Patent Description:
There are a wide variety of medical treatments that include the administration of a therapeutic fluid in precise, known amounts at predetermined intervals. Devices and methods exist that are directed to the delivery of such fluids, which may be liquids or gases, are known in the art.

One category of such fluid delivery devices includes insulin injecting pumps developed for administering insulin to patients afflicted with type I, or in some cases, type II diabetes. Some insulin injecting pumps are configured as portable or ambulatory infusion devices can provide continuous subcutaneous insulin injection and/or infusion therapy as an alternative to multiple daily injections of insulin via a syringe or an insulin pen. Such pumps are worn by the user and may use replaceable cartridges. In some embodiments, these pumps may also deliver medicaments other than, or in addition to, insulin, such as glucagon, pramlintide, and the like. Examples of such pumps and various features associated therewith include those disclosed in <CIT> and <CIT> and <CIT>; <CIT>; <CIT>; and <CIT>.

Ambulatory infusion pumps for delivering insulin or other medicaments can be used in conjunction with blood glucose monitoring systems, such as blood glucose meters (BGMs) and continuous glucose monitoring devices (CGMs). A CGM provides a substantially continuous estimated blood glucose level through a transcutaneous sensor that estimates blood analyte levels, such as blood glucose levels, via the patient's interstitial fluid. CGM systems typically consist of a transcutaneously-placed sensor, a transmitter and a monitor.

Ambulatory infusion pumps typically allow the patient or caregiver to adjust the amount of insulin or other medicament delivered, by a basal rate or a bolus, based on blood glucose data obtained by a BGM or a CGM, and in some cases include the capability to automatically adjust such medicament delivery. Some ambulatory infusion pumps may include the capability to interface with a BGM or CGM such as, e.g., by receiving measured or estimated blood glucose levels and automatically adjusting or prompting the user to adjust the level of medicament being administered or planned for administration or, in cases of abnormally low blood glucose readings, reducing or automatically temporarily ceasing or prompting the user temporarily to cease or reduce insulin administration. These portable pumps may incorporate a BGM or CGM within the hardware of the pump or may communicate with a dedicated BGM or CGM via wired or wireless data communication protocols, directly and/or via a device such as a smartphone. One example of integration of infusion pumps with CGM devices is described in <CIT>.

As noted above, insulin or other medicament dosing by basal rate and/or bolus techniques could automatically be provided by a pump based on readings received into the pump from a CGM device that is, e.g., external to the portable insulin pump or integrated with the pump as a pump-CGM system in a closed-loop or semi-closed-loop fashion. With respect to insulin delivery, some systems including this feature can be referred to as artificial pancreas systems because the systems serve to mimic biological functions of the pancreas for patients with diabetes.

Exercise is known to affect glucose levels in unpredictable ways and can cause challenges for accurate closed-loop or semi-closed loop treatment of diabetes even with use of a CGM. The body's response to exercise varies depending upon a number of factors, including intensity of exercise. For example, aerobic exercise tends to lower blood glucose while anaerobic exercise tends to increase blood glucose. With closed-loop therapy, the control algorithm will generally increase the delivery of insulin upon detecting a rise in glucose level after the user eats. If a user then begins to exercise aerobically after eating, the exercise plus the increase in insulin can cause a severe drop in blood glucose. The variability of the body's response to exercise makes accounting for such circumstances with closed loop therapy challenging.

<NPL>) and <NPL>) disclose a closed loop diabetes therapy system, which accounts for exercise in such therapy and comprises inner and outer loops relating to insulin on board (IOB), the natures of these inner loops being different, and the effect of the inner loops on the calculation being different from the claimed invention.

Disclosed herein are apparatuses that account for exercise in closed loop insulin delivery systems, namely, a system for closed loop diabetes therapy as set out in claim <NUM>. Rather than increasing a target insulin on board (IOB) as glucose levels rise, which would increase insulin delivery to address the raised glucose levels, the apparatuses and methods disclosed herein address exercise-induced glucose level increases by reducing the target IOB within the closed loop. By reducing the target IOB, the algorithm responds less aggressively to pre-exercise food, and does not build up the IOB that could potentially contribute to undesirably low glucose levels once the exercise also begins lowering glucose levels.

The invention may be more completely understood in consideration of the following detailed description of various embodiments of the invention in connection with the accompanying drawings, in which:.

<FIG> depicts an embodiment of a medical device according to the disclosure. In this embodiment, the medical device is configured as a pump <NUM>, such as an infusion pump, that can include a pumping or delivery mechanism and reservoir for delivering medicament to a patient and an output/display <NUM>. The output/display <NUM> may include an interactive and/or touch sensitive screen <NUM> having an input device such as, for example, a touch screen comprising a capacitive screen or a resistive screen. The pump <NUM> may additionally or instead include one or more of a keyboard, a microphone or other input devices known in the art for data entry, some or all of which may be separate from the display. The pump <NUM> may also include a capability to operatively couple to one or more other display devices such as a remote display, a remote control device, a laptop computer, personal computer, tablet computer, a mobile communication device such as a smartphone, a wearable electronic watch or electronic health or fitness monitor, or personal digital assistant (PDA), a CGM display etc..

In one embodiment, the medical device can be an ambulatory insulin pump configured to deliver insulin to a patient. Further details regarding such pump devices can be found in <CIT>.

In other embodiments, the medical device can be an infusion pump configured to deliver one or more additional or other medicaments to a patient.

<FIG> illustrates a block diagram of some of the features that can be used with embodiments, including features that may be incorporated within the housing <NUM> of a medical device such as a pump <NUM>. The pump <NUM> can include a processor <NUM> that controls the overall functions of the device. The infusion pump <NUM> may also include, e.g., a memory device <NUM>, a transmitter/receiver <NUM>, an alarm <NUM>, a speaker <NUM>, a clock/timer <NUM>, an input device <NUM>, a user interface suitable for accepting input and commands from a user such as a caregiver or patient, a drive mechanism <NUM>, an estimator device <NUM> and a microphone (not pictured). One embodiment of a user interface is a graphical user interface (GUI) <NUM> having a touch sensitive screen <NUM> with input capability. In some embodiments, the processor <NUM> may communicate with one or more other processors within the pump <NUM> and/or one or more processors of other devices, for example, a continuous glucose monitor (CGM), display device, smartphone, etc. through the transmitter/receiver. The processor <NUM> may also include programming that may allow the processor to receive signals and/or other data from an input device, such as a sensor that may sense pressure, temperature or other parameters.

<FIG> depict another pump system including a pump <NUM> that can be used with embodiments. Drive unit <NUM> of pump <NUM> includes a drive mechanism <NUM> that mates with a recess in disposable cartridge <NUM> of pump <NUM> to attach the cartridge <NUM> to the drive unit <NUM>. Pump system <NUM> can further include an infusion set <NUM> having a connector <NUM> that connects to a connector <NUM> attached to pump <NUM> with tubing <NUM>. Tubing <NUM> extends to a site connector <NUM> that can attach or be pre-connected to a cannula and/or infusion needle that punctures the patient's skin at the infusion site to deliver medicament from the pump <NUM> to the patient via infusion set <NUM>. In some embodiments, pump can include a user input button <NUM> and an indicator light <NUM> to provide feedback to the user.

In one embodiment, pump <NUM> includes a processor that controls operations of the pump and, in some embodiments, may receive commands from a separate device for control of operations of the pump. Such a separate device can include, for example, a dedicated remote control or a smartphone or other consumer electronic device executing an application configured to enable the device to transmit operating commands to the processor of pump <NUM>. In some embodiments, processor can also transmit information to one or more separate devices, such as information pertaining to device parameters, alarms, reminders, pump status, etc. In one embodiment pump <NUM> does not include a display but may include one or more indicator lights <NUM> and/or one or more input buttons <NUM>. Pump <NUM> can also incorporate any or all of the features described with respect to pump <NUM> in <FIG>. Further details regarding such pumps can be found in <CIT> and <CIT> and <NUM>] <NUM>/<NUM>.

Pump <NUM> or <NUM> can interface directly or indirectly (via, e.g., a smartphone or other device) with a glucose meter, such as a blood glucose meter (BGM) or a continuous glucose monitor (CGM). Referring to <FIG>, an exemplary CGM system <NUM> according to an embodiment of the present invention is shown (other CGM systems can be used). The illustrated CGM system includes a sensor <NUM> affixed to a patient <NUM> that can be associated with the insulin infusion device in a CGM-pump system. The sensor <NUM> includes a sensor probe <NUM> configured to be inserted to a point below the dermal layer (skin) of the patient <NUM>. The sensor probe <NUM> is therefore exposed to the patient's interstitial fluid or plasma beneath the skin and reacts with that interstitial fluid to produce a signal that can be associated with the patient's blood glucose (BG) level. The sensor <NUM> includes a sensor body <NUM> that transmits data associated with the interstitial fluid to which the sensor probe <NUM> is exposed. The data may be transmitted from the sensor <NUM> to the glucose monitoring system receiver <NUM> via a wireless transmitter, such as a near field communication (NFC) radio frequency (RF) transmitter or a transmitter operating according to a "Wi-Fi" or Bluetooth® protocol, Bluetooth® low energy protocol or the like, or the data may be transmitted via a wire connector from the sensor <NUM> to the monitoring system <NUM>. Transmission of sensor data to the glucose monitoring system receiver by wireless or wired connection is represented in <FIG> by the arrow line <NUM>. Further detail regarding such systems and definitions of related terms can be found in, e.g., <CIT>,<CIT> and <CIT>.

In an embodiment of a pump-CGM system having a pump <NUM>, <NUM> that communicates with a CGM and that integrates CGM data and pump data as described herein, the CGM can automatically transmit the glucose data to the pump. The pump can then automatically determine therapy parameters and deliver medicament based on the data. Such an automatic pump-CGM system for insulin delivery can be referred to as an automated insulin delivery (AID) or an artificial pancreas system that provides closed-loop therapy to the patient to approximate or even mimic the natural functions of a healthy pancreas. In such a system, insulin doses are calculated based on the CGM readings (that may or may not be automatically transmitted to the pump) and are automatically delivered to the patient at least in part based on the CGM reading(s). In various embodiments, doses can be delivered as automated correction boluses and/or automated increases or decreases to a basal rate. Insulin doses can also be administered based on current glucose levels and/or predicted future glucoses levels based on current and past glucose levels.

For example, if the CGM indicates that the user has a high blood glucose level or hyperglycemia, the system can automatically calculate an insulin dose necessary to reduce the user's blood glucose level below a threshold level or to a target level and automatically deliver the dose. Alternatively, the system can automatically suggest a change in therapy upon receiving the CGM data such as an increased insulin basal rate or delivery of a bolus, but can require the user to accept the suggested change prior to delivery rather than automatically delivering the therapy adjustments.

If the CGM data indicates that the user has a low blood glucose level or hypoglycemia, the system can, for example, automatically reduce a basal rate, suggest to the user to reduce a basal rate, automatically deliver or suggest that the user initiate the delivery of an amount of a substance such as, e.g., a hormone (glucagon) to raise the concentration of glucose in the blood, automatically suggest that the user, e.g., ingest carbohydrates and/or take other actions and/or make other suggestions as may be appropriate to address the hypoglycemic condition, singly or in any desired combination or sequence. Such determination can be made by the infusion pump providing therapy or by a separate device that transmits therapy parameters to the infusion pump. In some embodiments, multiple medicaments can be employed in such a system as, for example, a first medicament, e.g., insulin, that lowers blood glucose levels and a second medicament, e.g., glucagon, that raises blood glucose levels.

As with other parameters related to therapy, such thresholds and target values can be stored in memory located in the pump or, if not located in the pump, stored in a separate location and accessible by the pump processor (e.g., "cloud" storage, a smartphone, a CGM, a dedicated controller, a computer, etc., any of which is accessible via a network connection). The pump processor can periodically and/or continually execute instructions for a checking function that accesses these data in memory, compares them with data received from the CGM and acts accordingly to adjust therapy. In further embodiments, rather than the pump determining the therapy parameters, the parameters can be determined by a separate device and transmitted to the pump for execution. In such embodiments, a separate device such as the CGM or a device in communication with the CGM, such as, for example, a smartphone, dedicated controller, electronic tablet, computer, etc. can include a processor programmed to calculate therapy parameters based on the CGM data that then instruct the pump to provide therapy according to the calculated parameters.

A schematic representation of a control algorithm for automatically adjusting insulin delivery based on CGM data is depicted in <FIG>. This figure depicts an algorithm for increasing basal rate that utilizes a cascaded loop. The logic for decreasing basal rate is not depicted. In the depicted embodiment, there is a glucose set-point/command (cmd) that is determined at step <NUM>. The glucose set point is a target value at which the algorithm attempts to maintain a user's blood glucose. This value can vary based on a number of factors, including the user's physiology, whether the user is awake or asleep, how long the user has been awake, etc. In one embodiment, the glucose set point is <NUM>/dL if the user is exercising and <NUM>/dL if the user is not exercising. The glucose set point is compared to the actual CGM feedback (fdbk) at step <NUM> to determine a glucose error value (err) that is the difference between the set point and the feedback. The errGLUCOSE value at step <NUM> is multiplied by a constant (<NUM>/CF), in which CF is the user's correction factor, or amount by which one unit of insulin lowers the user's blood glucose. This calculation determines how much insulin is needed to correct the glucose error, which is how much insulin on board (IOB) is needed in the user's body. This IOB value then determines an appropriate estimated insulin on board (IOB) set point for the patient.

The estimated IOB level determined at step <NUM> is then taken as the command (cmdIOB) for the inner loop and based on a difference of an IOB feedback value (fdbkIOB) and the cmdIOB set point at step <NUM>, an IOB error value (errlOB) is determined. At step <NUM>, the errIOB value is multiplied by a constant k2 (relating to insulin-dependent glucose uptake in the body) and an estimate of the total daily insulin (TDI) of the user. This adjusts the errIOB to be proportional to the constant and the user's total daily intake of insulin. At step <NUM>, a limiter function is applied to the value calculated at step <NUM>. The limiter function prevents the calculated amount from being larger or smaller than preset limits. The result is an insulin amount dU, which is the amount by which the user's stored basal rate should be modified. The insulin delivery rate for the user for the next closed loop interval is therefore calculated by modifying the user's stored basal rate profile by the dU value at step <NUM>.

After the dose is calculated, it can be delivered to the user at step <NUM> and can also be used to update the estimated TDI for the user at step <NUM>. The dose can also be used to update the estimated IOB level for the user at step <NUM> by comparing the actual insulin delivered to the programmed basal rate. The updated estimated IOB then becomes the new fdbkIOB for the IOB comparison at step <NUM>. When new CGM values are received from the CGM, an estimated true CGM can be determined based on various factors such as, for example, the calibration status of the CGM sensor, and the estimated true CGM value then becomes the new fdbkGLUCOSE value for the outer loop comparison with cmdGLUCOSE at step <NUM>. The algorithm then proceeds through to calculate a new estimated IOB and to the inner IOB loop for calculation of an insulin dose as described above. In one embodiment, a new CGM value is received every <NUM> minutes and therefore the algorithm executes as set forth above every <NUM> minutes.

Applicant has determined that the difficulties in accounting for exercise in such closed loop controls are caused by the estimated IOB. For example, when the user consumes food the algorithm increases the estimated IOB in response to the increase in insulin delivered to address rising blood glucose, and that increased estimated IOB can cause blood glucose to go low during exercise. For example, for an individual with a total daily insulin (TDI) of <NUM> units, the algorithm of <FIG> would generally respond to a very high glucose level (e.g., <NUM>/dL) by increasing insulin delivery to maintain an IOB of three units. The goal of maintaining this IOB target is ultimately the problem when exercise is involved. In embodiments, the present disclosure addresses this issue by modifying the IOB algorithm instead of raising the glucose target. During exercise, the algorithm can be altered to reduce this IOB target. For example, in the above example for the individual with a TDI of <NUM> units, the IOB target can be reduced, such as, for example, by <NUM>%. The IOB target can be reduced on either a linear or non-linear schedule based on the intensity of the exercise. For example, for intense exercise such as running a marathon the IOB target could be reduced by <NUM>% whereas for more casual exercise such as a hike along the coast, the target could be reduced by <NUM>%.

In some embodiments, a user will indicate to the system that the user will be exercising, such as, for example, by selecting to enter an exercise mode through a user interface of a pump, remote control, etc. In other embodiments, the system can automatically determine that the user is exercising. In some embodiments, the system can make this determination based on information from one or more additional devices, such as, for example, a fitness or health monitoring device or application. The system may remain in exercise mode for a predetermined time that can be determined in various ways. For example, a user may enter or select an amount of time that the user will exercise or starting time and an ending time for exercise. The user may also be able to disable or close the exercise mode following the exercise through a user interface of a pump, remote control etc. In embodiments that automatically determine when the user is exercising based on information from one or more additional devices, the system can automatically determine when the user has stopped exercising based on the information from the one or more additional devices.

<FIG> depicts a first potential modification to the algorithm of <FIG> to account for exercise that involves the IOB set-point. When in exercise mode, a constant k<NUM>, which can be a fraction between <NUM> and <NUM>, is determined at step <NUM> and multiplied by the IOB set-point determined using the correction factor (CF) in step <NUM> in place of the <NUM>/CF factor utilized in <FIG>. In embodiments, this constant will be used to account for the exercise such that the glucose set point is not adjusted at step <NUM> and that step is bypassed. In other embodiments, the constant can be applied in addition to the glucose set point being adjusted at step <NUM>. By reducing the target IOB with the constant, the errIOB value determined by the comparison with the IOB feedback at step <NUM> is reduced. The algorithm therefore responds less aggressively to pre-exercise food and does not build up the estimated IOB that can eventually cause the dangerously low blood glucose level during subsequent exercise. Referring to <FIG>, when in exercise mode the algorithm deviates from the initial glucose level comparison and instead sets the k<NUM> constant at a value less than <NUM> and then proceeds to calculate the IOB set-point and insulin dose with the remainder of the algorithm as set forth above.

A second potential modification to the algorithm of <FIG> is depicted in <FIG>. This modification involves using a longer insulation duration time. The initial glucose set point may or not be adjusted for exercise in step <NUM>. As depicted in the bottom left portion of <FIG>, the algorithm initially bypasses the glucose level comparison when in exercise mode to instead modify the insulin duration time at step <NUM> for the estimated IOB calculation at step <NUM>. In embodiments, the algorithm typically assumes an insulin action time of four hours. By switching to a longer insulin action time, such as, for example, six hours, previous insulin deliveries are included in the estimated insulin on board determination at step <NUM> for a longer time, which increases the IOB feedback value and decreases the errorIOB value calculated at IOB comparison step <NUM> and used in calculating the insulin dose. The action of the control law is therefore reduced, which results in more conservative automatic boluses and basal increases because the algorithm will remember and consider active previous insulin deliveries for a longer time. The algorithm then executes as set forth above to calculate an insulin dose at step <NUM>, but using the modified insulin action time that results in a reduced errIOB value. In ultimately reducing the errIOB value, this embodiment essentially functions similarly to the previous embodiment employing the constant k<NUM>, but does so in a different manner by modifying a different portion of the closed loop algorithm.

It should further be noted that be increasing the estimated IOB the above embodiments provide a further safeguard against a manual bolus administered during exercise mode causing an unsafe drop in glucose. Manual boluses during closed loop mode take into account the estimated IOB in the system and only dose as needed to increase the current estimated IOB to match the amount requested in the bolus. Therefore, by increasing the estimated IOB the amount of insulin delivered in any given bolus request is necessarily reduced, which decreases the risk of the bolus in conjunction with exercise causing a dangerously low level of gluocose.

A third potential modification to the algorithm of <FIG> is depicted in <FIG> and involves introducing a temporary basal rate and doing so in a manner that does not allow the temporary basal rate to accelerate the burn down or reduction in IOB. Referring to <FIG>, this is done by determining a constant k<NUM> at step <NUM> in the control algorithm before conducting the initial glucose level comparison as in <FIG>. If the user is exercising, the constant is set to less than one and inserted into the algorithm to temporarily reduce the user's stored basal profile used in calculating the estimated IOB at step <NUM> and the insulin dose for the cycle at step <NUM>. This embodiment therefore results in a reduced dose because the stored basal profile used in the dose calculation at step <NUM> is reduced, whereas in the previous embodiments the dU in the dose calculation was reduced as a result of a reduced errIOB value. By inserting the temporary basal rate constant at the depicted location in the algorithm, the IOB is computed based on the deviation from the reduced basal rate profile, and therefore does not accelerate the burn down of IOB because both the dose calculated at step <NUM> and the IOB estimate at step <NUM> utilize the temporary rate. In contrast, if the temporary rate was introduced after the dose was calculated, it would alter the IOB estimate. As with previous embodiments, the initial glucose set point may or not be adjusted for exercise at step <NUM>.

Each of these three proposed modifications to the basal increase control algorithm of <FIG> could be employed individually or in any combination to better account for exercise in closed loop or semi-closed loop diabetes therapy. <FIG> depicts an embodiment in which the control algorithm includes all three modifications of <FIG>. Similar to the above, the initial glucose set point may or may not be adjusted at step <NUM>.

In addition, in some embodiments the number of modifications employed could also be a key aspect of accounting for exercise based on the intensity of the exercise. For example, in setting standard pre-sets for handling exercise, there can be multiple combinations of values such that for light workouts, for example, only one of the options is used, while for heavy workouts, for example, all options are used and may be used with more extreme constant values.

As depicted above, different settings can be prescribed for different levels of exercise including mild exercise, moderate exercise and intense exercise. More intense exercise can further be broken down into various levels including, for example, specific exercise activities such as a <NUM> minute workout, a <NUM> race and a marathon. In this embodiment, for mild exercise the algorithm is adjusted only to include the lengthening insulin duration time aspect of the disclosure whereas for moderate exercise both the IOB set-point reduction and lengthening insulin duration time aspects are incorporated. For the more intense types of exercise, all three aspects can be incorporated, with the k<NUM> and k<NUM> constants decreasing as the exercise intensity increases. It should be noted that Table <NUM> depicts one exemplary embodiment and that which and how many adjustments are applied to a given type and/or intensity of exercise can vary.

Although embodiments described herein may be discussed in the context of the controlled delivery of insulin, delivery of other medicaments, singly or in combination with one another or with insulin, including, for example, glucagon, pramlintide, etc., as well as other applications are also contemplated. Device embodiments discussed herein may be used for pain medication, chemotherapy, iron chelation, immunoglobulin treatment, dextrose or saline IV delivery, treatment of various conditions including, e.g., pulmonary hypertension, or any other suitable indication or application.

Claim 1:
A system for closed loop diabetes therapy comprising:
a pump mechanism configured to facilitate delivery of insulin to a user;
a user interface;
a communications device adapted to receive glucose levels from a continuous glucose monitor;
a processor (<NUM>) functionally linked to the pump mechanism, the user interface and the communications device, the processor (<NUM>) configured to:
calculate and deliver insulin doses to the user based on a closed loop insulin delivery algorithm, the closed loop insulin delivery algorithm including an outer glucose loop that compares glucose levels from the continuous glucose monitor to a glucose target to determine an insulin on board target for the user and an inner insulin on board loop that compares an estimated insulin on board for the user to the insulin on board target to determine an insulin on board error used to calculate insulin doses configured to maintain the insulin on board of the user at the insulin on board target and the glucose levels of the user at the glucose level target;
receive an indication that the user will be exercising;
activate an exercise mode for the closed loop insulin delivery algorithm in response to the indication that the user will be exercising, the exercise mode modifying the inner insulin on board loop of the closed loop delivery algorithm that calculates insulin doses to maintain the insulin on board of the user at the insulin on board target; and
calculate and deliver insulin doses to the user based on glucose levels from the continuous glucose monitor according to the exercise mode of the closed loop insulin delivery algorithm following the indication that the user will be exercising;
wherein the exercise mode modifies the inner insulin on board loop of the closed loop delivery algorithm by modifying one or both of:
the insulin on board error of the inner glucose loop; and
a stored basal rate for the user used in calculating the insulin doses to maintain the insulin on board target for the user.