WO2021037650A1

WO2021037650A1 - Skin-mountable combined drug delivery port device

Info

Publication number: WO2021037650A1
Application number: PCT/EP2020/073293
Authority: WO
Inventors: Henrik Bengtsson; Zeinab MAHMOUDI; Sarah Ellinor ENGELL
Original assignee: Novo Nordisk A/S
Priority date: 2019-08-23
Filing date: 2020-08-20
Publication date: 2021-03-04

Abstract

A patch device comprising a base portion having a mounting surface adapted to be mounted on a skin surface of a patient, and a combined catheter structure which in an operational state is adapted to protrude from the mounting surface, the combined catheter structure comprising a distal end adapted to be arranged in a patient's subcutaneous tissue. The combined catheter structure comprises a catheter lumen having a distal opening, and a sensor adapted to generate a signal indicative of a parameter value of a body fluid. An external fluid port in flow communication with the first catheter is adapted to receive an outlet of a drug delivery device such that in a mounted state a fluid communication is provided between the external fluid port and the patient subcutaneously tissue.

Description

SKIN-MOUNTABLE COMBINED DRUG DELIVERY PORT DEVICE The present invention generally relates to devices and assemblies allowing a patient to safely perform a subcutaneous injection. 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 for subcutaneous injection of a fluid drug formulation via a hollow nee- die have greatly improved the lives of patients who must self-administer drugs and biological agents. Drug delivery devices may take many forms, including simple disposable devices that are little more than an ampoule with an injection means to relatively complex pre-filled disposable devices which may even be spring-driven, or they may be durable devices adapted to be used with pre-filled cartridges. Regardless of their form and type, 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.

However, using a drug delivery device for subcutaneous injections usually means inserting a needle into the skin and inject a drug into the skin through the needle. Although smaller and smaller needle-tips are becoming available, a significant number of people feel uncomfortable inserting a needle into their skin. Not only the sting they feel, but also the mere sight of the needle and the thought of it entering their skin, cause discomfort for these people. To some of these people the anticipation of pain, increase their sensation of pain and makes the injections very unpleasant for these people. This may cause some of these people not to perform the injections quite as often as they should.

Addressing this issue injection ports have been developed which only require that the patient puncture their skin every few days to install an injection port, rather than injecting with a nee- die into their skin numerous times a day. Infusion ports employ a canula or tube inserted subcutaneously, and the patient injects the drug into the injection port adhering to their skin rather than directly into their cutaneous tissue, see e.g. US 9,987,476 which also discloses an injection port device provided with an additional canula allowing a sensor device to be inserted at a distance from the drug delivery canula. US 2016/0271382 and US 2011/0054390 show further examples of patch devices comprising an infusion cannula and a subcutaneous sensor device arranged at a distance from each other. EP 2 254 622 discloses a combined patch device and inserter assembly in which a connector part comprises a fluid patch which may be provided with a sensor allowing fluid in the fluid patch to come in contact with the sensor. Having regard to the above, it is a first object of the present invention to provide a skin- mountable drug delivery port which incorporates a sensor device in a user friendly and cost- effective way. It is a further object of the invention to provide a skin-mountable drug delivery port which helps patient overcome their fear for needles. It is a yet further object of the invention to provide methods and devices allowing an infusion fault to be detected.

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 a first aspect of the invention a patch device is provided, comprising a base portion having a mounting surface adapted to be mounted on a skin surface of a patient, e.g. by adhesive means, and a combined catheter structure which in an operational state is adapted to protrude from the mounting surface, the combined catheter structure comprising a distal end adapted to be arranged in a patient’s subcutaneous tissue. The combined catheter structure comprises a catheter lumen having a distal opening, and a sensor adapted to generate a signal indicative of a parameter value of a body fluid. The patch device further comprises an external fluid port in flow communication with the first catheter and adapted to receive an outlet of a drug delivery device, whereby in a mounted state a fluid communication is provided between the external fluid port and the patient subcutaneously tissue.

By this arrangement a patch device is provided which with a single combined catheter structure provides both an injection port and a sensor functionality. The patch device will typically be supplied to the user with the combined catheter structure in a non-protruding state or with a combined catheter structure adapted to be mounted on the base portion after the base portion has been mounted on a skin surface, the combined catheter structure subsequently being introduced subcutaneously. In this way a “single-site” patch device is provided combining drug infusion and sensor functionality at a common location. The sensor may be a CGM sensor. The term “patch device” also covers assemblies such as two-units embodiments comprising e.g. a mounting portion and a thereto mountable electronics portion.

The sensor may be arranged in the vicinity of the catheter lumen distal opening, e.g. within 1 mm, within 2 mm, within 3 mm or within 5 mm. The distance between the catheter lumen distal opening and the sensor may e.g. be calculated from the proximal-most portion of the catheter lumen distal opening and the distal-most portion of the sensor perse., e.g. the glucose reactive portion of a CGM sensor arrangement. In an exemplary embodiment the patch device further comprises processor circuitry operatively connected to the sensor and adapted to receive sensor generated signals. The processor circuitry may be adapted to operate the sensor corresponding to a standard operational state corresponding to the sensor being arranged in a natural subcutaneous environment, and an adjusted operational state corresponding to the sensor being arranged in a subcuta- neous environment in which an amount of a given drug has been injected via the catheter distal opening. Typically, in the adjusted operational state the sensor provides a less precise detection of parameter values but is less influenced by the presence of a given drug such as an insulin formulation. The term “adjusted operational state” may cover a plurality of different adjusted states. For a given operational state the adjustment may relate to the sensor ele- ment per se, or it may relate to how sensor element output values are treated by software algorithms, or both.

The patch device may be provided with detection means operatively connected to the processor circuitry and adapted to determine an injection condition indicative of an amount of drug being injected into the external fluid port, e.g. in the form of a switch or contact able to detect that a drug delivery device has engaged the fluid port, or in the form of a flow sensor adapted to detect that an amount of drug is being injected through the catheter lumen. The processor circuitry may be adapted to operate the sensor corresponding to the adjusted operational state when an injection condition has been detected. A flow sensor may be utilized to determine, at least approximately, the amount of injected fluid, this allowing one of a plurality of adjusted operational states to be selected.

In an exemplary embodiment the patch device is provided with detection means operatively connected to the processor circuitry and adapted to determine an injection condition indica- tive of an amount of drug being injected into the external fluid port, the processor circuitry comprising transmitter circuitry for transferring data to an external receiver: (i) measuring da- ta based on sensor signals, and (ii) injection condition data indicative of an amount of drug being injected into the external fluid port. In this way calculations taking into account the presence of injected fluid in the vicinity of the sensor can be performed in an external device. The patch device may be provided in combination with a drug delivery device, the drug delivery device comprising a distal end portion with a drug outlet adapted to be arranged in fluid communication with the catheter lumen via the external fluid port. The drug delivery device comprises wireless transmission means adapted to transmit dose data indicative of an amount of drug being injected into the external fluid port. The processor circuitry is adapted to receive the dose data and control the sensor operational state based on the received dose data. Depending on the size of the dose one of a plurality of adjusted operational states may be selected.

The processor circuitry may comprise transmitter circuitry for transferring measuring data based on sensor signals to an external receiver, e.g. in the form of raw sensor data for further processing, or processed data representing actual values, e.g. blood glucose (BG) values. Alternatively or in addition, data indicating that an amount of drug has been injected could be used to inform a user that for a given period of time the sensor has been operating in an adjusted or non-precise operational state, e.g. when received by a display device such as a smartphone running an app adapted to receive and display CGM sensor data from the patch device.

In exemplary embodiments the patch device is provided in combination with a drug delivery device, the drug delivery device comprising a distal end portion with a drug outlet adapted to be arranged in fluid communication with the catheter lumen via the external fluid port. The external fluid port and the end portion may be adapted to engage each other in a form fitting relationship securing a predetermined orientation of the drug delivery device relative to the base portion. The patch device and drug delivery device combination may be designed such that the external fluid port and the drug delivery device end portion prior to engagement comprise no user-visible needle.

For example, the external fluid port may comprise an initially hidden pointed hollow needle and the drug outlet may comprise a needle-penetratable septum. Alternatively, the drug outlet may comprise an initially hidden pointed hollow needle with the external fluid port com- prising a needle-penetratable septum. As a further alternative a needle-free flow communication can be established between the drug delivery device and the external fluid port, e.g. comprising elastomeric valve members which are controlled by pressure and/or engagement In a second aspect of the invention a patch device is provided in combination with a drug delivery device. The patch device comprises a base portion having a mounting surface adapted to be mounted on a skin surface of a patient, and a catheter which in an operational state is adapted to protrude from the mounting surface, the catheter comprising a distal end adapted to be arranged in a patient’s subcutaneous tissue. The catheter comprises a catheter lumen having a distal opening. The patch device further comprises an external fluid port in flow communication with the catheter and adapted to receive an outlet of the drug delivery device, whereby in a mounted state a fluid communication is provided between the external fluid port and the patient subcutaneously tissue. The external fluid port and the drug delivery device end portion comprise prior to engagement no user-visible needle.

For example, the external fluid port may comprise an initially hidden pointed hollow needle and the drug outlet may comprise a needle-penetratable septum. Alternatively, the drug outlet may comprise an initially hidden pointed hollow needle with the external fluid port comprising a needle-penetratable septum. As a further alternative a needle-free flow communica- tion can be established between the drug delivery device and the external fluid port, e.g. comprising elastomeric valve members which are controlled by pressure and/or engagement.

In this way subcutaneous drug injections can be performed without the user seeing a needle. In a further aspect of the invention a method of detecting an infusion fault is provided, the method comprising the steps of (i) establishing a combined infusion and detection site at which a fluid drug can be infused subcutaneously and a body fluid parameter value can be sensor-detected in close proximity to each other, (ii) providing a mathematical model allowing an expected parameter value response at the combined site to be calculated, the mathemat- leal model comprising a disturbance component taking into consideration the influence of infused drug on a sensor at the combined site, (ill) for a given amount of drug and a given period of time and using the mathematical model, calculate an expected parameter value response at the combined site, (iv) for the given period of time detect a parameter value response to an assumed infusion of the given amount of drug, (v) compare the calculated ex- pected parameter value response and the detected parameter value response, (vi) determine based on predetermined criteria whether or not the detected parameter value response cor- responds to the calculated expected parameter value response, and (vii) if the detected parameter value response does not correspond to the calculated expected parameter value response, indicate to a user that an infusion fault has taken place. Indeed, the above description of which values are calculated/detected respectively compared also covers the arithmetic “alternatives”, i.e. calculating the amount of disturbance and compare it with the difference between the calculated non-disturbed parameter value response (e.g. glucose concentration) and the actually measured parameter value response to the infused amount of drug (e.g. amount of insulin).

In this way, using parameter detection from a combined infusion and sensor site, a fault detection algorithm can by-pass the physiological delay in drug action, e.g. insulin action, and the resulting delay in fault detection. Therefore, this approach provides faster feedback than current fault detection algorithms based on e.g. CGM only. In exemplary embodiments the method is performed using the above-described patch devices.

The calculated and detected response may be in the form of one or more values for the given period of time, e.g. for a CGM sensor a plurality of values would be used allowing calculated and detected pseudo-continuous responses to be compared.

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. The drug may be a single drug compound or a premixed or co-formulated multiple drug compounds drug agent from a single reservoir. Representative drugs include pharmaceuticals such as peptides (e.g. insulins, insulin containing drugs, GLP-1 containing drugs as well as derivatives 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 description of the exemplary embodiments reference will be made to the use of insulin and GLP-1 containing drugs, this including analogues thereof as well as combinations with one or more other drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following the invention will be further described with reference to the drawings, wherein fig. 1A shows a perspective unit of a first embodiment of a patch device, fig. 1B shows a partial cross-sectional view of the patch device of fig. 1A, fig. 1C shows in cross-sectional view the patch device of fig. 1A in combination with a drug delivery device, fig. 1D shows in cross-sectional view the patch and drug delivery devices of fig. 1C in a first state of engagement, fig. 1E shows in cross-sectional view the patch and drug delivery devices of fig. 1C in a second state of engagement, fig. 2A shows in cross-sectional view a second embodiment of patch device in combination with a drug delivery device provided with a shield unit, fig. 2B shows in cross-sectional view the patch and drug delivery devices of fig. 2A in a first state of engagement, fig. 2C shows in cross-sectional view the patch and drug delivery devices of fig. 2A in a second state of engagement, fig. 3A shows in cross-sectional view a third embodiment of patch device in combination with a drug delivery device provided with a duckbill, fig. 3B shows in cross-sectional view the patch and drug delivery devices of fig. 3A in a first state of engagement, fig. 3C shows in cross-sectional view the patch and drug delivery devices of fig. 3A in a second state of engagement, and figs. 4A-4C show different glucose responses to (assumed) infusion of insulin.

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 representations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only. When the term member or ele- ment 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 sub-components just as two or more of the described components could be provided as unitary components, e.g. manufactured as a single injection moulded part. When it is defined that members are mounted axially free to each other it gen- erally indicates that they can be moved relative to each other, typically between defined stop positions whereas when it is defined that members are mounted rotationally free to each oth- er it generally indicates that they can be rotated relative to each other either freely or between defined stop positions. The terms “assembly” and “subassembly” do not imply that the described components necessarily can be assembled to provide a unitary or functional assembly or subassembly during a given assembly procedure but is merely used to describe components grouped together as being functionally more closely related.

Referring to figs. 1A-1E a first skin-mountable patch port device 100 is shown, providing in combination a subcutaneous CGM sensor and a drug injection port. More specifically, the patch device comprises a base portion 101 having a mounting surface 102 with an adhesive layer adapted to be mounted on a skin surface of a patient, a combined catheter structure 110, a sensor 120 with associated sensor circuitry 125, and a centrally arranged injection port 130 for a drug delivery device, e.g. of the pen type.

In the shown embodiment the combined catheter in combination with an insertion needle 111 projects from the mounting surface in an initial state as provided to the user and is adapted to be inserted subcutaneously as the patch device is mounted on a skin surface. Alternatively, the combined catheter may initially be arranged in a non-projecting position and be adapted to be introduced subcutaneously after the mounting surface has been attached to a skin surface. The combined catheter structure 110 comprises a distal end 112 adapted to be arranged in a patient’s subcutaneous tissue and comprises a catheter lumen 113 (initially occupied by the insertion needle) having a distal opening 115, e.g. at the distal end of the catheter. Forming part of the combined catheter the patch device further comprises a sensor 120 adapted to generate a signal indicative of a parameter value of a body fluid. In the shown embodiment the sensor is in the form of a flex-print 121 having a distal end portion carrying the parameter sensing structures 120 (i.e. the sensor perse) and a proximal portion 122 on which a number of electric terminals are arranged allowing the sensing structures to be connected to corresponding sensor circuitry 125 and power source 126 via conductors formed on the flex-print The sensor distal portion of the flex-print with the sensing structures is attached to the exterior surface of a catheter forming the catheter lumen, this allowing the sensing structures to be exposed to subcutaneous body fluids during use. The patch device may be in the form of a two-unit embodiment comprising e.g. a mounting portion with an in- sertable combined catheter and a thereto mountable electronics portion. Alternatively the patch may be unitary as in the shown embodiment and be intended for single use. An external user-accessible fluid port is in flow communication with the catheter and adapted to receive an outlet of a drug delivery device, whereby in a mounted state a fluid communica- tion is provided between the external fluid port and the patient subcutaneously tissue. In the shown first embodiment the patch device 100 comprises a patch body member 101 with a central bore 105 in which an upward-oriented pointed hollow port needle 131 mounted in flow communication (see fig. 1C) with the catheter lumen is mounted, the needle being covered by an elastomeric septum 132 formed as part of a spring-biased carrier disc 133, the disc being arranged to travel in the bore between an initial proximal position with the septum covering the pointed needle end and an actuated distal position in which the needle protrudes through the septum, the disc being biased towards the proximal position by a helical spring 134. The bore proximal end is adapted to receive a pen distal end 150 in a formfitting en- gagement, this minimizing pivoting movement of the pen during insertion and thus reduces the risk of damage to the port needle 131. The injection device used is a traditional pen injector not fitted with a needle unit and thus comprising a distal-most needle-penetratable cartridge septum 152. Fig. 1D shows the patch device 100 in a mounted state with the combined catheter structure 110 inserted subcutaneously, the insertion needle 111 withdrawn and the pen distal end 150 arranged in the injection port with the two septa abutting each other.

As the injection device is pushed down, the spring-loaded disc 133 fitted with the protective elastomeric septum 132 is pressed down as shown in fig. 1E. Thereby the hollow needle 131 inside the patch penetrates first the protective rubber septum 132 of the patch disc and then the septum 152 of the drug cartridge in the injector, whereby a fluid connection is established between the drug cartridge 155 in the injection device and the catheter 110 in the skin. The injection can then be performed and when the injection device 150 is removed afterwards, the hollow needle 131 is pulled out of first the cartridge septum and as the spring-load ensures the disc 133 with the protective elastomeric septum 132 follows the tip of the injection device, the needle is subsequently pulled out (fully or as shown partly) of the patch septum. As the disc with the patch septum reaches its end-of-travel, the cannula is again cov- ered by the protective elastomeric septum 132 as shown in fig. 1D.

Figs. 2A-2C discloses a second specific embodiment of a patch port device 200 in combination with a corresponding injection device 250. The injection device is fitted with a shield needle unit 260 comprising a body member 261 attached to the pen injector and provided with a pointed hollow needle in flow communication with the pen drug cartridge through the cartridge septum 252. The needle distal portion is covered by a spring-biased 264 protective shield 265 comprising a central portion 266 in which a biostatic chamber 267 comprising a rubber compound or sponge-like material soaked with a preservative is provided. In the initial and non-actuated state the pointed needle end 263 is positioned in the preservative ensuring biostatic conditions of the needle.

The patch device 200 comprises a patch body member 201 with a central bore 205 in which a valve housing 231 with an elastomeric needle-penetratable septum member 232 is mounted, the septum member being provided with a valve head 234 which in an initial state engages a valve seat in the valve housing to provide a closed valve. The valve housing comprises a fluid chamber 235 in flow communication with the catheter lumen 213, the flow communication being controlled by the valve. The bore proximal end forms a port socket 206 adapted to receive the pen distal end in a formfitting engagement. The patch device 200 further comprises a combined catheter 210 and associated sensor circuitry 225 generally identical to the corresponding structures in the above-described first patch device 100.

Fig. 2B shows the needle shield central portion 266 having just abutted the port septum member 232.

As shown in fig. 2C, when pressed against the patch receiving socket area 206 in formfitting engagement, the needle shield 265 of the injection device is pushed back and the hollow needle distal end 263 penetrates the port septum member 232. To ensure proper and stable alignment during drug injection the injection device distal end (here in the form of the central distal end 268 of the shield needle unit body member 266) may couple to the patch device port via a snap coupling.

As the needle shield 265 is pushed back, the needle distal end 263 exits the biostatic chamber 267 of the needle shield and enters through the elastomeric needle-penetratable septum member 232 with the integrated valve head. As the needle penetrates the valve head the needle-shield front pushes down the valve 234, thereby opening a clearance between the valve housing and the valve head. The tip of the needle enters the fluid chamber 235 in flow communication with the catheter lumen 213 and injection can be performed.

During injection, drug is out-dosed from the injection device into the fluid chamber. As this chamber fills, the drug passes through the clearance between valve housing and valve head and exits through a small outlet channel into the catheter lumen and proceeds into the subcutaneous tissue of the user. After the desired amount of drug has been injected the pen device is retracted thus overcoming the snap coupling. As the needle is pulled out of the socket after injection and the shield pressure on the elastomeric septum member is released, the elasticity of the member and the friction between the needle and the elastomeric valve head pulls the valve head proxi- mally to seal the clearance between valve head and valve housing. As the valve head meets the housing and the valve is sealed, the needle starts sliding out of the rubber valve head and out of the rubber membrane, while the needle shield simultaneously moves forward, driven by the needle shield spring. When the needle is completely covered by the needle shield, the needle shield leaves the patch receiving socket.

Figs. 3A-3C discloses a third specific embodiment of a patch device 300 in combination with a corresponding injection device 350, the injection device as well as the patch device comprising duckbill valves 353, 333 instead of needle and septum. To ensure sealing during storage prior to use the injection device duckbill valve may be manufactured with an initially closed septum adapted to brake during first use (not shown). Alternatively, an embodiment using a normal cartridge layout with a septum could be used, the duckbill forming part of a valve unit comprising a proximal back needle adapted to penetrate the drug cartridge septum. A circumferential skirt 351 surrounds the tip of the injection device duckbill valve.

The patch device 300 comprises a patch body 301 member with a central bore 305 in which a valve housing 331 with an elastomeric septum member 332 with a central duckbill 333 is mounted, the septum member being further provided with a valve head 334 which in an initial state engages a valve seat in the valve housing to provide a closed valve. The valve housing comprises a fluid chamber 335 in flow communication with the catheter lumen 313, the flow communication being controlled by the valve. The bore proximal end forms a port socket 306 adapted to receive the pen distal end in a formfitting engagement. The patch device 300 further comprises a combined catheter 310 and associated sensor circuitry 325 generally identical to the corresponding structures in the above-described first patch device 100.

Fig. 3B shows injection device duckbill 353 having just abutted the port septum member 232.

As shown in fig. 3C, when the user presses the injection device distal end against the patch receiving socket area the injection device housing (or valve unit housing) moves into the re- ceiving socket of the patch where it may snap into engagement by corresponding snap lock coupling means (not shown). The circumferential skirt 351 surrounding the tip of the injection device duckbill valve is pressed against the upper surface of the elastomeric septum member 332 to seal the transition zone. The skirt can be designed such that the sealing pressure counters some of the closing pressure of the duckbill. During injection drug is out-dosed from the injection device though the valve unit if fitted with a valve unit, and out through the duckbill valve of the injection device. This leads to a rapid build-up of hydrostatic pressure in the small volume confined by the two valves and the skirt, which cause the patch duckbill valve 333 to open into the fluid chamber 335. The sealing pressure of the skirt also pushes the patch duckbill valve 333 (which is e.g. suspended in the integrated elastomeric septum member) a little down inside the patch valve housing, which opens a small clearance between the duckbill valve head 334 and the valve housing 331. As this chamber fills, the drug passes through the clearance between valve housing and duckbill valve head and exits through a small channel into the catheter lumen and proceeds into the subcutaneous tissue of the user.

When reaching end-of-dose of the injection, the pressure on the drug cartridge and thus the pressure difference over the injection device valve drops, and the injection device valve closes. As the injection-device/valve unit is then pulled out of the socket, the pressure difference over the patch duckbill valve drops, causing it to close. At the same time the sealing pressure of the skirt is removed, enabling the duckbill valve-head to be pulled up by the suspending elastomeric membrane to seal the clearance between duckbill valve head and valve housing.

In the above-described embodiments the patch device comprises processor circuitry opera- lively connected to the sensor and adapted to receive sensor generated signals. As appears, the sensor 120 is arranged in the vicinity of the catheter lumen outlet which means that after injection of a volume of drug the sensor may be influenced by the drug. To address this issue, the processor circuitry may be adapted to operate the sensor corresponding to a standard operational state corresponding to the sensor being arranged in a natural subcutaneous environment, and an adjusted operational state corresponding to the sensor being arranged in a subcutaneous environment in which an amount of a given drug has been injected via the catheter distal opening. Typically, in the adjusted operational state the sensor provides a less precise detection of parameter values but is less influenced by the presence of a given drug such as an insulin formulation. For a given operational state the adjustment may relate to the sensor element per se, or it may relate to how sensor element output values are treated by software algorithms, or both. The sensor may be a CGM sensor. Although used to illustrate a different aspect of the present invention, in fig. 4B the full line could represent glucose sensor circuitry response output after an infused insulin amount with the sensor being operated in the standard operational state, whereas in fig. 4A the full line could represent glucose sensor circuitry response output after an infused insulin amount with the sensor being operated in an adjusted operational state.

The patch device may be provided with detection means operatively connected to the processor circuitry and adapted to determine an injection condition indicative of an amount of drug being injected into the external fluid port, e.g. in the form of a switch or contact able to detect that a drug delivery device has engaged the fluid port, or in the form of a flow or pressure sensor adapted to detect that an amount of drug is being injected through the catheter lumen. The processor circuitry is adapted to operate the sensor corresponding to the adjusted operational state when an injection condition has been detected.

The patch device may be provided in combination with a drug delivery device, the drug delivery device comprising a distal end portion with a drug outlet adapted to be arranged in fluid communication with the catheter lumen via the external fluid port. The drug delivery device comprises wireless transmission means adapted to transmit dose data indicative of an amount of drug being injected into the external fluid port. The processor circuitry is adapted to receive the dose data and control the sensor operational state based on the received dose data.

The processor circuitry may comprise transmitter circuitry for transferring measuring data based on sensor signals to an external receiver, e.g. in the form of raw sensor data for further processing, or processed data representing actual values, e.g. blood glucose (BG) values.

In a further aspect of the invention a method of detecting an infusion site failure will be de- scribed, the method being based on the provision of a combined infusion and detection site at which a fluid drug can be infused subcutaneously and a body fluid parameter value can be detected by a sensor in close proximity to each other, e.g. within a few millimeters. The combined site may be provided by a patch device as described above. Insulin infusion site failures are a common issue in insulin pump therapy in diabetes. Such failures may be caused by catheter kinking, insulin leakage, site inflammation, infusion set detachment or occlusions that lead to increased blood glucose concentrations. Infusion site failures can be hard to distinguish from physiological changes, and the delay in insulin action leads to late fault detection when using continuous glucose monitor (CGM) data. The prospect of fully automatic closed-loop systems induces a risk of a late detection of adverse events, as patients place increasing trust in their devices and will potentially become less aware of infusion site failures. Infusion site failures reduce the treatment quality and can, if left undetected, lead to diabetic ketoacidosis, an acute complication that may be fatal. Infusion site failures are the most common issue with insulin pump therapy and will continue to occur with other treatment forms utilizing infusion sets, e.g. fully automatic closed-loop sys- terns or CGM ports. This calls for automated real-time fault detection systems to ensure a timely alert for safe and effective treatment

To avoid infusion site failures, current protocols require the user to change their infusion set every few days. Several studies have shown that insulin infusion sets may be used over longer periods of time for some individuals. As a result, switching infusion sets at a fixed interval may lead to unnecessary disposal of functioning sets. This is both costly for the user and a burden for the environment. With reliable, timely fault-detection, only malfunctioning sets would be discarded, and the user would be able to use infusion sets over longer time periods without the risk of lowering treatment quality.

Over the time infusion sets are in use, insulin absorption dynamics have been shown to change. Inaccurate knowledge of insulin absorption kinetics may lead to suboptimal treatment as dose guidance algorithms are estimating doses based on faulty knowledge of how the drug is absorbed. An estimate of the current insulin absorption may be used as feedback to improve dose guidance.

Correspondingly, a solution to the problem is to employ data from a combined infusion and detection site at which a fluid drug can be infused subcutaneously and a body fluid parameter value can be detected by a sensor in close proximity to each other. In an exemplary embodiment the proposed solution uses sensor readings from a single-site device and insulin infusion data, e.g. connected pen data or insulin pump data, as input.

When insulin is infused using a single-site device, the raw sensor measurements of glucose concentration are compromised as the sensor is arranged in close proximity to the drug infu- sion outlet. This can be the result of e.g. dilution or chemical reactions affecting the sensor in the period following insulin infusion. The correlation between dose and timing of insulin infu- sion and the resulting change in glucose measurements can be used to detect whether insulin was infused successfully.

With readings from a single-site device, fault detection algorithms can by-pass the physiolog- leal delay in insulin action and the resulting delay in fault detection. Therefore, this approach provides faster feedback than current fault detection algorithms based on CGM only. The proposed solution leads to safer and more efficacious treatment by giving timely feedback to the infusion set user and to automated dose guidance algorithms, e.g. the control algorithm in CL systems.

The fault detection algorithm may be fed additional input to account for other conditions impacting glucose concentration (e.g. a specific time of day, level of physical activity, meal size etc.). The additional inputs are gathered from connected devices or sensors (e.g. mobile phone, wearable biosensors).

Exemplary embodiment

A model-based algorithm for fault-detection on single-site device used for insulin therapy is provided, e.g. insulin pump therapy, closed-loop systems, docking/CGM port for insulin infusion. The proposed algorithm will identify infusion site failures and changes in insulin absorp- tion. Output from the algorithm can be fed to alarm systems, that notify the user to infusion site failures. The algorithm can likewise provide input to closed-loop algorithms enabling adaptive and safe infusion strategies following changes in insulin absorption.

Implementation of the estimator A disturbance estimation algorithm is used to quantify the change in CGM measurements following the insulin injection. The disturbance estimator is a Kalman filter (KF). The model in the KF consists of a physiological state-space model for interstitial glucose concentrations. The state-space model can be linear or nonlinear and it can be in discrete-time or continuous-time. Below is the implementation of the discrete-time linear state-space model.

is the vector of states and IG is one of the states in the vector. « is the input

that can be insulin. « can also contain e.g. activity level and measured or announced meals, w and v are the process noise and measurement noise, respectively, y is the estimated system output, the CGM measurement.

The estimated change in CGM is calculated as the difference between the estimated CGM value, , and the measured CGM value, y_k :

The expected change in CGM is calculated as a function of the local disturbance induced by insulin. The function may be extended to include other disturbance sources e.g. level of physical activity.

The difference between estimated and expected change in CGM should approximate zero. The difference is evaluated with a statistical test to identify significant deviance from zero. The change detection is in place only during the time interval following insulin

injections, where the local effect of the injection is known to be active. In fig. 4A the dotted response line represents the disturbed expected/calculated glucose response to the infusion of the indicated amount of insulin. The full response line represents the actually measured glucose response to the assumed infused insulin amount. As appears, the measured response does not correspond to the calculated response, this indicating an infusion set fault.

In fig. 4B the full response line represents the actually measured glucose response to the actually infused insulin amount As appears, the measured response corresponds to the calculated response, this indicating that the insulin has been successfully infused. In fig. 4C the full response line represents the actually measured glucose response to the actually infused insulin amount. However, as appears, the measured response only partly corresponds to the calculated response, this indicating a condition of reduced insulin absorption. In the above description of exemplary 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 patch device (100, 200, 300) comprising: a base portion (101 , 201 , 301) having a mounting surface adapted to be mounted on a skin surface of a patient, a combined catheter structure (110, 210, 310) which in an operational state is adapted to protrude from the mounting surface, the combined catheter structure comprising a distal end adapted to be arranged in a patient’s subcutaneous tissue, comprising: a catheter lumen (113, 213, 313) having a distal opening, and a sensor (120) adapted to generate a signal indicative of a parameter value of a body fluid, an external fluid port (130, 206, 306) in flow communication with the catheter and adapted to receive an outlet of a drug delivery device, whereby in a mounted state a fluid communication is provided between the external fluid port and the patient subcutaneously tissue.

2. A patch device as in claim 1 , wherein the sensor (120) is arranged in the vicinity of the catheter lumen distal opening (115).

3. A patch device as in claim 1 or 2, further comprising: processor circuitry (125, 225, 325) operatively connected to the sensor and adapted to receive sensor generated signals.

4. A patch device as in claim 3, wherein the processor circuitry is adapted to operate the sensor corresponding to: a standard operational state corresponding to the sensor being arranged in a natural subcutaneous environment, and an adjusted operational state corresponding to the sensor being arranged in a subcutaneous environment in which an amount of a given drug has been injected via the cathe- ter lumen distal opening (115).

5. A patch device as in claim 4, further comprising: detection means operatively connected to the processor circuitry and adapted to determine an injection condition indicative of an amount of drug being injected into the external fluid port, wherein the processor circuitry is adapted to operate the sensor corresponding to the adjusted operational state when an injection condition has been detected.

6. A patch device as in claim 4, in combination with a drug delivery device, the drug delivery device comprising a distal end portion with a drug outlet adapted to be arranged in fluid communication with the catheter lumen via the external fluid port, wherein: the drug delivery device comprises wireless transmission means adapted to transmit dose data indicative of an amount of drug being injected into the external fluid port, and the processor circuitry is adapted to receive the dose data and control the sensor operational state based on the received dose data.

7. A patch device as in any of claims 2-6, wherein the processor circuitry comprises: transmitter circuitry for transferring measuring data based on sensor signals to an external receiver.

8. A patch device as in claim 3, further comprising: detection means operatively connected to the processor circuitry and adapted to de- termine an injection condition indicative of an amount of drug being injected into the external fluid port, the processor circuitry comprising transmitter circuitry for transferring to an external receiver

(i) measuring data based on sensor signals, and

(ii) injection condition data indicative of an amount of drug being injected into the external fluid port.

9. A patch device as in any of claims 1-8, in combination with a drug delivery device (150, 250, 350), the drug delivery device comprising a distal end portion with a drug outlet adapted to be arranged in fluid communication with the catheter lumen via the external fluid port.

10. A patch device in combination with a drug delivery device as in claim 9, wherein the external fluid port and the end portion are adapted to engage each other in a form fitting relationship securing a predetermined orientation of the drug delivery device relative to the base portion.

11. A patch device in combination with a drug delivery device as in claim 9 or 10, wherein the external fluid port and the end portion prior to engagement comprise no user-visible needle.

12. A patch device in combination with a drug delivery device as in claim 11 , wherein the external fluid port comprises an initially hidden pointed hollow needle (131) and the drug outlet (152) comprises a needle-penetratable septum.

13. A patch device in combination with a drug delivery device as in claim 11 , wherein the drug outlet comprises an initially hidden pointed hollow needle (262) and the external flu- id port comprises a needle-penetratable septum (232).

14. A patch device in combination with a drug delivery device as in claim 11 , wherein a needle-free flow communication (253, 233) can be established between the drug delivery device and the external fluid port.

15. A method of detecting an infusion fault, comprising the steps: using the patch device as in any of claims 1-14, establishing a combined infusion and detection site at which a fluid drug can be infused subcutaneously and a body fluid pa- rameter value can be sensor-detected in close proximity to each other, providing a mathematical model allowing an expected parameter value response at the combined site to be calculated, the mathematical model comprising a disturbance component taking into consideration the influence of infused drug on a sensor at the combined site, for a given amount of drug and a given period of time and using the mathematical model, calculate an expected parameter value response at the combined site, for the given period of time detect a parameter value response to an assumed infusion of the given amount of drug, compare the calculated expected parameter value response and the detected pa- rameter value response, determine based on predetermined criteria whether or not the detected parameter value response conesponds to the calculated expected parameter value response, and if the detected parameter value response does not conespond to the calculated expected parameter value response, indicate to a user that an infusion fault has taken place.