figures. The invention is not restricted to the illustrated or described embodiments.
Figure 1 is an exploded view of a medicament delivery device. In this example, the medicament delivery device is a drug delivery device 1, e.g. a device similar or identical to the one described in described in WO 2004/078239 A1.
The drug delivery device 1 of Figure 1 is a pre-filled, disposable injection pen that comprises a housing 10 and contains an insulin container 14, to which a needle 15 may be affixed. The needle is protected by an inner needle cap 16 and an outer needle cap 17 and/or another cap 18.
An insulin dose to be ejected from drug delivery device 1 may be programmed, or 'dialled in' by turning a dosage knob 12, and a currently programmed dose is then displayed via dosage window 13, for instance in multiples of units. For example, where the drug delivery device 1 is configured to administer human insulin, the dosage may be displayed in so-called International Units (IU), wherein one IU is the biological equivalent of about 45.5 micrograms of pure crystalline insulin (1/22 mg). Other units may be employed in drug delivery devices for delivering analogue insulin or other medicaments. It should be noted that the selected dose may equally well be displayed differently than as shown in the dosage window 13 in Figure 1.
The dosage window 13 may be in the form of an aperture in the housing 10, which permits a user to view a limited portion of a number sleeve 70 that is configured to move when the dosage knob 12 is turned, to provide a visual indication of a currently programmed dose. The dosage knob 12 is rotated, e.g. on a helical path, with respect to the housing 10 when turned during programming.
In this example, the dosage knob 12 includes one or more formations 71a, 71b, 71c to facilitate attachment of an electronic system to be described herein below.
The drug delivery device 1 may be configured so that turning the dosage knob 12 generates a haptic and/or acoustic feedback, e.g. mechanical click sound, perceivable by a user/patient. The number sleeve 70 mechanically interacts with a piston in insulin container 14. When needle 15 is stuck into a skin portion of the patient, and then injection button 11 is pushed, the insulin dose displayed in display window 13 will be ejected from drug delivery device 1. When the needle 15 of drug delivery device 1 remains for a certain time in the skin portion after the injection button 11 is pushed, a high percentage of the dose is actually injected into the patient's body. The drug delivery device may be configured such that several events of the injection process, e.g. the completion, may generate a haptic and/or acoustic feedback for the user. For example, the acoustic feedback may be a mechanical click sound, which, however, may be different from the sound produced when using dosage knob 12.
In one embodiment, during delivery of the insulin dose, the dosage knob 12 is moved to its initial position in an axial movement, that is to say without rotation, while the number sleeve 70 is rotated to return to its initial position, e.g. to display a dose of zero units.
Drug delivery device 1 may be used for several injection processes until either the insulin container 14 is empty or the expiration date of the medicament in the drug delivery device 1 (e.g. 28 days after the first use) is reached.
Furthermore, before using drug delivery device 1 for the first time, it may be necessary to perform a so-called "prime shot" to remove air from insulin container 14 and needle 15, for instance by selecting two units of insulin and pressing injection button 11 while holding drug delivery device 1 with the needle 15 upwards. For simplicity of presentation, in the following, it will be assumed that the ejected amounts substantially correspond to the injected doses, so that, for instance the amount of medicament ejected from the drug delivery device 1 is equal to the dose received by the user. Nevertheless, differences (e.g. losses) between the ejected amounts and the injected doses may need to be taken into account.
Figure 2 is a perspective view of the proximal end of the drug delivery device 1 when an electronic system 20 according to an embodiment of the disclosure is attached. In the following the term "distal" refers to the direction of the drug delivery device 1 in which a drug or medicament is discharged. Accordingly, the term "proximal" refers to the opposite direction, as further explained above. The electronic system 20 includes an electronic system housing 21 and a dose information unit. For the sake of facilitating the understanding, the dose information unit will be exemplarily described as being a display 22 for presenting dosage information 22a. However, other types of visual dose information units, e.g. analogue indicators such as markings etc. may be used. Alternatively or additionally, the dose information unit may comprise means for providing the dosage information non-visually, e.g. acoustically or haptically.
As shown in Figure 3, the electronic system 20 also includes a sensing unit 23 configured to provide information about, or monitor, a change in the spatial position of the electronic system 20 as a whole and a localization unit 25. The localization unit 25 is configured to assist the localization of the electronic system 20. In addition, the electronic system 20 includes a processor unit 24 operatively connected, inter alia, to the sensing unit 23 and localization unit 25. The processor unit 24 may include one or more processors, such as a microprocessor, a Digital Signal Processor (DSP), an Application Specific Integrated Circuit (ASIC), a Field Programmable Gate Array (FPGA) or the like, together with memory units 24.1 , 24.2, including program memory 24.1 and main memory 24.2, which can store software for execution by the processor unit 24. The electronic system housing 21 encompasses at least the sensing unit 23, localization unit 25 and the processor unit 24.
An interface 26 to the drug delivery device 1 , such as a sensor arrangement, comprising one or more sensors, is provided, wherein the processor unit 24 is operatively connected to the interface 26. In the example depicted in Figure 3, the interface 26 is an optical encoder, including a light source 26a, such as a light emitting diode (LED) and a light detector 26b, such as an optical transducer. The interface 26 can be configured to detect the presence of the drug delivery device 1 if the electronic system 20 is attached to the drug delivery device 1. Moreover, the interface 26 is also configured to detect movements of components of the drug delivery device 1 relative to the electronic system 20.
Furthermore, an output 27 is provided, which may be a wireless communications interface for communicating with another device, such as a smartphone, a smartwatch and/or a tablet computer, via a wireless network such as wi-fi or Bluetooth, or an interface for a wired communications link, such as a socket for receiving a Universal Series Bus (USB), mini-USB or micro-USB connector.
A power switch 28 is provided, together with a battery 29. In one example, the power switch 28 is configured to respond to pressure applied to the display 22 by powering the electronic system 20 on or off.
The depicted electronic system 20 is configured for measuring injected doses and/or other parameters of the drug delivery device 1 . Measuring other parameters may include, for example, the expiry date of the medication, the set dose for a scheduled injection, the type of medication, the temperature of the medication, etc. The electronic system 20 can be used to detect duration and timing details of the last dose ejected from the drug delivery device 1 , and the corresponding information may be displayed in an app of an external device such as a smartphone, a smartwatch and/or a tablet computer. The electronic system 20 is a reusable add-on device that can be repeatedly detachably attached to the drug delivery device 1. In the present example, the electronic system 20 is attached to the injection button 11 of the proximal end of the drug delivery device 1. According to an alternative example, the electronic system 20 is a reusable add-on device that can be attached to the housing 10 of the drug delivery device 1. The electronic system 20 may be attached to the housing 10 of the drug delivery device 1 such that the electronic system housing 21 covers the window 13. According to another alternative example, the drug delivery device is an autoinjector. It should also be noted that the electronic system 20 can also be used in reusable assemblies of drug delivery devices. For example, reference is made here to reusable drive units that can be equipped with different containers or syringes. The electronic system 20 may be an integral or inseparable part of a reusable assembly of a drug delivery device.
Regarding the functions of the electronic system 20 with respect to the localization of the electronic system, the electronic system 20 is configured to have a first state and a second state, wherein in the first state the sensing unit 23, the processor unit 24, and the localization unit 25 are not operating and in the second state the sensing unit 23, the processor unit 24, and the localization unit 25 are operating as described below. In both the first state and the second state, the power switch 28 is on.
The change from the first to the second state can be effected in various ways. For example, the electronic system 20 can be configured such that the electronic system changes from the first state to the second state when the electronic system is attached to the drug delivery device 1. In this case, the electronic system 20 can have a mechanical switch that is flipped when the electronic system 20 is attached to the drug delivery device 1. The mechanical switch can be configured such that the electronic system 20 remains in the second state when the electronic system 20 is detached from the drug delivery device 1 , such that the sensing unit 23, the processor unit 24, and the localization unit 25, continue to operate as described below. In this way, the method for locating the electronic system 20 can also be used if the electronic system 20 is accidentally thrown into a waste bin separately from the drug delivery device 1.
The detection of the presence of the drug delivery device 1 by the interface 26 may cause the electronic system 20 to switch from the first state to the second state, as soon as the interface 26 detects an attachment of the electronic system 20 to the drug delivery device 1 for the first time. The electronic system 20 remains in the second state when the interface 26 detects a detachment of the electronic system 20 from the drug delivery device 1 , such that the sensing unit 23, the processor 24, and the localization unit 25, continue to operate as described below.
According to a further example the electronic system 20 is configured to change from the first state to the second state if the interface 26 detects one or more movements of components of the drug delivery device 1 relative to each other or relative to the electronic system 20. The one or more movements may include, inter alia, a movement of a plunger, a needle shroud, a dose dial sleeve, the dosage knob 12, the insulin container 14, the needle 15 and/or a stopper in the insulin container.
Once the electronic system 20 is in the second state, the sensing unit 23 may continuously acquire information about the change of the spatial position of the electronic system 20. For this purpose, the sensing unit 23 may include, for example, an inertial sensor such as an accelerometer and/or a gyroscope sensor. As soon as the information fulfils a predefined criterion, the processor unit 24 instructs the localization unit 25 to assume a state in which it becomes recognizable to the user. The predefined criterion may be met if the sensing unit 23 does detect motion values representative of a throwaway movement or dropping of the electronic system 20.
It should be noted that instead of the inertial sensor, other sensors can be used that can detect handling of the electronic system 20. Examples may include vibration sensors, pressure sensors and/or acoustic sensors.
In general, the electronic system 20 can be configured such that the predefined criterion can be the presence of any detectable kinematic event about the electronic system 20, such as the motion and position of the electronic system 20, in the form of vectors, acceleration values, velocity values, vibration values, and so forth. Consequently, the sensing unit 23 may comprise means for acquiring this kinematic event. The electronic system 20 can be configured such that the predefined criterion comprises detecting a kinematic event about the electronic system 20 and elapsing a predefined time. In this case the electronic system 20 may comprise a timer (not shown) configured to assist the processor unit 24 in detecting the elapsing of the predefined time. The predefined time may be more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 seconds. Further, the predefined criterion may be detecting the kinematic event, or a first kinematic event, about the electronic system 20 and not detecting another second kinematic event, different from the first kinematic event, within the predefined time. The change of the condition of the localization unit 25 is thus suppressed if the user recognizes his wrong action within the predefined time and lifts the electronic system 20 out of the trash bin.
After the predefined criterion is fulfilled, the electronic system 20 helps the user to recognize when the reusable electronic system 20 has been thrown into a waste bin. This is facilitated by the localization unit 25 changing its condition from a first condition to a second condition. In the second condition the localization 25 can emit a physically perceptible signal. Additionally or alternatively, the electronic system 20 can emit a physically non-perceptible signal in the second condition. For this purpose, the localization unit 25 shown in Figure 3 comprises a physically perceptible component 25a and a non-physically perceptible component 25b. In the context of the present description, a physically perceptible component is an output device that is capable of converting types of signals into physical phenomena or perceptions. Such an output device can be, for example, a light, a loudspeaker and/or a vibration element. A non-physically perceptible component is an output device that is not capable of converting types of signals into physical phenomena or perceptions. Such an output device can be, a transmitter, receiver or transceiver.
As shown in Figure 3, the electronic system 20 can be configured to transmit and/or receive, e.g. with the help of the component 25b, a detectable signal in the second condition, wherein the signal is adapted to be detected by an external device 50. The external device 50 may be, inter alia, a smartphone a smartwatch and/or a tablet computer. The external device 50 may be configured to provide an alert or warning, using an app or software, when the external device 50 detects or receives the signal. The alert or warning may be a notice that is perceptible to the user, such as a sound, a vibration, or a message displayed on a screen of the external device 50. Alternatively or additionally, the electronic system 20 can be configured to light up, vibrate and/or to emit audible signals, e.g. with the help of the component 25a, in the second condition.
In the second condition, the physically perceptible component 25a flashes, lights up, vibrates and/or emits sounds that both alert the user to his incorrect action and assist the user in locating the electronic system 20. Alternatively or simultaneously, the non-physically perceptible component 25b transmits the detectable signal, such as a Bluetooth or WLAN (Wi-Fi) signal. The signal is received from the external device 50, such as the user's smartphone, alerts the user to his incorrect action and helps the user to find the electronic system 20.
According to an exemplary embodiment, the sensing unit 23 comprises an accelerometer, wherein the sensing unit 23 may configured to continuously measure the acceleration of the electronic system 20 in the second state. The processor unit 24 compares the detected acceleration values with an acceleration reference value. The acceleration reference value may be greater than or equal to 1 , 2, 3, 4, 5, 6, 7, 8 or 9 m/s2. As long as the processor unit 24 does not detect a match of an acceleration value, detected by the sensing unit 23, with the reference acceleration value, or does not detect an exceedance of the reference acceleration value by an acceleration value, detected by the sensing unit 23, the processor unit 24 does not instruct the localization unit 25 to switch to the second condition. However, as soon as the reference acceleration value, or an exceeding of the reference acceleration value, is measured the processor unit 24 instructs the localization unit 25 to switch to the second condition.
According to another exemplary embodiment, the sensing unit 23 comprises a gyroscope sensor, wherein the sensing unit 23 may be configured to continuously measure the angular velocity of the electronic system 20 in the second state. The processor unit 24 compares the detected angular velocity values with a reference angular velocity value. The reference angular velocity value may be greater than or equal to 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 7s. As long as the processor unit 24 does not detect a match of an angular velocity value, detected by the sensing unit 23, with the reference angular velocity value, or does not detect an exceedance of the reference angular velocity value by an angular velocity value, detected by the sensing unit 23, the processor unit 24 does not instruct the localization unit 25 to switch to the second condition. However, as soon as the reference angular velocity value, or an exceeding of the reference angular velocity value, is measured the processor unit 24 instructs the localization unit 25 to switch to the second condition.
In both exemplary embodiments, the switch to the second condition may include further preconditions. For example, an additional condition may be the elapse of a time interval immediately after the reference values were measured. The time interval may be, e.g. 15, 30, 45 or 60 seconds. In both of the above-mentioned exemplary embodiments, the switch to the second condition may not occur if any further movement, acceleration or repositioning, of the electronic system is detected by the sensing unit 23 within the time interval.
The comparison of the detected information of the sensing unit 23 with the predefined criterion may be performed by the processor unit 24. However, it is also possible that only the result of this comparison is provided to the processor unit 24. This may be done, for example, by a processor located outside the electronic system 20 or the drug delivery device 1 and communicating with the electronic system 20, for example, via a wireless electronic signal. Thus, the comparison of the detected information of the sensing unit 23 with the predefined criterion may be performed by a processor of a smartphone, a smartwatch and/or a tablet computer.
After the user has picked up the electronic system 20, the localization unit 25 is deactivated, e.g. by the user switching the electronic system 20 from the second state to the first state, using the mechanical switch. It is also possible that the localization unit 25 is deactivated and the electronic system 20 is set to the first state by means of a signal sent by the external device 50. For this purpose, the electronic system 20 may have a corresponding receiver that interacts with the processor unit 24.
Additionally, the electronic system 20 of Figure 3 is configured to output a warning signal if the electronic system 20 is detached from the drug delivery device 1 and if the electronic system 20 is in the second state. According to the exemplary embodiment depicted in Figure 3, the localization unit 25 is configured to output the warning signal. Alternatively, the electronic system 20 may comprise a warning unit (not shown), configured to output the warning signal, wherein the warning unit and the localization unit 25 are different units, which are both enclosed by the electric system housing 21 . The electronic system 20 outputs the warning signal if the electronic system 20 is in the second sate, detached from the drug delivery device 1 and when a predefined time is exceeded after the electronic system 20 is detached from the drug delivery device 1. The predefined time can be more than 5 seconds. The predefined time may be more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 seconds. Moreover, the electronic system 20 is configured such the electronic system outputs the warning signal if the electronic system 20 is detached from the drug delivery device 1 and if the electronic system 20 is not reattached to the drug delivery device 1 within the predefined time or, alternatively, not reattached to another drug delivery device different from, or equal to, the drug delivery device 1 within the predefined time.
Figure 4 shows the injection button 11 and dosage knob 12 of the drug delivery device 1 in more detail. In the illustrated embodiment, the injection button 11 includes a cavity 30 on its upper surface, configured to receive at least a portion of the electronic system 20. In this embodiment, a sidewall of the cavity 30 includes an aperture 31 , through which a portion of the number sleeve 70 may be visible.
Figure 5 depicts the number sleeve 70. In the illustrated embodiment, castellations 72 are formed, e.g. moulded, on one end of the number sleeve 70. One end of the number sleeve 70 is provided with castellations 72 that may act as light barriers for light emitted by the light source 26a.
In the embodiment shown in Figure 5, twelve castellations 72 are provided. The twelve castellations and the gaps between them have widths selected to provide 24 "edges". Each edge may correspond to one dose increment, such that up to a maximum dose of 24 units may be shown on the number sleeve 70. The castellations 72 are formed using a material that has a reflectivity that differs from the reflectivity of an inner surface of the injection button 11.
The number sleeve 70 is arranged to rotate helically along one direction as a dose is programmed into the drug delivery device 1 using the dosage knob 12. The number sleeve 70 is arranged to rotate helically in an opposite direction during delivery of a medicament dose by the drug delivery device 1.
Figure 6 is a cross-sectional view of part of the electronic system 20 and the drug delivery device 1.
As shown in Figure 6, the dosage knob 12 and the housing 21 of the electronic system 20 include co-operating formations 71a, 73a. In this particular embodiment, these formations are in the form of a projection 73a provided in the housing 21 of the electronic system 20 and a detent 71a provided in the dosage knob 12. As shown in Figure 1, the formations 71a, 71b, 71c have only a limited extent, so that the electronic system 20 cannot rotate relative to the dosage knob 12 when attached.
Since the electronic system 20 and dosage knob 12 cannot rotate relative to one another, they move correspondingly as a dosage is programmed into the drug delivery device 1. This may allow provision of a more ergonomic arrangement, since the electronic system 20 may provide a larger surface that may be gripped and rotated by the user during dosage programming. Alternatively or additionally, the electronic system 20 may be provided with formations on its outer surface to facilitate rotation of the electronic system 20 and, therefore, the dosage knob 12.
In arrangements where the electronic system 20 is to be releasably attachable to the drug delivery device 1, the co-operating formations 71a, 73a may provide a form fit engagement, e.g. a clip-type engagement, that allows for easy removal of the electronic system 20. Such an arrangement may be useful where the electronic system 20 is to be used with disposable drug delivery devices 1, since it allows the electronic system 20 to be removed from a drug delivery device 1 easily. This facilitates re-use and allows the user greater flexibility in attaching and removing the electronic system 20 at will.
Alternatively, the co-operating formations 71a, 73a may be configured to attach the electronic system 20 to the drug delivery device 1 permanently, for example, using a "snap-fit". In other embodiments, the electronic system 20 maybe permanently attached in other ways, for example, through bonding. Such permanent attachments may be useful where the injection device 1 is reusable.
In one embodiment, the number and/or positions of the co-operating formations 71a, 73a may be configured so that the electronic system 20 may only be attached to the drug delivery device 1 in one particular position. In this example, the housing 21 of the electronic system 20 may include an aperture 74 through which light emitted by the light source 26a may pass and may be detected by the light detector 26b when the electronic system 20 is in position. The cooperating formations 71a, 73a may be arranged so that, when the electronic system 20 is attached to the drug delivery device 1, the aperture 74 in the housing 21 of the electronic system 20 is aligned with the aperture 31 in the sidewall of the cavity 30 in the injection button 11 , as shown in Figure 6.
As shown by the arrow in Figure 6, light emitted by the light source 26a thus may pass through the apertures 74, 31 and into the injection button 11. If a castellation 72 of the number sleeve 70 is viewable through the aperture 31 , then the light will be reflected from the castellation 72, and back through the apertures 31 , 74, where it may be detected by the light detector 26b. Since the reflectivity of the castellations 72 differs from that of the inner surface of the injection button 11 , the amount of light detected by the light detector 26b will depend on how much of a castellation 72 may be viewed through the aperture 31.
In certain embodiments, the interface 26 may be arranged to emit and/or detect only light with particular polarization characteristics, in order to mitigate effects of stray light entering the aperture 74.
Figure 7 is a graph showing changes in the intensity of light received by the light detector 26b during programming and delivery of a medicament dose, while Figure 8 is a graph showing an output that may be generated by the interface 26 of this embodiment.
As noted above, while a dose is being programmed into the drug delivery device 1, during a time period t1 in Figures 7 and 8, the dosage knob 12 and the number sleeve 70 rotate helically. As the electronic system 20 moves in concert with the dosage knob 12, the amount of light reflected back towards the light detector 26b should remain substantially constant, since there is little or no relative rotational movement between the number sleeve 70 and the electronic system 20. The amount of reflected light should also remain substantially constant between the completion of dosage programming and the start of the injection, shown as a time period t2 in Figure 7, since the number sleeve 70, the dosage knob 12 and the electronic system 20 are not moved by the user.
The output of the interface 26, which may be a sensor arrangement, 26, shown in Figure 8, is therefore substantially constant during time periods t1 and t2. The actual level of the output during time periods t1 and t2 will depend on whether a castellation 72 is visible through the aperture 31 and, if so, how much of the aperture is covered by the castellation 72.
During the delivery of the medicament, shown as time period t3 in Figures 7 and 8, the number sleeve 70 rotates helically but the dosage knob 12 moves only axially, without rotating. Hence, the number sleeve 70 is rotating relative to the electronic system 20.
During time period t3, the castellations 72 of the number sleeve 70 will move across the aperture 31 as the number sleeve 70 rotates relative to the dosage knob 12 and the electronic system device 20, and the intensity of light received by the light detector 26b will vary accordingly, as shown in Figure 7. The number sleeve 70 may be more reflective than the inner surface of the injection button 11, and so the highest intensity levels shown in Figure 7 may correspond to positions where the amount by which the castellation 72 covers the aperture 31 is at its greatest.
The output of the light detector 26b during time period t3 will switch between a high and a low level, based on the received light intensity, as shown in Figure 8. Since the edges of the castellations 72 correspond to increments in the medicament dosage, the processor unit 24 may determine an amount of medication delivered by the drug delivery device 1 based on the number of transitions between the high level and the low level in the output of the sensor arrangement 26.
The length of time period t3 will depend on the administered dosage. Further, the length of time period t3 may depend on a time at which the medicament delivery is completed. When the medicament delivery is completed, the number sleeve 70 will cease to rotate relative to the dosage knob 12 and the electronic system 20, and the signal from the sensor arrangement 26 will stay at a substantially constant level. In some embodiments, the processor unit 24 is arranged to monitor the time period that has elapsed from the last transition or the last pulse in the output of the interface 26. When the elapsed time period reaches a predefined threshold t4, the medicament delivery is considered to have been completed and the processor unit 24 proceeds with determining the medicament dose delivered to the user, based on the number of detected transitions in the output of the sensor arrangement 26 during time period t3. In the particular example shown in Figures 7 and 8, there are eight transitions. Since the transitions correspond to the edges of the castellations which, in turn, correspond to the dosage increments in this particular embodiment, the determined medicament dose is 8 units.
The processor unit 24 then stores the determined medicament dose in main memory 24.2. The processor unit 24 may also store time stamp information, to provide a log recording delivery of medicament to the user.
The processor unit 24 may then power down the electronic system 20, in order to save energy.
When the electronic system 20 is powered on again, e.g. when the user activates the power switch 28, the processor unit 24 may control the display to show the determined medicament dose information 22a, to aid the memory of the user. Optionally, the processor unit 24 may monitor an elapsed time since the determined medicament dose was delivered and control the display to show that elapsed time information too. For example, the processor unit 24 may cause the display 22 to switch periodically between displaying the determined medicament dosage information 22a and the elapsed time.
The processor unit 24 may also transmit the determined medicament dosage and, where determined, the time stamp information to another device, such as a computer 40, as shown in Figure 9. As noted above, the output 27 may be configured to transmit the information using a wireless communications link. Alternatively, the electronic system 20 may be connected to the computer 40 using a wired connection 41 to allow the information to be uploaded to the computer 40. The processor unit 24 may be configured to transmit the information to the computer 40 periodically.
The specific embodiments described in detail above are intended merely as examples of how the present invention may be implemented. Many variations in the configuration of the electronic system 20 and/or the drug delivery device 1 may be conceived.
For example, it is not necessary that the formations 71a, 71b, 71c are provided on the number sleeve 70. Neither is it necessary that the formations are in the form of castellations 72, nor is it necessary that the widths of the castellations and the gaps between them correspond precisely to individual dosage increments, as exemplarily described above.
While it is exemplarily described herein that the interface 26 may be an optical sensing arrangement 26, other types of sensors may be used as well as, or instead of, optical sensors. For example, the interface may include a magnetic sensor, such as a Hall effect sensor. In such an example, one or more magnets may be mounted on the number sleeve, so that rotation of the number sleeve relative to the electronic system results in a varying magnetic field. In another example, a capacitive sensor may be used, where elements provided on the number sleeve may affect the capacitance between two plates provided in the electronic system. In other examples, mechanical sensors, with mechanical switches and/or tracks, may be used to detect the relative movement.
In the above , the injection button 11 is exemplarily described as including a central cavity 30 for receiving at least part of the electronic system 20. However, the central cavity 30 may be omitted if not required by the structure of the electronic system 20.
While the arrangement shown in Figure 6 includes co-operating formations in the form of a detent 71 a in the dosage knob 12 and a projection 73a in the housing 21 of the electronic system 20, other types of co-operating formations or attachment methods may be used.
While the embodiments above have been described in relation to collecting data from an insulin injector pen, it is noted that embodiments of the invention may be used for other purposes, such as monitoring of injections of other medicaments.
The terms “drug” or “medicament” are used synonymously herein and describe a pharmaceutical formulation containing one or more active pharmaceutical ingredients or pharmaceutically acceptable salts or solvates thereof, and optionally a pharmaceutically acceptable carrier. An active pharmaceutical ingredient (“API”), in the broadest terms, is a chemical structure that has a biological effect on humans or animals. In pharmacology, a drug or medicament is used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. A drug or medicament may be used for a limited duration, or on a regular basis for chronic disorders.
As described below, a drug or medicament can include at least one API, or combinations thereof, in various types of formulations, for the treatment of one or more diseases. Examples of API may include small molecules having a molecular weight of 500 Da or less; polypeptides, peptides and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids may be incorporated into molecular delivery systems such as vectors, plasmids, or liposomes. Mixtures of one or more drugs are also contemplated.
The drug or medicament may be contained in a primary package or “drug container” adapted for use with a drug delivery device. The drug container may be, e.g., a cartridge, syringe, reservoir, or other solid or flexible vessel configured to provide a suitable chamber for storage (e.g., shorter long-term storage) of one or more drugs. For example, in some instances, the chamber may be designed to store a drug for at least one day (e.g., 1 to at least 30 days). In some instances, the chamber may be designed to store a drug for about 1 month to about 2 years. Storage may occur at room temperature (e.g., about 20°C), or refrigerated temperatures (e.g., from about - 4°C to about 4°C). In some instances, the drug container may be or may include a dualchamber cartridge configured to store two or more components of the pharmaceutical formulation to-be-administered (e.g., an API and a diluent, or two different drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components prior to and/or during dispensing into the human or animal body. For example, the two chambers may be configured such that they are in fluid communication with each other (e.g., by way of a conduit between the two chambers) and allow mixing of the two components when desired by a user prior to dispensing. Alternatively or in addition, the two chambers may be configured to allow mixing as the components are being dispensed into the human or animal body.
The drugs or medicaments contained in the drug delivery devices as described herein can be used for the treatment and/or prophylaxis of many different types of medical disorders. Examples of disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further examples of disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis. Examples of APIs and drugs are those as described in handbooks such as Rote Liste 2014, for example, without limitation, main groups 12 (antidiabetic drugs) or 86 (oncology drugs), and Merck Index, 15th edition.
Examples of APIs for the treatment and/or prophylaxis of type 1 or type 2 diabetes mellitus or complications associated with type 1 or type 2 diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the terms “analogue” and “derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, by deleting and/or exchanging at least one amino acid residue occurring in the naturally occurring peptide and/or by adding at least one amino acid residue. The added and/or exchanged amino acid residue can either be codable amino acid residues or other naturally occurring residues or purely synthetic amino acid residues. Insulin analogues are also referred to as "insulin receptor ligands". In particular, the term ..derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, in which one or more organic substituent (e.g. a fatty acid) is bound to one or more of the amino acids. Optionally, one or more amino acids occurring in the naturally occurring peptide may have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or amino acids, including non-codeable, have been added to the naturally occurring peptide.
Examples of insulin analogues are Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine); Lys(B3), Glu(B29) human insulin (insulin glulisine); Lys(B28), Pro(B29) human insulin (insulin lispro); Asp(B28) human insulin (insulin aspart); human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Vai or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Examples of insulin derivatives are, for example, B29-N-myristoyl-des(B30) human insulin, Lys(B29) (N- tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®); B29-N- palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-gamma-glutamyl)-des(B30) human insulin, B29-N-omega- carboxypentadecanoyl-gamma-L-glutamyl-des(B30) human insulin (insulin degludec, Tresiba®); B29-N-(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin; B29-N-(w- carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(co-carboxyheptadecanoyl) human insulin.
Examples of GLP-1 , GLP-1 analogues and GLP-1 receptor agonists are, for example, Lixisenatide (Lyxumia®), Exenatide (Exendin-4, Byetta®, Bydureon®, a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide (Victoza®), Semaglutide, Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®), rExendin-4, CJC- 1134-PC, PB-1023, TTP-054, Langlenatide / HM-11260C (Efpeglenatide), HM-15211, CM-3, GLP-1 Eligen, ORMD-0901 , NN-9423, NN-9709, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1 , CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091 , MAR-701, MAR709, ZP- 2929, ZP-3022, ZP-DI-70, TT-401 (Pegapamodtide), BHM-034. MOD-6030, CAM-2036, DA- 15864, ARI-2651 , ARI-2255, Tirzepatide (LY3298176), Bamadutide (SAR425899), Exenatide- XTEN and Glucagon-Xten. An example of an oligonucleotide is, for example: mipomersen sodium (Kynamro®), a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia or RG012 for the treatment of Alport syndrom.
Examples of DPP4 inhibitors are Linagliptin, Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.
Examples of hormones include hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.
Examples of polysaccharides include a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra-low molecular weight heparin or a derivative thereof, or a sulphated polysaccharide, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. An example of a hyaluronic acid derivative is Hylan G-F 20 (Synvisc®), a sodium hyaluronate.
The term “antibody”, as used herein, refers to an immunoglobulin molecule or an antigenbinding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab')2 fragments, which retain the ability to bind antigen. The antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix complement. In some embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, the antibody can be an isotype or subtype, an antibody fragment or mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region. The term antibody also includes an antigen-binding molecule based on tetravalent bispecific tandem immunoglobulins (TBTI) and/or a dual variable region antibody-like binding protein having cross-over binding region orientation (CODV).
The terms “fragment” or “antibody fragment” refer to a polypeptide derived from an antibody polypeptide molecule (e.g., an antibody heavy and/or light chain polypeptide) that does not comprise a full-length antibody polypeptide, but that still comprises at least a portion of a full- length antibody polypeptide that is capable of binding to an antigen. Antibody fragments can comprise a cleaved portion of a full length antibody polypeptide, although the term is not limited to such cleaved fragments. Antibody fragments that are useful in the present invention include, for example, Fab fragments, F(ab')2 fragments, scFv (single-chain Fv) fragments, linear antibodies, monospecific or multispecific antibody fragments such as bispecific, trispecific, tetraspecific and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), monovalent or multivalent antibody fragments such as bivalent, trivalent, tetravalent and multivalent antibodies, minibodies, chelating recombinant antibodies, tribodies or bibodies, intrabodies, small modular immunopharmaceuticals (SMIP), binding-domain immunoglobulin fusion proteins, camelized antibodies, and immunoglobulin single variable domains. Additional examples of antigen-binding antibody fragments are known in the art.
The term “immunoglobulin single variable domain” (ISV), interchangeably used with “single variable domain”, defines immunoglobulin molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain. As such, immunoglobulin single variable domains are capable of specifically binding to an epitope of the antigen without pairing with an additional immunoglobulin variable domain. The binding site of an immunoglobulin single variable domain is formed by a single heavy chain variable domain (VH domain or VHH domain) or a single light chain variable domain (VL domain). Hence, the antigen binding site of an immunoglobulin single variable domain is formed by no more than three CDRs.
An immunoglobulin single variable domain (ISV) can be a heavy chain ISV, such as a VH (derived from a conventional four-chain antibody), or VHH (derived from a heavy-chain antibody), including a camelized VH or humanized VHH. For example, the immunoglobulin single variable domain may be a (single) domain antibody, a "dAb" or dAb or a Nanobody® ISV (such as a VHH, including a humanized VHH or camelized VH) or a suitable fragment thereof. [Note: Nanobody® is a registered trademark of Ablynx N.V.]; other single variable domains, or any suitable fragment of any one thereof.
“VHH domains”, also known as VHHs, VHH antibody fragments, and VHH antibodies, have originally been described as the antigen binding immunoglobulin variable domain of “heavy chain antibodies” (i.e. , of “antibodies devoid of light chains”; Hamers-Casterman et al. 1993 (Nature 363: 446-448). The term “VHH domain” has been chosen in order to distinguish these variable domains from the heavy chain variable domains that are present in conventional 4- chain antibodies (which are referred to herein as “VH domains”) and from the light chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VL domains”). For a further description of VHH’s, reference is made to the review article by Muyldermans 2001 (Reviews in Molecular Biotechnology 74: 277-302).
For the term “dAb’s” and “domain antibody”, reference is for example made to Ward et al. 1989 (Nature 341: 544), to Holt et al. 2003 (Trends Biotechnol. 21 : 484); as well as to WO 2004/068820, WO 2006/030220, WO 2006/003388. It should also be noted that, although less preferred in the context of the present invention because they are not of mammalian origin, single variable domains can be derived from certain species of shark (for example, the so-called “IgNAR domains”, see for example WO 2005/18629). The terms “Complementarity-determining region” or “CDR” refer to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. The term “framework region” refers to amino acid sequences within the variable region of both heavy and light chain polypeptides that are not CDR sequences, and are primarily responsible for maintaining correct positioning of the CDR sequences to permit antigen binding. Although the framework regions themselves typically do not directly participate in antigen binding, as is known in the art, certain residues within the framework regions of certain antibodies can directly participate in antigen binding or can affect the ability of one or more amino acids in CDRs to interact with antigen.
Examples of antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6 mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).
Pharmaceutically acceptable salts of any API described herein are also contemplated for use in a drug or medicament in a drug delivery device. Pharmaceutically acceptable salts are for example acid addition salts and basic salts.
Those of skill in the art will understand that modifications (additions and/or removals) of various components of the APIs, formulations, apparatuses, methods, systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.
An example drug delivery device may involve a needle-based injection system as described in Table 1 of section 5.2 of ISO 11608-1 :2014(E). As described in ISO 11608-1 :2014(E), needlebased injection systems may be broadly distinguished into multi-dose container systems and single-dose (with partial or full evacuation) container systems. The container may be a replaceable container or an integrated non-replaceable container.
As further described in ISO 11608-1 :2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user). Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).
As further described in ISO 11608-1:2014(E), a single-dose container system may involve a needle-based injection device with a replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation). As also described in ISO 11608-1 :2014(E), a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).
Any invention described herein is not limited by the description in conjunction with the exemplary embodiments. Rather, the invention and the associated disclosure comprise any new feature as well as any combination of features, particularly including any combination of features in the patent claims, even if said feature or said combination per se is not explicitly stated in the patent claims or exemplary embodiments.
Reference numerals
1 drug delivery device
10 housing
11 injection button
12 dosage knob
13 window
14 insulin container
15 needle
16 inner needle cap
17 outer needle cap
18 cap
20 electronic system
21 electronic system housing
22 display
22a dosage information
23 sensing unit
24 processor unit
24.1 program memory
24.2 main memory
25 localization unit
25a physically perceptible component
25b non-physically perceptible component
26 Interface
26a light source
26b light detector
27 output
28 power switch
29 battery
30 cavity
31 aperture 40 computer
50 external device 70 number sleeve
71a formation
71b formation
71c formation
72 castellation 73a projection
74 aperture