WO2018015242A1

WO2018015242A1 - Drug delivery device for detection of an end-of-dose

Info

Publication number: WO2018015242A1
Application number: PCT/EP2017/067523
Authority: WO
Inventors: André LARSEN
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 2016-07-21
Filing date: 2017-07-12
Publication date: 2018-01-25
Anticipated expiration: 2019-01-21

Abstract

The invention relates to a method of providing an end-of-dose notification to a user, comprising the steps of (i) providing a drug delivery device comprising a cartridge containing a drug to be expelled, and a user-settable dose expelling mechanism, (ii) setting a dose to be expelled, (iii) expelling the set dose from the cartridge, (iv) monitoring volume change in the cartridge during expelling, and (v) notify the user when volume change has stopped, this indicating an end-of-dose state. In a further aspect the invention relates to a corresponding drug delivery device.

Description

DRUG DELIVERY DEVICE FOR DETECTION OF AN END-OF-DOSE

The present invention generally relates to a drug delivery device adapted to expel a drug of dose from a drug cartridge. More specifically, the invention relates to the issue of informing a user of an end-of-dose condition.

BACKGROUND OF THE INVENTION

In the disclosure of the present invention reference is mostly made to the treatment of diabetes, however, this is only an exemplary use of the present invention.

Drug delivery devices in the form of injection devices for subcutaneous administration of fluid drugs have greatly improved the lives of patients who must self-administer drugs and biological agents. Drug injection devices may take many forms, from simple disposable devices to highly sophisticated electronically controlled motorized instruments with numerous functions. Regardless of their form, they have proven to be great aids in assisting patients to self- administer injectable drugs and biological agents. They also greatly assist care givers in administering injectable medicines to those incapable of performing self-injections.

In particular pen-style injection devices have proven to provide an accurate, convenient, and often discrete, way to administer drugs and biological agents, such as insulin. Typically, injection devices use a pre-filled cartridge containing the medication of interest, e.g. 1.5 or 3.0 ml of insulin or growth hormone. The cartridge is typically in the form of a generally cylindrical transparent ampoule with a needle pierceable septum at one end and an opposed piston designed to be moved by the dosing mechanism of the injection device. The injection devices are generally of two types: "Durable" devices and "disposable" devices. A durable device is designed to allow a user to replace one cartridge with another cartridge, typically a new cartridge in place of an empty cartridge. In contrast, a disposable device is provided with an integrated cartridge which cannot be replaced by the user; when the cartridge is empty the entire device is discarded.

A further distinction can be made for the drive means delivering the force to move the cartridge piston forwards during expelling of a dose of drug. Traditionally injection devices have been manually actuated by the user pushing an extendable button during expelling, however, alternatively the driving force may be provided by a spring being pre-strained or strained dur- ing dose setting and subsequently released, this allowing for "automatic" dispensing of drug. Irrespective of the type of delivery device, when injecting medical drugs by use of injection devices, the internal parts of the device apply pressure to a fluid drug in a container to overcome flow resistance in the device, i.e. mostly the attached injection needle, and the tissue/skin of the recipient. This causes some of the parts to deform elastically during out- dosing, which means that after the mechanism reaches the end-of-dose state and the out- dosing mechanism itself stops moving, the stored energy in the deformed parts is released and cause further out-dosing.

More specifically, injection systems using a cartridge comprising an elastic rubber piston is characterised in that the piston will be more or less deformed when the piston driver, e.g. typically a piston rod, is advanced, this typically providing the largest contribution to elastic deformation build-up during out-dosing.

When the piston driver stops moving when having reached its end-of-dose position, the pis- ton will relax to its original form. The selected dose is thus not fully delivered until the piston has reached its form just before starting the injection. How much the piston is deformed depends mainly on the friction between the piston and the (glass) cartridge plus the counter pressure that builds up when the liquid has to pass through the very thin needle. This is the main reason why the user is recommended to keep the needle inserted for some period - typically six seconds. Removing the needle before six seconds have elapsed might lead to an under-dose of up to 1 IU for a traditional 100 lU/ml insulin formulation which could be substantial for small doses. Indeed, for higher drug concentrations the issue will be aggravated.

Waiting six seconds may be cumbersome and some users might ignore it with the risk of an under-dose as a consequence. In most cases more than 95% of the dosage is delivered within 1-2 seconds after stopping the piston drive.

Having regard to the above, it is an object of the present invention to provide a method and a drug delivery device adapted to receive or comprising a drug-filled cartridge, and which are adapted to detect one or more properties during or after out-dosing which then can be used to determine or detect that a given dose has been (almost) fully delivered, which in most cases will be before six seconds has elapsed, and notify the user correspondingly. The properties should be detected in a simple and effective way, the arrangement being sensitive, cost-effective and reliable. DISCLOSURE OF THE INVENTION

In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objects or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments.

Thus, in accordance with a first aspect of the invention a method of providing an end-of-dose notification to a user is provided, comprising the steps of providing a drug delivery device comprising a cartridge containing a drug to be expelled and a user-settable dose expelling mechanism, setting a dose to be expelled, expelling the set dose from the cartridge, monitor- ing volume change in the cartridge during expelling, and notify the user when volume change has reached a pre-determined value, e.g. stopped, this indicating an end-of-dose state.

In the present context the definition "monitoring volume change in the cartridge during expelling" includes the period after the dose expelling mechanism has stopped moving (or is close to having stopped) and covers the situations in which volume change is monitored (i) both before and after the dose expelling mechanism has stopped moving (or is close to having stopped), and (ii) only after the dose expelling mechanism has stopped moving (or is close to having stopped). In this way a simple and reliable method is provided allowing a user to be informed when a "true" end-of-dose state has been reached.

The volume change may be calculated using a capacitive sensor arrangement, wherein the capacitive sensor arrangement may comprise at least one transmitter member arranged on the outer surface of the cartridge.

In an exemplary embodiment the dose expelling mechanism comprises an indicator member rotating during expelling of a dose, the method comprising the further step of detecting rotational movement of the indicator member, wherein the monitoring of volume change in the cartridge starts when rotational movement of the indicator member has been detected, i.e. detection starts during rotation. Alternatively, the method comprises the further step of determining when rotational movement of the indicator member has stopped or reached a predetermined value, wherein the monitoring of volume change in the cartridge starts when it has been determined that rotational movement of the indicator member has stopped or reached a pre-determined value. Rotational movement of the indicator member may be detected using a capacitive sensor arrangement. An expected end-of-delivery time may be calculated based on at least the expelled dose size, the expelled dose size being calculated based on a determined amount of rotation of the indicator member, wherein the expected end-of-delivery time is displayed to the user. The displayed end-of-delivery time is displayed as a count-down value.

In accordance with a second aspect of the invention a drug delivery device is provided comprising a drug-filled cartridge or means for receiving a drug-filled cartridge, the cartridge comprising an axially displaceable piston and a distal outlet portion. The drug delivery device comprises a drug expelling mechanism comprising dose setting means allowing a user to set the size of a dose of drug to be expelled, and a piston rod adapted to move the piston of a cartridge in a distal direction to thereby expel drug from the cartridge. The drug delivery device further comprises electronic circuitry comprises sensor means adapted to monitoring volume change in a cartridge during expelling, and means for notifying the user when volume change has stopped, this indicating an end-of-dose state.

By this arrangement a simple and reliable device is provided allowing a user to be informed when a true end-of-dose state has been reached. The sensor means may comprise a capacitive sensor arrangement adapted to detect a variable volume parameter, and a comprised cartridge may comprise at least one capacitive transmitter member arranged on the outer surface of the cartridge.

In an exemplary embodiment the drug expelling mechanism comprises an indicator member rotating during expelling of a dose, and the electronic circuitry comprises sensor means adapted to detect rotational movement of the indicator member. The electronic circuitry is adapted to calculate an expected end-of-delivery time based on at least the expelled dose size, wherein the expelled dose size being calculated based on a determined amount of rotation of the indicator member. The electronic circuitry may comprise a display, wherein the expected end-of-delivery time is displayed to the user on the display. The means for notifying the user when volume change has stopped or reached a pre-determined value may also be provided by the display.

In a further exemplary embodiment the drug expelling mechanism comprises an indicator member rotating during expelling of a dose, and the electronic circuitry comprises sensor means adapted to detect rotational movement of the indicator member. In such an arrange- ment the monitoring of volume change in the cartridge starts when rotational movement of the indicator member has been detected. Alternatively the monitoring of volume change in the cartridge starts when it has been determined that rotational movement of the indicator member has stopped or reached a pre-determined value.

The drug delivery device may comprise a cartridge holder portion adapted to accommodate a cartridge, the cartridge holder portion comprising the electronic circuitry. In an exemplary embodiment the drug delivery device comprises a flexible sheet on which is formed or mounted the electronic circuitry, comprising the sensor means, a display, a processor, and an energy source. One or more or all of the sensor means, display, processor, and energy source may be in the form of printed electronics.

As used herein, the term "drug" is meant to encompass any flowable medicine formulation capable of being passed through a delivery means such as a cannula or hollow needle in a controlled manner, such as a liquid, solution, gel or fine suspension, and containing one or more drug agents. Representative drugs include pharmaceuticals such as peptides (e.g. insulins, insulin containing drugs, GLP-1 containing drugs as well as derivates thereof), proteins, and hormones, biologically derived or active agents, hormonal and gene based agents, nutritional formulas and other substances in both solid (dispensed) or liquid form. In the de- scription of exemplary embodiments reference will be made to the use of insulin containing drugs, this including analogues thereof as well as combinations with one or more other drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following exemplary embodiments of the invention will be further described with reference to the drawings, wherein figs. 1 A and 1 B show a generic drug delivery device with and without a cap mounted, fig. 2 shows a drug cartridge comprising capacitive transmitters,

fig. 3 shows in a sectional view a piston rod distal portion, and

figs. 4A and 4B show a drug delivery device with an electronic label.

In the figures like structures are mainly identified by like reference numerals. DESCRIPTION OF EXEMPLARY EMBODIMENTS

When in the following terms such as "upper" and "lower", "right" and "left", "horizontal" and "vertical" or similar relative expressions are used, these only refer to the appended figures and not necessarily to an actual situation of use. The shown figures are schematic represen- tations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only. In that context it may be convenient to define that the term "distal end" in the appended figures is meant to refer to the end of the injection device which usually is adapted to carry an injection needle as depicted e.g. in fig. 1 B whereas the term "proximal end" is meant to refer to the opposite end pointing away from the injection needle end. When the term member or element is used for a given component it generally indicates that in the described embodiment the component is a unitary component, however, the same member or element may alternatively comprise a number of subcomponents just as two or more of the described components could be provided as unitary components, e.g. manufactured as a single injection moulded part.

Before turning to embodiments of the present invention per se, an example of a prefilled drug delivery will be described, such a device providing the basis for the exemplary embodiments of the present invention. Although the pen-formed drug delivery assembly 100 shown in figs. 1A and 1 B may represent a "generic" drug delivery device, the actually shown device is a FlexTouch® prefilled drug delivery pen as manufactured and sold by Novo Nordisk A S, Bagsvaerd, Denmark. A more detailed description of such a device can be found in e.g. WO 2014/161952 which is hereby incorporated by reference.

The pen assembly 100 comprises a cap part 1 10 and a main drug delivery device (or part) 105 having a proximal body or drive assembly portion with a housing 101 in which a drug expelling mechanism is arranged or integrated, and a distal cartridge holder 120 in which a drug-filled transparent cartridge 130 with a distal drug outlet in the form of a needle- penetrable septum 131 is arranged and retained in place by a non-removable cartridge holder attached to the proximal portion, the cartridge holder having openings allowing a portion of the cartridge to be inspected as well as distal coupling means 125 allowing a needle assembly to be releasably mounted. The cartridge holder 120 comprises proximal coupling means 121 adapted to engage corresponding coupling means arranged on the cap interior surface. Alternatively, the cap may be designed to engage coupling means arranged on the main device distal portion. The cartridge is provided with a piston driven by a piston rod forming part of the expelling mechanism and may for example contain an insulin, GLP-1 or growth hormone formulation. A proximal-most rotatable dose setting member 180 serves to manually set a desired dose of drug shown in display window 102 and which can then be expelled when the button 190 is actuated. Depending on the type of expelling mechanism embodied in the drug delivery device, the expelling mechanism may comprise a spring as in the shown embodiment which is strained during dose setting and then released to drive the piston rod when the release button is actuated. Alternatively the expelling mechanism may be fully manual in which case the dose member and the actuation button moves proximally during dose setting corresponding to the set dose size, and then is moved distally by the user to expel the set dose, e.g. as in a FlexPen® manufactured and sold by Novo Nordisk A/S. Although figs. 1A and 1 B show a drug delivery device of the pre-filled type, i.e. it is supplied with a pre-mounted cartridge and is to be discarded when the cartridge has been emptied, in alternative embodiments the drug delivery device may be designed to allow a loaded cartridge to be replaced, e.g. in the form of a "rear-loaded" drug delivery device in which the cartridge holder is adapted to be removed from the device main portion, or alternatively in the form of a "front-loaded" device in which a cartridge is inserted through a distal opening in the cartridge holder which is non-removable attached to the main part of the device.

Turning to an exemplary embodiment of the present invention, fig. 2 discloses a modified traditional drug cartridge 200 comprising a cylindrical main portion 201 and a neck portion 202. The main portion is provided with a pair of transmitters 210, 21 1 formed from conductive material on the outer surface, the transmitters taking up approximately 25% of the cylindrical surface in the shown embodiment. The circumferential width of each of the transmitters vary along the length of the cartridge, the first transmitter 210 having a circumferential width which diminishes towards the distal end of the cartridge, and the second transmitter 21 1 having a circumferential width which increases towards the distal end of the cartridge. In the shown embodiment the combined circumferential width for the two transmitters is constant along the length of the transmitters.

The portion of the drug delivery device surrounding the cartridge, typically termed a cartridge holder, comprises electronic sensor circuitry adapted to interact with the cartridge transmitters. Two alternating electrical fields shifted in phase are applied on each of the two transmitters on the outer surface of the cartridge. This induces an alternating electrical field in the drug with a phase depending on the size of each of the areas of the two transmitters covered by the drug. A capacitive receiver 220 arranged on the opposite side of the cartridge pick up the electrical field and by measuring the phase-shift, the remaining drug volume in the cartridge can be determined. By monitoring the volume level and the changes thereof, the continued expelling of drug after the piston rod stops rotating can be detected and an end-of-dose notification can be communicated to the user, e.g. by means of a display. As the end-of-dose detection is based on de- termination of volume change as a function of time, and not on determination of absolute volume values, the method is not sensitive to normal variations in e.g. cartridge dimensions and thus robust.

Especially for a disposable device it is essential that the sensor system and the display are manufactured cost-effectively. Correspondingly, in an exemplary embodiment the drug delivery device cartridge holder portion comprises a flexible sheet on which is formed or mounted electronic circuitry comprising sensor means adapted to provide the above-described functionality, e.g. electric field generators, capacitive receiver plates, a processor, a display and an energy source, the flexible sheet being mounted at least in part to the exterior and/or inte- rior surface of the cartridge holder housing. Based on input from the capacitive receiver the processor is adapted to control the display to indicate that end-of-dose event has been detected. To cost-effectively provide a flexible "label-like" electronic assembly one or more or all of the sensor means, display, processor, and energy source may be in the form of printed electronics, see e.g. WO 2015/071354 which is hereby incorporated by reference.

By the above arrangements a very simple and inexpensive electronic system is provided on a drug delivery device, the low cost allowing it to be formed integrally with a pre-filled disposable drug delivery device. Indeed, the electronic system could also be incorporated in a durable device.

In an alternative embodiment the energy source may be incorporated in the device cap, this allowing e.g. a conventional button type "battery" cell to be utilized. In such an arrangement the "label electronics" may comprise a capacitor adapted to store energy provided by the battery, the label and the cap comprising corresponding galvanic contacts allowing charging of the capacitor during the time when the cap is mounted on the cartridge holder. In such an arrangement the contacts may be utilized to detect removal of the cap, this providing that the electronics are powered on. The cap may be provided with a replaceable or rechargeable battery allowing the cap to be used as a durable component in combination with disposable pen devices. With reference to fig. 3 a further embodiment of a drug delivery device 300 with additional detection means will be described. In addition to the above-described volume-sensing circuitry the drug delivery device expelling mechanism is provided with output means allowing rotational movement of an expelling mechanism component to be detected during drug expelling. Many known drug expelling mechanisms, including the above-mentioned FlexTouch® pre- filled drug delivery pen, comprise components which rotate during drug expelling corresponding to the expelled dose, e.g. a piston driver and the piston rod as in the FlexTouch® pen, see the above-mentioned WO 2014/161952. As the piston rod also moves axially just as it has a relatively small diameter and is arranged at a distance from the outer pen housing, the piston rod may not be considered the best component to provide a detectable rotational output. The piston driver in the FlexTouch® has a larger diameter and does not move axially during drug expelling, however, the driver is positioned in the device main part at a distance from the cartridge holder portion. Correspondingly, to provide an output during drug expelling that can be detected by circuitry arranged on or in the cartridge holder portion, the pen device 300 shown in fig. 3 is provided with an indicator disc 310 which engages the piston rod 330 and rotates therewith yet allows the piston rod to move axially relative to the indicator disc, this allowing the indicator disc to be arranged axially stationary relative to the housing and cartridge holder. The indicator disc comprises a circumferential edge portion 31 1 on which a number of conductive sensor areas 312 are provided, e.g. by printing.

The electronic circuitry arranged in the cartridge holder portion 320 comprises additional ca- pacitive sensor means 321 allowing rotation of the indicator disc to be detected as the disc conductive areas pass the sensor means. In a simple configuration the system may be adapted to merely sense motion which may be used to initiate volume sensing, e.g. starting when rotation is initially detected or when rotation stops.

In a more advanced configuration the electronic circuitry may be adapted to detect and count the number of passing disc sensor areas to thus determine the amount of expelled drug, i.e. the dose size. A determined dose size may be used to provide different information to the user. For example, for a pre-filled device the initial drug volume is known and it would thus be possible after each expelled dose to calculate and display the amount of remaining drug. Correspondingly, the detected dose amounts could be stored in a dose log and subsequently transmitted to an external device, e.g. via an antenna incorporated in the flexible label. If the electronic circuitry is provided with a timer, e.g. a simple relative timer, a time-dose log could be created, the relative time being "translated" to real time when the log is transmitted to an external device with a build-in real time clock.

When for a given expelling event the remaining volume in the cartridge is known as well as the actually expelled dose size, it would be possible to predict fairly accurately from a mathematical model based on knowledge of the different components in the particular device the expected end-of-dose time which may then be displayed on the electronically controlled display, e.g. 3 seconds. When the volume-sensing circuitry then detects and end-of-dose state this may be indicated in the display. Alternatively a countdown value could be displayed on the electronically controlled display. Such a countdown value would enhance user confidence in the device and encourage the user to follow the instructions as displayed rather than trusting own judgement. Indeed, such a countdown functionality would require the calculated end-of-dose time to be fairly accurate compared with the volume-sensing based detection of a "real" end-of-dose state, e.g. within 1 second of difference.

Fig. 4A shows a drug delivery device 400 in which a flexible electronic label 440 is mounted on the cartridge holder portion 420, the label comprising electronic circuitry provided with ca- pacitive sensing means for sensing both the current cartridge drug volume and rotation of the above-described indicator disc, as well as a display adapted to display both a detected ex- pelled dose size 441 , a calculated count-down value 442 and an indicator 443 (see fig. 4B) for a detected end-of-dose state. In the shown embodiment the electronic label is manufactured using, at least in part, printed electronics. In figs. 4A and 4B the display window 402 should correctly show "0" instead of "12" as the expelling mechanism in the shown states has returned the scale drum the zero position.

In the above description of the preferred embodiments, the different structures and means providing the described functionality for the different components have been described to a degree to which the concept of the present invention will be apparent to the skilled reader. The detailed construction and specification for the different components are considered the object of a normal design procedure performed by the skilled person along the lines set out in the present specification.

Claims

1. A method of providing an end-of-dose notification to a user, comprising the steps of:

(i) providing a drug delivery device (300, 400) comprising:

- a cartridge (200) containing a drug to be expelled, and

a user-settable dose expelling mechanism,

(ii) setting a dose to be expelled,

(iii) expelling the set dose from the cartridge,

(iv) monitoring volume change in the cartridge during expelling, and

(v) notify the user when volume change has stopped or reached a pre-determined value, this indicating an end-of-dose state.

2. A method as in claim 1 , wherein the dose expelling mechanism comprises an indicator member (310) rotating during expelling of a dose, the method comprising the further step of:

detecting rotational movement of the indicator member, wherein the monitoring of volume change in the cartridge starts when rotational movement of the indicator member has been detected.

3. A method as in claim 1 , wherein the dose expelling mechanism comprises an indicator member (310) rotating during expelling of a dose, the method comprising the further step of:

determining when rotational movement of the indicator member has reached a pre- determined value stopped, wherein the monitoring of volume change in the cartridge starts when it has been determined that rotational movement of the indicator member has stopped or reached a pre-determined value.

4. A method as in claim 2, wherein:

an expected end-of-delivery time is calculated based on at least the expelled dose size, the expelled dose size being calculated based on a determined amount of rotation of the indicator member, and

- the expected end-of-delivery time is displayed to the user.

5. A method as in claim 4, wherein:

the displayed end-of-delivery time is displayed as a countdown value (442).

6. A method as in any of claims 2-5, wherein rotational movement of the indicator member (310) is detected using a capacitive sensor arrangement (312, 321 , 440).

7. A method as in any of claims 1-6, wherein volume change is calculated using a capacitive sensor arrangement (210, 21 1 , 220, 440), and wherein the capacitive sensor arrangement may comprise at least one transmitter member (210, 21 1 ) arranged on the outer surface of the cartridge.

8. A drug delivery device (300, 400) comprising:

a drug-filled cartridge (200) or means (320, 420) for receiving a drug-filled cartridge, the cartridge comprising an axially displaceable piston and a distal outlet portion,

- a drug expelling mechanism comprising:

dose setting means allowing a user to set the size of a dose of drug to be expelled, and

a piston rod (330) adapted to move the piston of a cartridge in a distal direction to thereby expel drug from the cartridge, and electronic circuitry comprising:

sensor means (210, 21 1 , 220, 440) adapted to monitor volume change in a cartridge during expelling, and

means (442, 443) for notifying the user when volume change has reached a pre-determined value or stopped, this indicating an end-of-dose state.

9. A drug delivery device as in claim 8, wherein the sensor means comprises a capacitive sensor arrangement (210, 21 1 , 220, 440) adapted to detect a variable volume parameter.

10. A drug delivery device as in claim 9, wherein a comprised cartridge comprises at least one capacitive transmitter member (210, 21 1 ) arranged on the outer surface of the cartridge.

1 1 . A drug delivery device as in claim 10, wherein: the drug expelling mechanism comprises an indicator member (310, 312) rotating during expelling of a dose,

the electronic circuitry comprises sensor means (321 , 440) adapted to detect rotational movement of the indicator member,

- the electronic circuitry is adapted to calculate an expected end-of-delivery time based on at least the expelled dose size, the expelled dose size being calculated based on a determined amount of rotation of the indicator member,

the electronic circuitry (440) comprises a display (442),

the expected end-of-delivery time is displayed to the user on the display, and - the means for notifying the user when volume change has reached a predetermined value or stopped is provided by the display.

12. A drug delivery device as in claim 10, wherein:

the drug expelling mechanism comprises an indicator member (310, 312) rotating during expelling of a dose, and

the electronic circuitry comprises sensor means (321 , 440) adapted to detect rotational movement of the indicator member, wherein the monitoring of volume change in the cartridge starts when rotational movement of the indicator member has been detected, or wherein the monitoring of volume change in the cartridge starts when it has been determined that rotational movement of the indicator member has stopped.

13. A drug delivery device as in any of claims 8-12, comprising a cartridge holder portion (320, 420) adapted to accommodate a cartridge, the cartridge holder portion comprising the electronic circuitry.

14. A drug delivery device as in claim 13, comprising a flexible sheet (440) on which is formed or mounted the electronic circuitry, the electronic circuitry comprising the sensor means, a display, a processor, and an energy source.

15. A drug delivery device as in claim 14, wherein one or more or all of the sensor means, display, processor, and energy source is/are in the form of printed electronics.