Treatment methods and devices

Abstract

The present invention relates to a novel medical use of glucagon and compounds with glucagon activity as vasodilators to assist in the delivery of therapeutic agents or to assist in the operation of sensor devices that measure the levels of analytes in blood. In particular, the compounds are administered in time synchronization with the active agent and / or in conjunction with the measurement of the analyte by an internal sensor at a site proximate to the site of administration of the active agent and / or the site of sensing of the analyte by an internal sensor. This includes, among others, the delivery of insulin in the treatment of diabetes and the measurement of blood glucose levels by a glucose sensor. Also provided herein is an integrated system for carrying out medical uses and treatments.

Description

[Technical field]

[0001] The present disclosure and the present invention generally relate to medical uses and treatments, and more particularly to novel medical uses of glucagon and other compounds with glucagon activity.Herein, it is proposed to use compounds with glucagon activity as vasodilators to assist in the delivery of therapeutic agents or to assist in the operation of sensor devices that measure blood analyte levels.This includes, among others, the delivery of insulin in the treatment of diabetes and the measurement of blood glucose levels by glucose sensors.Herein, devices for carrying out medical uses and treatments are also provided. [Background technology]

[0002] The treatment and management of diabetes, especially type 1 diabetes (T1D), has been an ongoing challenge for many years. The benefits of tight control of blood glucose levels to reduce microvascular complications of diabetes and indeed mortality in diabetes are recognized, but this must be balanced against the increased risk of hypoglycemia and the increased burden of self-management with intensive glucose control. To this end, advances in continuous glucose monitoring (CGM) technology and insulin infusion pumps are leading to the development of artificial pancreas (AP), an automated system that combines CGM with insulin pumps and insulin dosing algorithms to automatically and continuously regulate insulin delivery to control blood glucose levels. Both single hormone (insulin only) and dual hormone (insulin and glucagon) systems are being developed (Peters and Haidar, 2018, Diabet.Med.35, 450-459). In dual hormone artificial pancreas systems, glucagon is used for its hormonal effect to increase blood glucose for the control of hypoglycemia.

[0003] Such developments are extremely promising for improving diabetes management, but continuous improvements are needed. Subcutaneous (SC) artificial pancreas systems have proven difficult to fully automate, especially due to slow kinetics, including a significant delay in glucose lowering response with subcutaneously administered insulin, which may take 1-2 hours to see a significant effect on blood glucose levels. In addition, typically subcutaneous glucose sensing has a delay of at least 6-8 minutes, which may be even longer in some subjects. These delays have hindered the development of SC AP systems, and so far only hybrid systems are available. The user informs the system about the amount of carbohydrates ingested, which the system converts into an insulin dose (meal bolus). For a truly automated artificial pancreas, a rapid effect of insulin on glucose levels is required after meals and during and after physical activity, which means that the delay in glucose sensing and the effect of subcutaneously delivered insulin need to be reduced.

[0004] Because intraperitoneal (IP) delivery of insulin typically results in a rapid response and indeed good glucose control, efforts are underway to develop intraperitoneal artificial pancreas systems to attempt to increase insulin kinetics and achieve rapid insulin effects in response to elevated blood glucose levels. This includes the field of dual hormone artificial pancreases (Am et al., Scientific Reports, 2020, 10, 13735). However, the development of IP APs is technically challenging, and new approaches for insulin delivery and glucose sensing are continually being sought. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Peters and Haidar, 2018, Diabet.Med.35, 450-459 [Non-Patent Document 2] Am et al., Scientific Reports, 2020, 10, 13735 Summary of the Invention [Problem to be solved by the invention]

[0006] The present development addresses this need and is based on the vasodilatory effect of glucagon. Glucagon has already been reported to have vasodilatory activity, but at the level of the large blood vessels, i.e. the aorta (Selley et al., Horm. Metab. Res., 2016, 48, 476-483), and the therapeutic exploitation or use of this effect has not yet been proposed. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 provides a schematic diagram for a SC CGM device. [Diagram 2] FIG. 1 presents a flow chart illustrating the operation of the insulin-only artificial pancreas. [Diagram 3] FIG. 1 presents a flow chart showing the operation of the bi-hormonal artificial pancreas. [Figure 4] FIG. 13 provides a schematic diagram for SC CGM with sustained release of glucagon in the vicinity of the sensing site. [Diagram 5] FIG. 13 provides a schematic diagram for SC CGM with glucagon at the skin surface directly above the sensing site. [Figure 6] FIG. 13 presents a schematic diagram for an SC CGM with a delivery line for glucagon near the sensing site. [Figure 7] FIG. 13 presents a schematic diagram for an SC CGM with one delivery line for glucagon and one delivery line for insulin that merge just before the end near the sensing site. [Figure 8]FIG. 13 provides a schematic diagram for an SC CGM with alternative approaches for delivery of glucagon and insulin near the sensing site: (A) separate glucagon and insulin lines; and (B) merged separate glucagon and insulin delivery lines. [Figure 9] FIG. 13 provides a schematic diagram of a delivery line for insulin, with glucagon at the skin surface just above the insulin delivery site. [Figure 10] FIG. 1 presents a schematic diagram for an insulin delivery device with sustained release glucagon at the tip of the delivery line. [Figure 11] FIG. 13 provides a schematic diagram for an SC CGM with an insulin delivery line and glucagon at the skin surface directly above the sensing and insulin delivery sites. [Figure 12] FIG. 13 provides a schematic diagram for an SC CGM with sustained release glucagon at the tip of the sensor and an insulin delivery line terminating near the sensing and glucagon release sites. [Figure 13] FIG. 13 provides a schematic diagram of an insulin delivery line coated with SC CGM and sustained release glucagon and terminating near the sensing site. [Figure 14] FIG. 1 is a graph showing blood flow in human subjects following injection of 0.1 mg of glucagon or placebo (0.9% saline) at subcutaneous sites on the lateral sides of both upper arms as measured by laser Doppler, with 95% confidence intervals shown as dashed lines for glucagon and dotted lines for placebo; blood perfusion units are shown over time (min). [Figure 15] FIG. 1 is a graph showing blood flow in human subjects following injection of varying doses of glucagon (0.1 mg, 0.015 mg, and 0.01 mg) or placebo (0.9% saline) at subcutaneous sites on both lateral upper arms as measured by laser Doppler; blood perfusion units are shown over time (min). [Figure 16]FIG. 1 is a graph showing blood flow in human subjects following injection of varying doses of glucagon (0.1 mg, 0.015 mg, and 0.01 mg) at subcutaneous sites on the lateral sides of both upper arms, measured by laser Doppler and subtracting the effect on blood flow caused by placebo (0.9% saline); blood perfusion units are shown over time (min). [Figure 17] FIG. 1 is a graph showing blood flow in human subjects following injection of 0.1 mg of glucagon or placebo (0.9% saline) at contralateral subcutaneous sites on the abdomen as measured by laser Doppler, with 95% confidence intervals shown as dashed lines for glucagon and dotted lines for placebo; blood perfusion units are shown over time (min). [Figure 18] FIG. 1 is a graph showing blood flow in human subjects following injection of varying doses of glucagon (0.1 mg, 0.015 mg, and 0.01 mg) or placebo (0.9% saline) at subcutaneous sites on both sides of the abdomen as measured by laser Doppler; blood perfusion units are shown over time (min). [Figure 19] FIG. 1 is a graph showing blood flow in human subjects following injection of varying doses of glucagon (0.1 mg, 0.015 mg, and 0.01 mg) at subcutaneous sites on both sides of the abdomen, subtracted for the effect on blood flow caused by placebo (0.9% saline), as measured by laser Doppler; blood perfusion units are shown over time (min). [Figure 20] FIG. 1 is a graph showing blood flow in a human subject following injection of 0.1 mg of glucagon at subcutaneous sites on both sides of the abdomen using injections lasting 1-3 seconds or injections lasting at least 10 seconds as measured by laser Doppler; blood perfusion units are shown over time (min). [Figure 21]FIG. 1 is a graph showing blood flow in human subjects following injection of 0.1 mg of glucagon or placebo (0.9% saline) at contralateral abdominal subcutaneous sites using injections lasting 1-3 seconds or injections lasting at least 10 seconds as measured by laser Doppler; blood perfusion units are shown over time (min). [Figure 22] FIG. 1 is a graph showing blood flow in human subjects following injection of 0.05 mg of glucagon or placebo (0.9% saline) at a subcutaneous site in the thigh as measured by laser Doppler, with 95% confidence intervals shown as dashed lines for glucagon and dotted lines for placebo; blood perfusion units are shown over time (min). [Diagram 23] 1 is a graph showing blood flow in human subjects following injection of varying doses of glucagon (0.05 mg, 0.03 mg, and 0.01 mg) or placebo (0.9% saline) at a subcutaneous site in the thigh as measured by laser Doppler; blood perfusion units are shown over time (min). [Figure 24] FIG. 1 is a graph showing blood flow in human subjects following injection of varying doses of glucagon (0.05 mg, 0.03 mg, and 0.01 mg) at a subcutaneous site in the thigh, subtracted for the effect on blood flow caused by placebo (0.9% saline), as measured by laser Doppler; blood perfusion units are shown over time (min). [Diagram 25] 1 is a graph showing blood flow in human subjects after injection of 0.015 mg glucagon or placebo (0.9% saline) at subcutaneous sites on both lateral upper arms, measured by laser Doppler, where the injections were performed at varying distances from the laser Doppler probe (under the probe, 1.6 cm from the center of the probe, 3 cm from the center of the probe, 5 cm from the center of the probe).The effect on blood flow caused by placebo (0.9% saline) was subtracted, and blood perfusion units are shown over time (min). [Figure 26]Graph showing continuous CGM data in human subjects from 12 meals in non-diabetic women and 11 meals in non-diabetic men collected by Dexcom G6. Subjects had two CGMs placed in symmetrical locations on the lateral side of each upper arm. 1-3 minutes before the start of eating, 0.1 ml of glucagon (1 mg / ml) was injected into one CGM site and 0.1 ml of placebo (0.9% saline) was injected into the contralateral CGM site. Glucagon delivery sites were measured before each meal with new randomization. Glucose levels were zeroed at the start of each meal (baseline and change from baseline are shown in the figure). Values ​​are given as mean values. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] To address the problem of delayed insulin effect and glucose sensing, particularly in the field of subcutaneous insulin delivery and subcutaneous glucose sensing, it is proposed herein to use the hormone glucagon, or more generally, compounds with glucagon activity, as a local vasodilator to increase blood flow at the location of insulin administration and / or glucose sensing. This acts to improve the kinetics of administered insulin and glucose sensing, reducing the delayed insulin effect, and improving the performance of glucose sensors to achieve more accurate and / or faster measurement of blood glucose levels when needed, for example, when glucose levels change at the time of meal or physical exercise.

[0009] According to this new proposal, glucagon is not used for its usual hormonal effect, which counteracts or prevents episodes of low blood glucose levels, but for its vasodilatory effect. The inventors have surprisingly found that glucagon, when administered subcutaneously, exerts a vasodilatory effect on small blood vessels in the skin at the local level, and is capable of increasing blood flow at the site of administration by several hundred percent. Thus, the inventors have observed a vasodilatory effect at the capillary level, i.e., in the subcutaneous microcirculation. It is conceivable that this local effect on small blood vessels at the site of administration is also found at other sites, including, in particular, intraperitoneal administration sites. Thus, glucagon and compounds with glucagon activity can be used more generally to improve local blood flow at the site of administration, and thereby to assist or enhance the delivery of therapeutic agents in general, and not just insulin. Similarly, compounds with glucagon activity can be used to improve local blood flow at the site of operation of a sensor for any blood analyte, and not just glucose.

[0010] Accordingly, a first broad aspect provided herein is a compound having glucagon activity for use in delivering an active therapeutic agent to a subject and / or measuring blood levels of an analyte in a subject, wherein the compound is administered together with the active agent and / or in conjunction with measurement of the analyte by an internal sensor, and wherein the compound is administered to the subject at a site proximate to the site of administration of the active agent and / or the site(s) of sensing of the analyte by the internal sensor, and wherein the administration of the active agent and / or said sensing of the analyte by the sensor is synchronized in time.

[0011] As mentioned above, the compound having glucagon activity is itself an active agent, and thus the co-administered active therapeutic agent is considered a second active agent.

[0012] In one embodiment herein, there is provided a compound having glucagon activity for use in the delivery of a second active therapeutic agent to a subject, said use comprising a step of co-administering the compound with the second agent, the compound being administered to the subject in temporal synchronization with the second agent at a site proximate to the site of administration of the second agent.

[0013] It will be understood that the delivery of active therapeutic agent is made in the field of therapeutic use of this agent.Therefore, the compound with glucagon activity is used in the delivery of (second) therapeutic agent in the treatment and / or prevention of medical condition that is responsive to this agent.In other words, the compound with glucagon activity is used in the treatment and / or prevention of condition by (second) therapeutic agent.

[0014] In another embodiment, provided herein is a compound having glucagon activity for use in conjunction with an internal sensor in measuring blood levels of an analyte in a subject, comprising administering the compound at a site proximate to the sensor and in temporal synchronization with the time of sensing of the analyte by the sensor.

[0015] As further described below, in some embodiments, administration may occur each time sensing by the sensor occurs (i.e., each time the sensor performs sensing). In other embodiments, administration may occur continuously or periodically at the time sensing occurs, or continuously or periodically over the time that sensing by the sensor occurs. Thus, the compound may be administered such that it is in the vicinity of the sensor at the time sensing by the sensor is performed, for example, the compound may be administered from a controlled release ("sustained release") depot or reservoir (or any other sustained release formulation or preparation) placed or applied in the vicinity of the sensor or administered as part of the sensor.

[0016] From the above, it will be understood that "temporally synchronized," whether in conjunction with administration of an active agent or with sensing by a sensor, means that administration of the compound is synchronized with administration of a therapeutic active agent or sensing by a sensor, or, more generally, synchronized such that the compound is present or effective (i.e., active or capable of exerting an effect) near the site of administration of the active agent or near the site of sensing at the time that administration and / or absorption or sensing of the active agent occurs. This is discussed further below.

[0017] For such use, the compound having glucagon activity can be provided in the form of a composition comprising the compound.In certain embodiments, the composition can be referred to as a pharmaceutical composition.In certain embodiments, the composition can include one or more pharma- ceutically acceptable carriers or excipients.

[0018] In a second broad aspect herein, there is provided a method of delivering a therapeutic active agent to a subject and / or measuring blood levels of an analyte in the subject by an internal sensor, the method comprising administering to the subject a compound having glucagon activity in conjunction with the therapeutic active agent and / or in conjunction with measurement of the analyte by the internal sensor, wherein the compound is administered at a site proximate to the site of administration of the active agent or proximate to the sensor and in temporal synchronization with the time of administration of a second active agent and / or sensing of the analyte by the sensor.

[0019] In one embodiment, a method is provided for delivering a therapeutically active agent to a subject, comprising co-administering to the subject a compound having glucagon activity in conjunction with the therapeutically active agent, wherein the compound is administered at a site proximate to the site of insulin administration and in temporal synchronization with the second active agent.

[0020] As mentioned above, the method may be a method of treating and / or preventing a condition that is responsive to a therapeutically active agent.

[0021] In another embodiment, a method is provided for measuring blood levels of an analyte in a subject using an internal sensor, comprising administering to the subject a compound having glucagon activity, wherein the compound is administered at a site proximate to the sensor and in temporal synchronization with the time of sensing of the analyte by the sensor.

[0022] In a third aspect herein there is provided the use of a compound having glucagon activity in the manufacture of a pharmaceutical for use in delivering an active therapeutic agent to a subject and / or measuring blood levels of an analyte in a subject, where the pharmaceutical comprises an active agent and / or is administered in conjunction with measuring an analyte by an internal sensor, and where the compound is administered to the subject at a site proximate to the site(s) of administration of the active agent and / or the site(s) of sensing of the analyte by the sensor, and in temporal synchronization with the administration and / or sensing of the analyte by the sensor.

[0023] Where the medicament is for use in the delivery of an active therapeutic agent, the compound may be provided or formulated together with the active agent in a single composition or preparation, or the compound and active agent may be provided or formulated separately in separate compositions or preparations. Thus, the medicament may take the form of a composition containing both the compound and the active agent, or it may take the form of a kit containing (i) the compound and (ii) the active agent.

[0024] A pharmaceutical agent may be provided herein for use in any aspect of the invention. The pharmaceutical agent comprises a compound and an active agent for coordinated, separate or sequential administration to a subject, within the confines that administration of the compound is synchronized in time with administration of the active agent, as described and further defined below.

[0025] In various aspects and embodiments described above and further described below and elsewhere herein, the compound with glucagon activity acts to improve local blood flow at the site of its administration. By improving blood flow, the compound improves the effect or delivery of the active agent and / or improves the measurement of the blood level of an analyte in a subject by a sensor. In some embodiments, the absorption of the active agent may be improved. In some embodiments, the performance of the sensor may be improved. For example, the time spent for measuring the blood level of an analyte may be reduced.

[0026] In a related aspect herein, there is provided a sensor system for measuring blood levels of an analyte in a subject, comprising: (i) a sensor configured to measure a blood level of an analyte in a subject and provide sensor data related to the blood analyte level; (ii) a compound delivery means configured to administer to said subject a compound having glucagon activity; (iii) a control system configured to receive the sensor data from the sensor. Including, (a) the delivery means comprises a sustained release reservoir of a compound having glucagon activity configured to administer the compound to a site in the vicinity of the sensor; or (b) the delivery means is controllable to administer a compound having glucagon activity to said subject, and the control system is configured to control the delivery device to administer the compound to a site proximate to the sensor in time synchronization with the operation of the sensor that measures the blood analyte level; A sensor system is provided.

[0027]

[0023] In another related aspect herein, there is provided a delivery system for administration of an active therapeutic agent to a subject, comprising: (i) a compound delivery means configured to administer to said subject a compound having glucagon activity; (ii) a delivery device configured to administer an active therapeutic agent to the subject. Including, (a) the compound delivery means comprises a sustained release reservoir of a compound having glucagon activity configured to administer the compound to a site proximate to the site of administration of the active therapeutic agent; or (b) the compound delivery means is controllable to administer a compound having glucagon activity to said subject, and the delivery system further comprises a control system configured to control the compound delivery means to administer the compound to a site proximate to the active agent administration site and in temporal synchronization with administration of the active agent; A delivery system is provided.

[0028] In certain embodiments, the therapeutic active agent is insulin, and the compound and insulin are co-administered in the treatment of diabetes, particularly type 1 diabetes.Therefore, the compound is used in the delivery of insulin.In particular, the compound is used in such an embodiment to enhance or improve the effect or delivery of insulin.

[0029] Further, in certain embodiments, the analyte is glucose and the sensor is a glucose sensor. More particularly, in such embodiments, the compound is used to improve the measurement of blood glucose levels in a subject by a glucose sensor.

[0030] Thus, in a more particular aspect, there is provided a compound having glucagon activity for use in the treatment and / or management of a subject with diabetes by co-administration with insulin and / or in conjunction with glucose sensing, the compound being administered to a subject at a site proximate to the site of insulin administration and / or the site(s) of glucose sensing by an in-body glucose sensor and temporally synchronized with the insulin administration and / or glucose sensing.

[0031] In one embodiment, this aspect provides a compound having glucagon activity for use in delivering insulin to a subject, said use comprising co-administering the compound with insulin, said compound being administered to the subject at a site proximate to the site of insulin administration and in temporal synchronization with the insulin.

[0032] In another embodiment, this aspect provides a compound having glucagon activity for use in conjunction with an in vivo glucose sensor in measuring blood glucose levels in a subject, said use comprising administering the compound at a site proximate to the glucose sensor and synchronized in time with the time of glucose sensing by the sensor.

[0033] Related aspects of the present specification also provide a method of treating and / or managing a subject with diabetes, comprising co-administering a compound having glucagon activity to a subject at a site proximate to the site of insulin administration and / or glucose sensing by an in vivo glucose sensor, in a time-synchronized manner with insulin administration and / or glucose sensing.

[0034] In one embodiment, this aspect provides a method of delivering insulin to a subject comprising co-administering to the subject a compound having glucagon activity in conjunction with insulin, wherein the compound is administered at a site proximate to the insulin administration site and in temporal synchronization with the second active agent.

[0035] In another embodiment, the present aspect provides a method for measuring the level of glucose in a subject's blood by an in vivo glucose sensor, comprising the step of administering to the subject a compound having glucagon activity, wherein the compound is administered at a site proximate to the glucose sensor and in temporal synchronization with the time of glucose sensing by the sensor.

[0036] A still further aspect provides the use of a compound having glucagon activity in the treatment and / or management of a subject with diabetes by co-administration with insulin and / or in the manufacture of a medicament for use in conjunction with glucose sensing, where the medicament includes insulin and / or is administered in conjunction with glucose measurement by an internal sensor, and where the compound is administered to a subject at a site proximate to the site of administration of the active agent and / or the site(s) of glucose sensing by the sensor, in temporal synchronization with insulin administration and / or glucose sensing.

[0037] As mentioned above, the medicament is a medicament for the delivery of insulin. In this aspect, the medicament may comprise insulin and the compound in the same composition or formulation or in separate compositions or formulations, including the kits discussed above.

[0038] Also provided herein is an integrated system for controlling blood glucose levels in a subject with diabetes, comprising: (i) one or more glucose sensors configured to measure a blood glucose level of a subject and provide sensor data related to the blood glucose level; (ii) a compound delivery means configured to administer to said subject a compound having glucagon activity; (iii) an insulin delivery device configured to administer insulin to the subject; (iv) a control system configured to receive sensor data from the glucose sensor(s), determine an insulin dose to administer to the subject based on at least the sensor data, and control the insulin delivery device to administer said dose. Including, (a) the compound delivery means comprises a sustained release reservoir of a compound having glucagon activity configured to administer the compound to a site proximate the site of insulin administration and / or proximate the glucose sensor; or (b) the compound delivery means is controllable to administer a compound having glucagon activity to said subject, and the control system is configured to control the compound delivery means to administer the compound to a site proximate an insulin administration site in time synchronization with administration of insulin, thereby improving blood flow in the vicinity of the insulin administration site, and / or to control the compound delivery means to administer the compound to a site proximate a glucose sensor in time synchronization with operation of the glucose sensor to measure blood glucose levels, thereby improving blood flow in the vicinity of the glucose sensor. An integrated system is also provided.

[0039] Administration of a compound to a site "proximate" the insulin administration site and / or to a site "proximate" the glucose sensor can include administration of the compound within 3 cm or 2.5 cm of the insulin administration site and / or within 3 cm or 2.5 cm of the glucose sensor (particularly the site of sampling / sensing on the glucose sensor) and can include administration of the compound in close proximity to the insulin administration site and / or glucose sensor (and particularly the site of sampling / sensing on the glucose sensor), where close proximity means within 2 cm, e.g., within 1.5 cm or within 1 cm.

[0040] The compound delivery means in (a) can be any of the sustained release means discussed above, including, for example, a transdermal patch, a sustained release coating, or a depot formulation. The compound delivery means in (a) may alternatively comprise a compound infusion line connected to a pump in communication with a reservoir containing the compound, in which case the compound delivery means is configured to provide continuous or semi-continuous compound administration.

[0041] The compound delivery means in (b) may include a compound infusion line connected to a pump in communication with a reservoir containing the compound. The compound delivery means may be controlled to administer the compound taking into account the timing of administration(s) and / or sensing. Alternatively, the compound delivery means in (b) may be configured to administer repeated or multiple doses of the compound to create and maintain a high local concentration of the compound in the vicinity such that the compound is present at the time of insulin administration and / or absorption or sensing. In an embodiment, the control system is further configured to control the compound delivery means to administer the compound in a site in the vicinity of the insulin administration site in time synchronization with insulin administration.

[0042] Additionally, provided herein is a sensor system for measuring a level of glucose in the blood of a subject, comprising: (i) a glucose sensor configured to measure a blood glucose level of a subject and provide sensor data related to the blood glucose level; (ii) a delivery means configured to administer to said subject a compound having glucagon activity; (iii) a control system configured to receive sensor data from the glucose sensor. Including, (a) the delivery means comprises a sustained release reservoir of a compound having glucagon activity configured to administer the compound to a site in the vicinity of the glucose sensor, thereby improving blood flow to the vicinity of the glucose sensor; or (b) the delivery means is controllable to administer a compound having glucagon activity to said subject, and the control system is configured to control the delivery means to administer the compound to a site proximate the glucose sensor in time synchronization with operation of a glucose sensor that measures blood glucose levels, thereby improving blood flow to the vicinity of the glucose sensor; A sensor system is provided.

[0043] Administration of a compound to a site "in the vicinity" of a glucose sensor can include administration of a compound within 3 cm or 2.5 cm of the glucose sensor (particularly the site of sampling / sensing on the glucose sensor) and can include administration of a compound in close proximity to the glucose sensor (and particularly in close proximity to the site of sampling / sensing on the glucose sensor), where close means within 2 cm, e.g., within 1.5 cm or within 1 cm.

[0044] The compound delivery means in (a) can be any of the sustained release means discussed above, including, for example, a transdermal patch, a sustained release coating, or a depot formulation. The compound delivery means in (a) may alternatively comprise a compound infusion line connected to a pump in communication with a reservoir containing the compound, in which case the compound delivery means is configured to provide continuous or semi-continuous compound administration.

[0045] The compound delivery means in (b) may include a compound infusion line connected to a pump in communication with a reservoir containing the compound. The compound delivery means may be controlled to administer the compound taking into account the timing of the sensing. Alternatively, the compound delivery means in (b) may be configured to administer repeated or multiple doses of the compound to create and maintain a high local concentration of the compound in the vicinity such that the compound is present at the time the sensing is performed.

[0046] Further provided herein is an insulin delivery system for administration of insulin to a subject, comprising: (i) a compound delivery means configured to administer to said subject a compound having glucagon activity; (ii) an insulin delivery device configured to administer insulin to the subject; (iii) a control system configured to measure an insulin dose to be administered to the subject and to control an insulin delivery device to administer said dose. Including, (a) the compound delivery means comprises a sustained release reservoir of a compound having glucagon activity configured to administer the compound to a site proximal to the site of insulin administration; or (b) the compound delivery means is controllable to administer a compound having glucagon activity to said subject, and the control system is configured to control the compound delivery means to administer the compound to a site proximate to the insulin administration site and in temporal synchronization with the administration of insulin; An insulin delivery system is provided.

[0047] Administration of a compound to a site "in the vicinity" of an insulin administration site can include administration of a compound within 3 cm or within 2.5 cm of the insulin administration site, and can include administration of a compound adjacent to the insulin administration site, where adjacent means within 2 cm, e.g., within 1.5 cm or within 1 cm.

[0048] The compound delivery means in (a) can be any of the sustained release means discussed above, including, for example, a transdermal patch, a sustained release coating, or a depot formulation. The compound delivery means in (a) may alternatively comprise a compound infusion line connected to a pump in communication with a reservoir containing the compound, in which case the compound delivery means is configured to provide continuous or semi-continuous compound administration.

[0049] The compound delivery means in (b) may include a compound infusion line connected to a pump in communication with a reservoir containing the compound. The compound delivery means may be controlled to administer the compound taking into account the timing of the administration(s). Alternatively, the compound delivery means in (b) may be configured to administer repeated or multiple doses of the compound to create and maintain a high local concentration of the compound in the vicinity such that the compound is present at the time of insulin administration and / or absorption.

[0050] The devices depicted in Figures 4-13 may also be used as an integral part of an artificial pancreas.

[0051] Various embodiments presented herein are based on the novel application of vasodilatory properties of glucagon and other compounds with glucagon activity.The vasodilatory activity of such compounds increases blood flow at their administration site, and this increase in local blood flow is beneficial for the methods and uses that rely on local blood flow for their effects, such as drug delivery and the operation of sensors that measure analytes in blood.Therefore, the inventors have discovered that this vasodilatory activity can be utilized in the use of novel compounds with glucagon activity in the delivery of active agents to subjects and / or in the measurement of blood levels of analytes in subjects.

[0052] By administering a compound to the site of administration of an active agent (i.e., a drug) or the site of analyte sensor sensing, the local blood flow at this site is increased. This leads to an improvement in the effect of the administered active agent (e.g., the effect is seen quickly or the time lag or delay of the effect after administration is reduced, as discussed further below). In this way, the delivery of the active agent can be improved. Similarly, increasing the local blood flow at the site of sensor sensing can improve the performance of the sensor, for example, by reducing the delay in measuring the analyte level in blood.

[0053] In particular, as shown in the following examples, it has been observed that when glucagon is administered, there is an immediate and large increase in local blood flow. This decreases over time, for example, for 30 minutes. In particular, it has been observed that blood flow returns to a level above the baseline level before glucagon administration, and this increase is maintained for a long time. The administration of the same volume of placebo (physiological saline solution) has little such acute effect, and no long-term effect. Thus, the administration of a compound with glucagon activity increases local blood flow in the administration area for a period of time that is useful for using the increased blood flow to deliver another active agent or activate a sensor.

[0054] These discoveries have application, inter alia, to the delivery of insulin and to the sensing of blood glucose levels by glucose sensors, as set forth above and further discussed herein, and thus to the treatment and / or management of diabetes.

[0055] As mentioned above, the term "synchronous in time" means that the administration of the compound is synchronized with the administration of the active agent or the sensing by the sensor, so that the compound is present in the vicinity or still exerts a vasodilatory effect at the time when the administration and / or absorption or sensing of the active agent occurs. In other words, the administration of the compound is timed to coincide with the time of the administration and / or absorption or sensing of the therapeutic active agent, or the effect of the compound is timed to coincide with this time, or the compound is present in the vicinity at the time when the therapeutic active agent is administered, or while it is absorbed, or at the time of sensing by the sensor. It will be understood that in some circumstances, the vasodilatory effect of the compound may continue for a period of time after it is absorbed, a phenomenon known to be caused by hormones. Thus, it is required that the compound or its effect is present in the vicinity, but not necessarily that the compound itself is present; the effect may continue or be maintained after it is absorbed. In other words, the effect of the compound may last for a long time and can be observed after the compound itself is no longer present.Thus, the vasodilatory effect of the compound, which increases local blood flow, occurs in the vicinity of the time when the active agent is administered or absorbed or when sensing occurs.As will be discussed in more detail below, this can be achieved in a variety of ways, including, for example, timing of administration (possibly multiple times) and / or sensing, such that administration occurs at or near the time of administration or sensing of the active therapeutic agent, long-term administration, continuous administration or quasi-continuous administration, or repeated or multiple administration of the compound, which creates and maintains a high local concentration of the compound in the vicinity, so that the compound or at least the vasodilatory effect of the compound is present at the time when the active agent is administered or sensed.

[0056] The term "compound with glucagon activity" includes any compound that acts on glucagon receptor or, in other words, interacts with glucagon receptor to stimulate the effect of the receptor. That is, a compound with glucagon activity causes or results in any of the downstream effects resulting from the interaction of glucagon with glucagon receptor. In particular, the compound interacts with glucagon receptor and results in vasodilation. Thus, in particular, the compound has a vasodilatory effect, and more particularly, can exert substantially the same vasodilatory effect as glucagon. The vasodilatory effect induced by the compound can be a direct or indirect result of the interaction with glucagon receptor. This includes any compound that exerts a glucagon effect. Thus, alternatively, a compound with glucagon activity can be defined as a compound that has or mimics the effect of glucagon at glucagon receptor. Thus, a compound with glucagon activity can be defined as a glucagon agonist. Additionally, a compound having glucagon activity may alternatively be defined as glucagon or an analog thereof.

[0057] The term "glucagon" includes any known or reported wild-type or natural glucagon molecule in any species and any naturally occurring variant or fragment thereof. A glucagon analog is any compound that is not a naturally occurring glucagon compound but has glucagon activity or exerts glucagon effect. It includes synthetic or artificial derivatives or variants or fragments of the natural glucagon molecule. Glucagon analogs are known and described in the literature. Glucagon is a peptide hormone, and a variety of glucagon analogs in the form of peptide derivatives or other peptide compounds have been developed. Thus, in one embodiment, the compound can be defined as a glucagon peptide, a term that includes natural or wild-type glucagon or its derivatives or variants or fragments that retain glucagon activity, or glucagon analogs that are peptides or peptide-based. More particularly, glucagon analogs may include substitutions, additions, and / or deletions of one or more amino acids compared to the native glucagon peptide, including chemical modifications to one or more amino acid residues, including insertions and truncations or extensions at the C-terminus and / or N-terminus, as well as covalent modifications such as the addition of various chemical groups (e.g., amide groups, ester groups, alkyl or acyl groups, lipophilic groups, etc.). However, glucagon analogs are not limited to peptides, but include any compound having glucagon activity, e.g., small molecule compounds.

[0058] Compounds having glucagon activity include pharma- ceutically acceptable salts of the compounds, such as acid addition salts, metal salts, ammonium salts and alkylated ammonium salts.

[0059] Glucagon-like peptide 1 (GLP-1) can bind to glucagon receptor and exert glucagon effect. Therefore, GLP-1 is included as a compound having glucagon activity. Furthermore, compounds having glucagon activity, including glucagon itself, can act at GLP-1 receptor. Therefore, in one embodiment, under the general heading of "compounds having glucagon activity", also include compounds that can interact with GLP-1 receptor and cause vasodilatory effect.

[0060] However, in another embodiment, the term "compound having glucagon activity" does not include GLP, and in particular does not include any compound with activity at GLP-1 or the GLP-1 receptor or capable of binding to the GLP-1 receptor.

[0061] In the art, there are several patent applications known, which disclose different glucagon-based analogues and GLP-1 / glucagon receptor coagonists, such as WO2008 / 086086, WO2008 / 101017, WO2007 / 056362, WO2008 / 152403 and W096 / 29342.Other glucagon analogues disclosed are PEGylated (e.g., WO2007 / 056362) or acylated (e.g., W096 / 29342) at specific positions of natural human glucagon.Glucagon peptides for preventing hypoglycemia are disclosed, for example, as in US7314859.

[0062] Long-acting glucagon analogues or more stable glucagon analogues are described in WO2013 / 040678 by Novo Nordisk A / S. This document and other documents mentioned above are incorporated herein by reference.The compounds described in these documents can be used.

[0063] Reference may also be made to the glucagon analogue dasiglucagon available from Zealand Pharma A / S and stabilized glucagon delivery devices (pen and syringe) available from Xeris Pharmaceuticals Inc, which may also be used.

[0064] The sequence of human glucagon (glucagon 1-29) is as follows: His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr (SEQ ID NO: 1) , as set forth in SEQ ID NO:1.

[0065] Included herein as compounds are Glucagon 1-30, Glucagon 1-31, and Glucagon 1-32, which have extensions of 1, 2, and 3 amino acids, respectively, at the C-terminus of SEQ ID NO:1.

[0066] Glucagon analogs can include peptides that include an amino acid sequence having at least 80% sequence identity, such as at least 85, 90 or 95% sequence identity, to the sequence of SEQ ID NO:1.

[0067] Furthermore, derivatives or analogs of glucagon may be made to improve the administerability of the compound. Glucagon is water-soluble, and in some cases it is desirable to promote the lipid solubility of the compound, for example, to aid in the absorption of the compound through the skin. Thus, for example, lipophilic or other lipid-soluble groups may be attached to the compound to make derivatives that are more lipid-soluble.

[0068] Glucagon is known primarily for its role in maintaining blood glucose levels, since it stimulates glycogenolysis and gluconeogenesis from pyruvate, lactate, glycerol and some amino acids, thereby counteracting the effects of insulin.While various extrahepatic effects of glucagon have been described, such as positive inotropic and chronotropic effects, in the gastrointestinal tract glucagon acts as a smooth muscle relaxant, but also affects glomerular filtration rate, adipose tissue, thyroid gland and central nervous system.Glucagon exerts these effects through the G protein-coupled glucagon receptor, via the activation of adenyl cyclase, which increases cAMP levels and activates the phospholipase C (PLC) protein kinase C (PKC) pathway. However, in addition to activating cAMP-dependent protein kinase A (PKA), glucagon has also been shown to activate extracellular signal-regulated protein kinase (ERK1 / 2) in a clonal cell line of human embryonic kidney cells, as described in Jiang et al., PNAS USA, 2001, 98, 10102-10107. Any of these activities can be used as the basis of an assay to determine whether a compound has glucagon activity or to measure the level of this activity. For example, such an assay can include a step of determining whether a compound is capable of increasing cAMP levels in cells expressing the glucagon receptor and a membrane-bound cAMP biosensor. An assay based on the detection of cAMP is described in WO2103 / 041678 as follows (Assay I). The assay uses HEK-293 cells with a membrane-bound cAMP biosensor (ACTOne™) into which the glucagon receptor has been cloned. Cells (14000 cells per well) are incubated overnight (37°C, 5% CO2) in 384-well plates. The next day, cells are loaded with a calcium-responsive dye that distributes exclusively to the cytoplasm. Probenecid, an inhibitor of organic anion transporters, is added to prevent the dye from being released from the cells. A PDE inhibitor is added to prevent the degradation of the formatted cAMP.The plate is placed into the FLIPR TETRA and test compounds for glucagon activity are added. After 6 minutes, endpoint data can be collected. The increase in intracellular cAMP is proportional to the increase in calcium concentration in the cytoplasm. When calcium is bound, a fluorescent signal is generated. EC50 values ​​can be calculated by Prism5.

[0069] By way of example, a compound having glucagon activity can be any compound, e.g., a glucagon peptide, that binds to or activates the glucagon receptor with an affinity or potency (EC50) of less than 1 μM, e.g., less than 100 nM, or less than 1 nM, e.g., as measured by the cAMP assay described above.

[0070] As used herein, the term "insulin" includes any animal species, particularly human insulin molecule, as well as its analogs and derivatives, including artificial and synthetic analogs. Currently, a variety of insulin analogs and derivatives are known and reported in the art, and are used in clinical practice. Any such insulin compounds are included. Insulin analogs and derivatives include compounds and peptides with sequence modified amino acid sequences and / or chemical modifications similar to those described above for glucagon.

[0071] Rapid-acting insulin analogs are available. Rapid-acting analogs are easily absorbed from subcutaneous injection sites and may act more quickly than natural insulin. Such analogs may be useful for providing bolus levels of insulin (post-prandial insulin) required at mealtimes. Examples of such analogs include lispro, aspart, and glulisine. Long-acting insulin analogs are also available, but such analogs typically would not be used in accordance with the disclosure herein. Thus, in particular, the insulin analogs and insulin derivatives herein are those with an activity profile similar or equivalent to that of natural insulin, those that are rapid acting, those that are used with meals, those that are used in insulin pumps, and those that are used in artificial pancreases, among others.

[0072] The term "diabetes" includes all types and forms of diabetes, including type 1 diabetes (T1D) and type 2 diabetes (T2D). The uses, methods and systems herein are particularly useful in the treatment or management of type 1 diabetes, but glucose monitoring, particularly continuous glucose monitoring (CGM), may be required in all types of diabetes, and administration of insulin may be required in certain subjects with type 2 diabetes, such as subjects with long-term and / or advanced disease in which insulin production may be reduced. The term "diabetes" also includes any diabetic state, or indeed any state or condition in which external control of glucose levels may be required or may provide clinical benefit. This includes conditions in which the pancreas has been damaged or removed, or is not functional enough to produce insulin for any reason, such as as a result of disease or trauma. In certain embodiments, diabetes treated or managed as described herein does not include type 2 diabetes.

[0073] A "therapeutically active agent", alternatively referred to as a drug, includes any agent, e.g., any compound, substance, or moiety, that exerts a beneficial or therapeutic effect on the subject to which it is administered. Thus, a "therapeutically active agent" includes any agent that is a pharmacologic active agent (e.g., a pharmaceutical compound) and has clinical utility. As mentioned above, insulin is a particular therapeutically active agent for use herein, but an active agent can be any agent that is known, reported, or proposed for medical use to treat or prevent any medical condition or disease.

[0074] A therapeutically active agent may be administered to a subject in an amount effective for the agent to exert or achieve its intended therapeutic effect, e.g., which may cure, alleviate, arrest, slow the progression of, or in any way ameliorate the condition being treated or any of its symptoms.

[0075] In one embodiment, the condition to be treated is any condition that is responsive to or would benefit from a therapeutically active agent, hi another embodiment, the condition does not include type 2 diabetes.

[0076] Similarly, a compound having glucagon activity can be administered in an amount that is effective to achieve a local vasodilatory effect or an effect of increasing local blood flow at its administration site. Vasodilatory activity can be evaluated or measured by measuring blood flow via laser Doppler method at the administration site on or within the body of a human or non-human animal subject after administration of the compound. For example, the compound can be injected subcutaneously, and blood flow just below the skin surface can be measured at the injection site. Such a method is described in Example 1. However, for the methods and uses herein in which the compound is used for its effect in delivering a therapeutic active agent (e.g., insulin) or in conjunction with the operation of a sensor (e.g., glucose sensor), it is not necessary, and in fact may not be desirable, for the compound to exert its usual therapeutic effect of increasing blood glucose or countering episodes of hypoglycemia. Thus, the amount or dose administered can be, and in fact will typically be, less than the dose administered or typically used to treat hypoglycemia. Dosages for the compounds are discussed in more detail below.

[0077] As used herein, the terms "treatment" and "treating" and other variants thereof refer to the management and care of a subject with the goal of combating a condition (including any disease or disorder, as indicated above). "Prevention" includes preventing or delaying the onset of a condition or any symptoms, signs or complications thereof. A therapeutically active agent may be administered to treat or prevent any condition that is responsive to or would benefit from administration of the agent.

[0078] The subject can be any human or non-human animal subject, particularly a mammalian subject, more particularly a human subject.The methods, uses and systems presented herein are particularly useful in the treatment or management of human subjects with diabetes.However, veterinary uses are also included, and the subject can be any domestic animal, breeding animal, sport animal, zoo animal, or laboratory or research animal, or wild animal.Thus, the subject can be, for example, a canine, feline, equine, bovine, ovine or murine animal.

[0079] A "sensor" as referred to herein is a device for measuring the level of an analyte. The analyte to be measured is referred to as the target analyte. The sensor herein is an internal sensor. That is, the sensor is a sensor that is attached or carried in or on the subject's body. Thus, the device may contact the subject's internal and / or external body surfaces, e.g., the subject's tissue. The sensor may actually be attached on or within the subject's tissue. The device may directly measure the target analyte in the internal tissue or fluid that is contacted by the sensing element (e.g., sensor probe, e.g., sensor electrode) of the sensor device, or may sample the subject's fluid or tissue and detect and measure the amount of the target analyte present in the sample. For example, the device may be capable of directly measuring the target analyte in the interstitial fluid of any internal tissue. This may be accomplished by a sensor element (e.g., probe) provided within the device that contacts or is placed within the tissue. Typically, the sensor will be a subcutaneous (SC) sensor, but may be designed to be placed at other locations or inside or on the surface of the body, for example, intraperitoneally (IP) or within other body cavities or organs. Thus, the sensor may be an external device, or a partially indwelling device or a fully indwelling device.

[0080] Typically, the sensor and / or delivery device, e.g., artificial pancreas, is a partially indwelling sensor and / or partially indwelling delivery device, with the controller (control system) element, power element and pump element being external and connected to the subject through a delivery line (e.g., infusion tube) that is internal to the subject. A plumbing-free ("patch pump") form is also available. However, a fully indwelling device is not excluded. Thus, while a partially indwelling device is powered by an external battery pack and / or equipped with an external control system, a fully indwelling device is equipped with an internal (indwelling) battery and control system, and may be equipped with, for example, a means for wireless communication. Advances in anti-fouling technology and battery capacity mean that a fully indwelling device can be implanted for an extended period of time, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or more. Furthermore, a fully indwelling device can be charged from an external power source at the skin above the indwelling device.

[0081] Consistent with this is the term "sensing" generally referring to the measurement of an analyte or, more specifically, the level of the analyte in a subject. "Sensing" may be thought of as taking a reading or measurement of an analyte at a point in time. In the uses, methods and systems herein, the measurement of blood analyte levels, i.e., the level of the analyte present in the blood of a subject, is of particular importance. This does not mean that the sensor is required to perform measurements directly in or on the subject's blood, but does not exclude this, but rather that it is capable of providing information indicative of the blood level of the analyte of the subject. For example, the sensor may measure the interstitial fluid level of the analyte, which is accessed, for example, by a subcutaneous sensor, from which its level present in the blood can be estimated. Thus, there may be a predetermined relationship, or such a relationship may be measured, between the level of the analyte in the sampled body tissue or fluid and the blood level of the analyte. The relationship may be used to measure the blood level of the analyte. In other words, the measured value for the level of the analyte in the sampled body tissue or fluid can be converted to a value for or indicative of the blood level of the analyte. This may be done by reference or comparison to a reference diagram or graph or calibration curve, etc., according to principles known in the art, and may be performed by software or algorithms implementing the medical uses and methods set forth above, for example, by the control system of the device. Thus, "measurement" includes direct and indirect measurement or estimation or evaluation of the blood level of the analyte. The concentration of the analyte may be measured, or any other measurement or value indicative of the level of the analyte may be measured.

[0082] Such sensors provide the subject with the convenience of being able to measure or monitor or track the analyte level itself. However, it is to be understood that this does not exclude that the sensor may also be used, particularly or exclusively, by a physician or other medical practitioner. An internal sensor does not further require that a sample be separately taken and administered or applied to the sensor. The internal sensor automatically takes or takes a sample or reading when needed or when programmed or instructed to do so. A variety of such sensors are known and available in the art, typified by glucose sensors routinely used by diabetic subjects in the management of their diabetes.

[0083] The analyte may be any analyte that is desired to be measured in the blood of a subject, among others. Glucose is a typical representative analyte, but may be any other molecule occurring in the blood of a subject. For example, the analyte may be a metabolite, such as pyruvate or lactate, that indicates the state or condition of the subject. For example, it may be desired to track or monitor such analytes, such as monitoring energy expenditure or utilization, including during or after surgery or hospitalization, fitness or sports recovery, etc. Monitoring such analytes may be advantageous in monitoring patients in intensive care units.

[0084] Continuous glucose monitoring (CGM) sensors have been developed for measuring and monitoring glucose levels. Thus, the sensor may be a CGM sensor. The term "continuous" does not imply that the sensor is continuously sensing glucose without interruption, but rather that repetition of measurements (sensing) occurs over time, for example, 24 hours or more. "Continuous" sensing may occur over the time that the sensor is on or in the body. Sensing may occur at regular intervals and / or at predetermined or programmed intervals, for example, at regular intervals. For example, sensing may occur at 5-minute intervals or at longer intervals. Alternatively or in addition, sensing may occur or be performed with greater frequency at times when blood glucose levels are changing or are predicted to be changing. For example, the frequency of sensing may be increased during meal times or activity, and / or the frequency of sensing may be reduced at night. The user may inform or command the sensor when to take a reading, or the reading may be taken automatically, or both.

[0085] One or more sensors can be used in a subject at any one time. For example, sensors can be located in different sites or positions in or on the body. This can be useful to introduce redundancy, for example, if one sensor fails, another sensor can take a reading. Furthermore, it can be advantageous to take readings at different sites or tissues and / or use different sensor modalities at different sites. In this way, a robust system can be provided. An artificial pancreas or glucose sensor system can contain one or more glucose sensors. Thus, a compound with glucagon activity can be administered in conjunction with one or more sensors.

[0086] In some embodiments, the compound is administered each time sensing by the sensor occurs, i.e., each time the sensor takes a reading. However, administration each time sensing occurs is not necessary, since the compound can be administered so that it is present or has an effect in the vicinity of the sensor when the sensor is sensing. For example, the duration of the compound's action can last for a time period during which more than one reading can be taken (e.g., 20, 30, 40, 50, or 60 minutes or more). Alternatively, the compound can be administered continuously or over an extended period, for example, from a controlled release preparation (e.g., a sustained release reservoir) or by continuous infusion, so that it is present in the vicinity of the sensor each time sensing by the sensor occurs. In some embodiments, controlled release can be administered over a time period during which one or more sensor readings can be taken. Thus, the compound can be administered, for example, in a form sufficient to have a sustained effect on local blood flow, and therefore on the performance of the sensor, more or less. This can range from each reading to several times daily.

[0087] The compound having glucagon activity is administered to a site that is in the vicinity of the administration site of a therapeutic active agent (e.g., insulin) or the sensor site, more particularly, the site where sensing or sampling by the sensor occurs. The vicinity of the site can be defined as an area within 3 cm from the site, more particularly, an area within a radius of 3 cm from the site. In some embodiments, the vicinity can be an area within 2.5, 2, 1.5, or 1 cm from the site, or more particularly, an area with a radius of 2.5, 2, 1.5, or 1 cm from the site.

[0088] In certain embodiments, "in the vicinity" may be defined as within 3 cm, or within 2.5, 2.0, 1.5, 1.4, 1.3, 1.2, 1.1 or 1.0 cm, of the sensor, or even more specifically, of the sensing or sampling element of the sensor device (e.g., the sensor probe, e.g., an electrode or equivalent element).

[0089] In another embodiment, reference to "in the vicinity" is made by reference to the center of the sensor or the center of the sensor's probe, i.e., in this embodiment, "in the vicinity" means within 3 cm, or within 2.5, 2.0, 1.5, 1.4, 1.3, 1.2, 1.1 or 1.0 cm, of the sensor, or even more specifically, of the sensing or sampling element of the sensor device (e.g., the center of the sensor probe, e.g., an electrode or equivalent element).

[0090] In certain embodiments, the compound may be administered in close proximity to the site of administration of a therapeutic active agent (e.g., insulin) or to the sensor site, more particularly to the site where sensing or sampling by the sensor occurs (where this site is defined according to any embodiment above). By "in close proximity" is meant an area within 2 cm of the site, or more particularly within a radius of 2 cm, e.g., 1.5 or 1 cm, from the site. As mentioned above, in the field of sensors, this may be the distance from the sensor itself, or more particularly from the sensing or sampling element or center of the sensor device.

[0091] The compound is administered in synchrony with the administration of the therapeutic active agent (e.g., insulin) to be delivered or the sensing by the sensor. This means that the administration of the compound is timed to coincide with the administration of the therapeutic active agent or the sensing by the sensor, or the compound is present, active, or still effective in the vicinity of the time when the therapeutic active agent is administered and / or absorbed or the sensing by the sensor. Thus, the vasodilatory effect of the compound, which increases local blood flow, occurs in the vicinity of the time when the active agent is administered or the sensing occurs. The administration or delivery of such an agent or the sensing by the sensor benefits from the increase in local blood flow, as will be discussed in more detail below. In other words, the compound is administered in synchrony or in synchrony with the administration and / or sensing of the active agent, or the compound is administered in the vicinity of the administration site and / or sensing of the active agent, in synchrony, synchrony, or effective with the time of administration and / or absorption and / or sensing. In other words, administration of the compound is either contemporaneous or coordinated with administration of the active agent and / or sensing by the sensor, or administration of the compound delivers the compound contemporaneously or coordinated with administration and / or absorption of the active agent and / or sensing by the sensor.

[0092] In fact, the compound is administered or delivered so as to be present and / or active or effective at the same time or at substantially the same time (i.e., about the same time) as the active agent or sensing. Thus, the compound can be administered before, during, or immediately after administration or sensing of the therapeutic active agent. For example, administration can be within 30 minutes, or more specifically, within 25, 20, 15, 12, or 10 minutes, or within 6, 5, 4, 3, 2, or 1 minutes, of administration or sensing of the therapeutic active agent. As can be seen from FIG. 15, the vasodilatory effect of glucagon may be seen for several minutes (such as 35-40 minutes), and furthermore, the vasodilatory effect continues to exceed the baseline for a period of time. Thus, the vasodilatory effect of the compound can last for a period of time after administration. Furthermore, since an active agent such as insulin can be absorbed for a long period of time, for example, 2-3 hours, after it is administered, precise synchronization of the administration time of the compound and the administration time of the active agent is not required. Thus, there is some latitude in the timing of administration and sensing, and it is not necessary to be exactly or precisely at the same time. Indeed, as discussed above, the key issue is that the compound may be present or exert a vasodilatory effect in the vicinity of the administration site of the therapeutic active agent or the sensing site of the sensor at the time of administration and / or absorption or sensing. This may be achieved using repeated administration or prolonged administration of the compound. This may create an increase in local pressure in the tissue, which may counteract the diffusion effect. Thus, the administration window may be prolonged, for example, 35, 40, 45, 50, 55, 60 minutes or more, so long as the administration, such as administration, ensures the presence of the compound or the vasodilatory effect of the compound in the vicinity of the time of administration and / or absorption or sensing of the active agent. This may be achieved by repeated administration of multiple doses over a period of time, for example, over a day, or by continuous administration, for example, continuous infusion or controlled release from a slow-release preparation.

[0093] Timing can be determined by the nature and mode of administration and the formulation (composition) administered. For example, the compound may be co-formulated with the active therapeutic agent of the same composition (i.e., they may be provided by a mixture or used in a mixture), in which case administration would be seen as coordinated. In another example, the active agent and the compound may be provided by separate formulations, but they may be mixed at the time of use just prior to administration, for example, by mixing manually before injection or in a delivery device (e.g., in an artificial pancreas or delivery system). For example, they may be mixed or administered by the same delivery line, or two separate delivery lines may be connected, such as before the point of administration. Alternatively, in another example, the compound and the active agent may be administered separately, for example, by separate injections or delivery lines. In yet another example, the compound may be delivered, for example, from a sustained or controlled release preparation, or by other sustained or repeated administration over the time course during which the therapeutic active agent is administered or sensing is performed. Such different administration modes are shown, for example, in Figures 7, 8 and 9. Typically, when administration is separate, compound can be administered before active agent.In the case of sensor, administration can be timed to occur before or at the same time as the time of sensing by sensor, for example, within a few minutes, for example, 6, 5, 4, 3, 2 or 1 minute.However, as discussed above, due to the duration of the action of administered compound, the time that administration precedes sensing can be extended, for example, 30, 25, 20, 15, 12 or 10 minutes.

[0094] Thus, administration and sensing may be coordinated or sequential, as long as they are synchronized in time, as discussed above. In the case of administration of an active agent, this may be the same administration or a separate administration. Details such as different administration routes are discussed below.

[0095] As mentioned above, the effect of the compound is to improve or, more specifically, increase local blood flow at and near its administration site.Local blood flow may be increased near its administration site, with "nearby" being defined as above.Increasing blood flow improves the effect of a therapeutic agent co-administered with the compound or improves the sensing by a sensor.For example, the effect of insulin may be improved, and the performance of a glucose sensor may be improved, i.e., the measurement of blood glucose level by a glucose sensor may be improved.

[0096] Improved effect means that the therapeutic benefit or therapeutic effect that the therapeutic agent is administered to achieve is improved. This can be in any form, such as, for example, a rapid and / or large effect is achieved, or the dose of the active agent is allowed to be reduced, the pharmacokinetics and / or pharmacodynamics are improved, etc. In the case of insulin, this effect can be defined as an improvement in glucose control. Thus, the effect can be the effect of reducing blood glucose levels. Thus, the improvement in insulin effect can be a faster, more rapid, lower blood glucose level, or a rapid onset of reducing blood glucose level. For example, the delay in the subject's response time to insulin (or indeed other therapeutic agent) or, more specifically, the response time of blood glucose level can be reduced, or the time lag or waiting time of the response to insulin can be shortened. In other words, the pharmacodynamics of the response to insulin can be improved, for example, quickly. The effect of insulin in stabilizing or normalizing blood glucose level can be improved, for example, by achieving a rapid effect or a rapid response of blood glucose level to insulin. Improved insulin effect can also result in more predictable absorption of insulin by reducing the day-to-day variation of insulin absorption observed by subcutaneous insulin injection, which can also result in more predictable effects on glucose levels. These various effects can be seen in comparison to or compared to the effects achieved by the same insulin administration in the absence of the compound. Another aspect is that a single insulin administration can reduce the time it takes to act on glucose levels, reducing the risk of hypoglycemia. The same or similar considerations can be applied to other therapeutic agents.

[0097] Similarly, in the case of a sensor, the kinetics of sensing may be improved or accelerated. This may be evident in faster sensing, e.g., faster results or, more particularly, reduced delay, lag or latency in sensing and / or more accurate results. Such improvement may be seen in comparison to or in comparison with the sensing obtained in the absence of the compound, i.e., in comparison to or in comparison with the effect (or result) achieved by the sensor in the absence of the compound.

[0098] Without wishing to be bound by theory, the effect of the compound or improved local blood flow may be such as to increase the absorption of a co-administered therapeutically active agent, such as insulin.

[0099] Increased absorption can be seen as an aspect of improved delivery of administered therapeutic active agents. That is, the delivery of active agents to their target tissues or bloodstream (circulation) can be improved, for example, increased or accelerated (in other words, the amount of therapeutic agent delivered or the rate of delivery can be increased). Thus, more generally, a compound can have the effect of improving the delivery of co-administered therapeutic active agents to a subject. Delivery in this field can be understood to refer to the delivery of a therapeutic active agent to its site of action or uptake in the body, for example, the delivery of a drug (e.g., insulin) to the site where it is absorbed by the body, including delivery to circulation.

[0100] Compounds with glucagon activity are administered to the vicinity of the therapeutic administration site or sensor to achieve vasodilatory effect, not glucose-increasing effect.The dose of the compound can be selected or measured accordingly.Surprisingly, it has been found that the dose required to achieve vasodilatory effect is low, and is much lower than the dose of glucagon reported to be used for current therapeutic or diagnostic indications.In some subjects, in certain body regions, vasodilatory effect has been observed with glucagon at a dose of <0.01mg.

[0101] Thus, generally, low doses are used, typically lower than the doses administered to treat or combat hypoglycemia or episodes of hypoglycemia. Thus, the doses are lower than the rescue doses administered in cases of hypoglycemia. Such rescue doses are typically 1 mg.

[0102] In particular, the compound may be administered to a subject at a minute dose, which is less than the dose required to counteract actual hypoglycemia or less than the dose required to achieve a clinically significant increase in blood glucose levels. Very low or minute doses of a compound with glucagon activity are not intended to increase blood glucose or treat hypoglycemia, but may have a detectable or measurable effect on increasing blood glucose levels. The term "clinically significant" is intended to convey a dose that is sufficient to achieve an increase in blood glucose levels that is beneficial in treating hypoglycemia. Hypoglycemia is defined as a blood glucose level of <3.9 millimoles per liter (<70 mg / dl). More specifically, hypoglycemia may be accompanied by a blood glucose level of <3.9 millimoles per liter, along with clinical signs that the affected subject requires assistance (e.g., requires clinical assistance).

[0103] In certain embodiments, the compound is administered in a microdosage of 0.2 mg or less, more particularly 0.15 mg or less, In more particular embodiments, the compound is administered in a microdosage of 0.1 mg or less, or 0.09, 0.08, 0.07, 0.06, or 0.05 mg or less.

[0104] In the field of diabetes treatment or management, a compound having glucagon activity may be administered separately to treat or prevent hypoglycemia. That is, the compound may be used further or additionally for its conventional or hormonal purpose of increasing blood glucose levels. Since glucagon has an opposite effect to insulin, it will be understood that the use of such a compound involves the administration of the compound at a completely separate and different time from insulin. In other words, the use of such a compound for its therapeutic glucose-increasing effect is not synchronized in time with insulin administration. In such use, since the compound is administered to increase blood glucose while insulin is administered to decrease blood glucose, they will not be administered at or near the same time, but at different times. Herein, the dose of the compound administered for such effect is referred to as a therapeutic dose (as opposed to an "enhancement" dose administered to improve the effect or delivery of a therapeutic agent or the function of a sensor).

[0105] Conventionally, the dose of compound administered to treat or counteract actual clinical hypoglycemia, i.e., rescue dose, is a large dose (e.g., 1 mg or the order of 0.5 mg in children), whereas in diabetes management or when blood glucose levels are detected to be starting to drop, for example, by sensors or by clinical signs, low doses of compound may be used according to the disclosure herein. Still further, low doses of compounds with glucagon activity may be administered periodically or at specific time intervals or at certain or predetermined time points, for example, when hypoglycemia is predicted, to prevent hypoglycemia from occurring, to reduce the possibility or risk of hypoglycemia occurring, or to reduce the severity of hypoglycemia. Such preventive or "control" doses may be of the order of the microdoses indicated above. Repeated administration of low or micro doses of compound may be sufficient to prevent hypoglycemia from occurring.

[0106] For such therapeutic use, the therapeutic dose of the compound may be administered by the same means as the "boosting" dose, for example, in the field of delivery devices or systems (e.g., artificial pancreas), from the same reservoir, through the same line or channel, etc. Thus, the site of administration of the compound for the two different purposes may be the same, or alternatively, different. However, the administration of the therapeutic compound to counteract hypoglycemia will be a time-spaced administration, distinct from the administration of the compound to achieve a vasodilatory effect in conjunction with an additional therapeutic active agent (insulin) or sensing. In an embodiment, the administration for the therapeutic effect to counteract hypoglycemia will be at a completely different time than the administration to enhance the effect on insulin. In an embodiment, there may be a long-term or controlled release of the compound for its vasodilatory effect (i.e., in conjunction with the delivery of the therapeutic agent and / or sensing of the analyte) and separate administration for the effect to counteract hypoglycemia. In general, such administration may be at different doses or different administration rates.

[0107] In another embodiment, the administration of the compound for its therapeutic antihypoglycemic effect may be at the same or similar dose and / or route of administration as the administration for the vasodilatory (enhancing) effect. In this case, in some embodiments, the two administrations may be distinguished by the site of administration, i.e., the two administrations may be at different sites. In particular, in some embodiments, the therapeutic administration will not be at the site of administration of the therapeutic agent or in the vicinity of sensing by the sensor.

[0108] Regarding the vasodilatory effect (or alternatively stated, "enhancing" effect), the methods, uses and systems herein involve administration of a compound with glucagon activity for one or both of two purposes, namely administration of an active therapeutic agent or administration of a compound in conjunction with a sensor. These two uses may be independent of each other or may be performed together. Thus, the sensing of an analyte by a sensor can complement and, in fact, inform the administration of a therapeutic active agent. Thus, administration of an active agent with a compound may occur in response to sensing by a sensor. This may be especially true in the field of insulin administration and glucose sensing. However, a therapeutic active agent may also be co-administered with a compound in response to sensing by another sensor or in response to another result, for example, sensing by a different sensor, for example, a sensor that is not an internal sensor or is not used in conjunction with the compound.

[0109] The compound having glucagon activity and the additional therapeutic agent (e.g., insulin) will typically be provided for administration in the form of a pharmaceutical composition, whether combined in a single composition or, more appropriately, combined as separate compositions. A pharmaceutical composition may include the compound or agent and one or more pharma- ceutically acceptable carriers or excipients.

[0110] Such carriers or excipients are well known and described in the pharmaceutical art and will depend on the route of administration of the composition. The compound (or composition) may be administered by any desired route, which may depend on the nature of the therapeutic agent.

[0111] Typically, to take advantage of the vasodilatory effect of the compound, the compound and therapeutic agent will be administered to a selected or desired site or location in the body where absorption is enhanced by local vasodilatation. In this regard, it is particularly useful in low-perfusion tissues, where it may be difficult to achieve a sufficient local drug concentration to exert the desired effect. In some cases, this is the case with antibiotics. Thus, the use, the method and the device can be applied to antibiotic administration, for locally administering antibiotics for the treatment of local infection.

[0112] Thus, administration may be to an internal site, suitably by injection or infusion. Administration may be localized to an internal tissue or organ or body cavity site. In some embodiments, administration is to a site with absorption, such as intradermal, subcutaneous, intramuscular, or intraperitoneal, intranasal, or at a mucosal surface, such as intratracheal, e.g., intrapulmonary. For example, administration may be subcutaneous (SC) or intramuscular (IM) or intraperitoneal (IP) or to any desired body cavity or organ.

[0113] In some embodiments, administration may be oral, e.g., buccal or sublingual, or nasal (e.g., by nasal spray), pulmonary (e.g., by inhalation), vaginal, rectal, ocular, or urethral.

[0114] In some embodiments, the administration of the compound is not pulmonary, e.g., not by inhalation. In another embodiment, where the compound is GLP-1, the administration is not pulmonary or by inhalation. In even more particular embodiments, where the condition being treated is type 2 diabetes and / or the sensing is glucose sensing in a subject with type 2 diabetes, the administration of the compound is not pulmonary or by inhalation.

[0115] In particular, administration may be parenteral.

[0116] In certain embodiments, administration is subcutaneous or intraperitoneal.

[0117] Similarly, the sensor may be placed in any desired site or location within the body. This may include any site, tissue or organ with a rich blood supply (which reduces sensor lag), including, for example, the nasal cavity. Typically, however, sensing will be done subcutaneously or intraperitoneally. Subcutaneous sensors may be worn externally on the body surface and perform subcutaneous sensing, for example, the sensor may access subcutaneous fluids or tissues. Subcutaneous sensors may be positioned at any desired or convenient site on the body surface, which may depend on whether the subcutaneous sensor is a standalone sensor or part of an integrated device. A typical location for a glucose sensor is on the abdomen, but for example, the sensor may also be positioned on the arm, for example, the upper arm, or the leg, for example, the thigh. Alternatively, the sensor can be a partially indwelling sensor, and can perform sensing, for example, in a body cavity, for example, in the peritoneal cavity, or in a body tissue or organ. This can include, for example, a venous sinus, and the sensor can be located intracranially or along the spinal cord to measure analytes in the CSF. For example, in the diagnosis or monitoring of metabolic disease or its treatment, or more generally, in therapeutic monitoring, a sensor that measures, for example, metabolites at such sites can be valuable.

[0118] Pharmaceutically acceptable carriers or excipients may include buffer systems, preservative(s), toxic agent(s), chelating agent(s), stabilizer(s) and surfactant(s). In one embodiment of the present invention, the pharmaceutical formulation is an aqueous formulation, i.e., a formulation that contains water. The range of such agents and components is known in the art and available to the skilled artisan.

[0119] Further possible additional ingredients may include humectants, emulsifiers, antioxidants, bulking agents, metal ions, oil vehicles, proteins (e.g., human or non-human serum albumin, gelatin, or other proteins) and zwitterions (e.g., amino acids such as betaine, taurine, arginine, glycine, lysine, and histidine). Other ingredients may include carriers, such as, for example, polymers, particles, encapsulating agents, and the like.

[0120] In addition to formulation auxiliary, pharmaceutical composition may also contain other components or ingredients, including agents such as penetration enhancers, e.g., skin penetration enhancers, that may assist in the administration or delivery of compounds, depending on the administration mode and administration site, e.g., when compounds are applied to the skin in the vicinity of subcutaneous sensor or subcutaneous administration of therapeutic agents.Such skin penetration enhancers are widely used in the cosmetic and pharmaceutical fields to promote the penetration of drugs or other agents through the skin.Skin penetration enhancers may act directly or indirectly on components in the skin in different ways.Typical such agents include azone, urea, fatty acid, sulfoxide (e.g., DMSO), surfactant, terpene, alcohol, e.g., ethanol and glycol.Alternatively, skin penetration enhancers may be vesicular carriers (e.g., including liposomes or other microvesicles) or enzyme inhibitors that modify lipids in the stratum corneum.

[0121] In some embodiments, it may be advantageous to administer the compound in a long-term or slow-release format (also referred to herein as "controlled release"). For example, at the sensor site, the compound may be administered by a sustained release formulation or preparation, or by a sustained release reservoir. In the case of a subcutaneous sensor, this may take the form of a skin adhesive patch that is placed or applied near the sensing site. This is advantageous because the subcutaneous sensor is fixed to the skin. A transdermal delivery device for glucagon, for example, an adhesive patch or reservoir for transdermal delivery, may be provided as part of the sensor, for example, as shown in FIG. 5, or may be provided as a separate patch or reservoir for application to the skin near the sensor. In the case of subcutaneous delivery devices for therapeutically active agents (e.g., insulin), such as infusion pumps, the subcutaneous delivery line may also be secured to the skin, and again, the use of a skin patch or reservoir for transdermal delivery for administration of sustained release compounds is advantageous, for example, near the site where the delivery line penetrates the skin, as shown in Figures 9 or 11. In such formats, it may be beneficial to use a skin penetration enhancer to facilitate or aid in the delivery or absorption of the compound, and it may be beneficial to use the more lipid-soluble derivatives discussed above.

[0122] An alternative sustained release format is one in which the compound is provided on the delivery line of the delivery device (e.g., an infusion pump), particularly at the tip, or in a sustained release coating at or toward the end of the delivery line, e.g., that penetrates the skin, or in the subcutaneous or other internal portion of the sensor, such as the sensor membrane, sensor needle or sensor electrode (such as the sensor membrane, sensor needle or sensor electrode present in a glucose sensor) or the sampling portion of the sensor, so that the compound is administered when the therapeutic agent is administered or sensing by the sensor is performed.

[0123] Yet another sustained release format is a depot preparation (or, in other words, a depot composition) or implant that contains the compound in combination with a sustained release carrier or sustained release material that delays or extends the release of the compound. Such preparations may be administered to or deposited at a site that is in the vicinity of the administration site of the therapeutic agent or the sensing site of the sensor. Thus, such preparations may be part of an integrated sensor, for example, in or in the vicinity of the sensor injection needle or the sensor electrode, as shown in FIG. 4. Sustained release carriers as well as materials suitable for such use are known in the art and include, for example, various polymeric materials. An example of such a sustained release format is a micro-ampule or capsule that contains or encloses or encapsulates a formulation (composition) of the compound in a form that allows the compound to be released in a sustained manner (for example, through the capsule wall) and can be administered to the insulin delivery site or sensing site.

[0124] Compounds with glucagon activity can be administered in different ways, for example depending on the choice and design of the device by which it is administered. Thus, administration by injection or infusion can be acute or sustained over time, for example an acute bolus injection administered for example over 1-3 seconds, or a sustained bolus injection for example over 10-15 seconds. The infusion can be for a longer period, for example over several minutes or hours. Continuous infusion can be performed. Thus, administration of glucagon can be continuous or intermittent for durations ranging from a few seconds to several minutes or hours, or can be continuous for several days. For example, the infusion can be stopped at night when glucose excursions are limited, and can be intermittent during the day. This can depend on the site of administration, but generally such injections or infusions can be applied to subcutaneous injections or infusions, or to injections or infusions at other sites, for example intraperitoneal injections or infusions.

[0125] In the treatment or management of diabetes, insulin is typically administered by parenteral means, generally subcutaneous injection or infusion, or intraperitoneal injection or infusion, which represent the preferred routes of administration herein.

[0126] Insulin is typically administered by some subjects via multiple daily injections (MDI). Thus, in some embodiments, the compound is co-administered with insulin by multiple daily injections. Insulin may also be co-formulated with the compound, for example, in a mixture, and insulin and the compound may be mixed before administration, for example, before taking into a syringe. Alternatively, insulin and the compound may be administered by separate injections, for example, multiple separate injections every day. Thus, doses or boluses of the compound may be administered by separate injections throughout the day. This may be at different frequencies throughout the day.

[0127] Another common administration route for insulin is via an infusion pump, commonly referred to as an insulin pump, i.e., continuous subcutaneous insulin infusion (CSII). The compound may be administered together with insulin via the insulin pump, or via a different pump. Those skilled in the art will recognize that this can be done in various ways. For example, the compound may be co-formulated with insulin for delivery via a pump, or the pump may contain or be equipped with a separate reservoir of the compound, which may be delivered by the same or different delivery line as insulin. Two separate delivery lines may be connected to one delivery line before puncturing the skin, etc. In some embodiments, a continuous infusion of the compound, for example, a microdose of the compound, may be done. In another embodiment, the administration of the compound may be timed with the administration of insulin.

[0128] Insulin and compounds can be administered from a device that administers them through the skin by microneedles. These can be, for example, short, 1-3 mm microneedles that are commonly known in the art and used in delivery devices. The delivery needles for each can be easily configured to be adjacent to each other. In some embodiments, the needles for administration of the compound and insulin can be positioned adjacent to each other in the device, but the penetration into the skin can be to different depths. For example, these needles can be needles of different lengths.

[0129] Moreover, in the management of diabetes, it is common for subjects to use an internal glucose sensor, such as a CGM sensor.Typically, this is a subcutaneous sensor.Therefore, for such glucose sensor, particularly for subcutaneous glucose sensor system, compound is preferably administered subcutaneously.Therefore, compound may be administered as part of an insulin delivery system, or may be administered as part of an integrated pump system for compound and insulin delivery.

[0130] As mentioned above, artificial pancreas (AP) is developed to automate insulin delivery and glucose sensing in an integrated manner. Therefore, artificial pancreas can be considered as an integrated device or system for controlling blood glucose levels, including one or more glucose sensors and control systems and a delivery device for insulin. According to the developments herein, artificial pancreas is further modified to include a delivery device for compounds. This may be the same delivery device as insulin delivery device, or it may be a separate delivery device. Therefore, artificial pancreas represents another way of administering compounds.

[0131] The delivery device, or more generally, the delivery means, may take the form of a pump or an injection or infusion device or a transdermal delivery system, such as an adhesive patch or reservoir for transdermal delivery, e.g., as a coating, depot or reservoir within the device configured to contact the skin-contacting portion of the device or to allow the compound to be delivered or released at the site of glucose sensing and / or insulin administration.

[0132] Thus, in various embodiments, the compound and / or insulin each comprise: (i) may be administered from an artificial pancreas that is an integrated device that includes one or more delivery devices for administration of insulin and compounds and a glucose sensor; or (ii) is administered from an insulin pump, which may be an insulin pump or a separate pump, and / or a pump for delivery of said compound; or (iii) may be administered as part of a multiple daily injection schedule; or (iv) the compound is administered by continuous infusion near the site of insulin administration or a glucose sensor; or (v) The compound is administered in the form of a sustained release preparation.

[0133] Different sustained release preparations are discussed above.

[0134] Today, the artificial pancreas used in clinical practice tends to be SC AP.However, as mentioned above, IP AP or mixed SC / IP AP is being developed, which combines intraperitoneal insulin administration with intraperitoneal glucose sensing, for example, when subcutaneous glucose sensing is combined with intraperitoneal insulin delivery.The present method and use are applicable for use with any such artificial pancreas.

[0135] In certain embodiments, the compound may be used in conjunction with a subcutaneous glucose sensor, and insulin may be administered subcutaneously or by any means, with or without co-administration of the compound. In other words, in some embodiments, the compound may be used alone to improve glucose sensing, without being used in conjunction with insulin administration. This may be a desirable option, for example, when the glucose sensor is a subcutaneous glucose sensor, and insulin is administered intraperitoneally or in another body cavity.

[0136] Thus, in one embodiment, the compound is administered subcutaneously and insulin is administered subcutaneously, intraperitoneally, or into any other body cavity or organ or tissue, for example, intramuscularly.

[0137] Further, in certain embodiments, the glucose sensor is a subcutaneous glucose sensor, an intraperitoneal glucose sensor, or is placed in any other body cavity or organ or tissue.

[0138] In any such embodiment, the organ may not include the lung. More particularly, in one embodiment where the compound is GLP-1, the organ does not include the lung.

[0139] In further embodiments, the compound is administered subcutaneously in conjunction with a subcutaneous glucose sensor(s). Such embodiments may include administration of additional insulin, e.g., intraperitoneally, with or without co-administration of the compound.

[0140] Thus, it will be understood that the use of compounds to enhance delivery of therapeutic agents and the use of compounds to enhance sensors can be employed independently of one another or in combination.

[0141] In any such embodiment, the compound may be further administered separately subcutaneously to raise blood glucose levels when required, either at the same site as the compound near the insulin administration site or the glucose sensor site to combat or prevent hypoglycemia, or at a different site.

[0142] In certain embodiments, as will be further discussed below, the methods and uses herein may be advantageously applied in various automated formats, including a standalone sensor system format, a standalone delivery system format, or an integrated sensor and delivery system format. In the case of insulin delivery and glucose sensing, these may be considered as standalone glucose sensor systems, standalone insulin delivery systems (so-called insulin pumps), or artificial pancreases. Each such system is adapted to allow compound administration in conjunction with insulin / other therapeutic active agent administration and / or glucose / other analyte sensing by sensors. The means or device incorporated into the system for compound administration may be the same as or different from the device incorporated for insulin (or other therapeutic active compound) administration.

[0143] In the case of an artificial pancreas, it may be designed to administer a compound in conjunction with glucose sensing or insulin administration alone, or in conjunction with both glucose sensing and insulin administration. Such various configurations are depicted in Figures 11, 12, and 13. For example, if the entire artificial pancreas is SC AP, it may be desirable and advantageous to use a compound in both fields. However, in other embodiments, it may be desirable to administer a compound in conjunction with only subcutaneous insulin administration, or in conjunction with only glucose sensing (see Figures 5-10). For example, in the case of a mixed artificial pancreas that combines intraperitoneal insulin administration with subcutaneous glucose sensing, the compound may be administered in conjunction with only the glucose sensor. However, in other mixed systems, the compound may be administered continuously with both glucose sensing and insulin administration, or in conjunction with only insulin administration. Furthermore, full IP AP may allow administration of a compound in conjunction with both glucose sensing and insulin administration, where the compound is administered intraperitoneally near the site of glucose sensing and near insulin administration.

[0144] Thus, in one aspect, the artificial pancreas, also referred to herein as an integrated system for controlling blood glucose levels in subjects with diabetes, is configured to administer a compound in conjunction with sensing of glucose by a glucose sensor. Thus, the system includes a glucose sensor system, which may be the same or different, as indicated above, including an insulin delivery system and a compound delivery system, and one or more glucose sensors. Based at least in part on the sensor data from the glucose sensor(s) that provide information about blood glucose levels, the control system of the artificial pancreas measures the insulin dose to be administered and controls the insulin delivery device to administer the insulin. If desired, additional data or information, such as pre-programmed data or information or data or information input by the user, may also be used to measure the insulin dose. The control system may further be configured to control the compound delivery device to administer the compound to a site in the vicinity of the glucose sensor in time synchronization with the operation of the glucose sensor that measures the blood glucose level. As mentioned above, the compound acts to improve blood flow in the vicinity of the glucose sensor. Blood flow to the vicinity of the sensor can be improved, which may improve the performance of the sensor. Alternatively, delivery of the compound can be controlled by a time-release system for the compound contained in or equipped with the device.

[0145] The details discussed and described above in relation to proximity and temporal synchronization, compound doses, etc. are all applicable in the context of any of the systems described herein.

[0146] If desired, the control system may be further configured to control the compound delivery device to administer the compound at a site proximate to the site of insulin administration and synchronized in time with the administration of insulin.

[0147] Still further, if desired, the control system may be further configured to determine a therapeutic dose of a compound to be administered to the subject to increase the subject's blood glucose level based on at least the sensor data, and to control a compound delivery device to administer said therapeutic dose of a compound to the subject to counteract hypoglycemia or predicted hypoglycemia.

[0148] In various exemplary embodiments, the integrated system or artificial pancreas comprises: (i) a subcutaneous system, where the glucose sensor is a subcutaneous glucose sensor and the compound and insulin are administered subcutaneously; or (ii) an intraperitoneal system, where the glucose sensor is an intraperitoneal glucose sensor and the compound and insulin are administered intraperitoneally; or (iii) A combined subcutaneous / intraperitoneal system, where the glucose sensor is a subcutaneous glucose sensor, the compound is administered subcutaneously at a site proximal to the glucose sensor, and insulin is administered intraperitoneally, optionally with the compound administered intraperitoneally in conjunction with insulin administration.

[0149] In any such embodiment, the system may further include optional intraperitoneal or subcutaneous administration of a compound to treat or prevent hypoglycemia. In case (iii), the compound may be administered subcutaneously, for example, at a site in the vicinity of the glucose sensor to treat or prevent hypoglycemia. Thus, the compound delivery system in such a case may be configured and controlled by the control system to perform two separate functions: administering the compound in conjunction with glucose sensing by the sensor, and separately, administering a therapeutic dose of the compound to treat or prevent hypoglycemia, if needed or desired.

[0150] Similarly, the various elements and system parts discussed above may be present in a sensor system for measuring the level of glucose in a subject's blood, and may be present in an insulin delivery system for administration of insulin to a subject.

[0151] More broadly, as indicated above, it can be seen that similar sensor systems can be provided for the detection of any analyte in the blood of a subject or the delivery of any therapeutically active agent to a subject.

[0152] The dosage and route of administration of the compound and, if appropriate, other therapeutic agents may be as discussed above. Thus, for example, the concentration and / or volume of the compound administered and / or the rate of administration (e.g., speed) may be measured and altered or adjusted to achieve the desired effect.

[0153] For example, it is known in the art that CGM may not work well in the first time after insertion. Therefore, it may be desirable or appropriate to take this into account when setting administration parameters. Furthermore, by analogy, the rate, concentration and volume of compound administration may affect the performance of the device. When CGM is first used in conjunction with a compound, it will be important to measure and take into account the possible short-term negative effects of compound administration on the sensor.

[0154] FIG. 1 is a schematic diagram of a typical CGM device known in the art. Such a device includes a housing 4 held against the surface 1 of the skin using an adhesive backing or adhesive pad 6. The device further includes a glucose sensor 5 that extends through the surface 1 of the skin into the subcutaneous tissue 2 and into the capillaries 3. The glucose sensor 5 is a needle-like electrode electrically connected to an electronic circuit disposed within the housing 4. The glucose sensor 5 in this example includes a platinum-iridium wire (forming the working electrode) with a mediator and an enzyme immobilized on its surface. A silver / silver chloride wire wrapped around the working electrode forms the counter electrode. The enzyme electrode catalyzes the reduction-oxidation reaction of glucose, and the resulting transfer of electrons results in a current or voltage at the glucose sensor 5 with a magnitude that depends on the glucose concentration (i.e., glucose level) in the interstitial fluid. The glucose concentration in the interstitial fluid can be converted to a corresponding glucose concentration in the plasma.

[0155] Other forms of glucose sensors, including needle-like electrodes, are, of course, known and may be used in place of the configuration described above. Additionally, other types of glucose sensors that do not include needle-like electrodes are also known and may be used in place of the configuration described above. For example, subcutaneous implants that use other technologies (e.g., fluorescence, osmotic or other techniques) to measure glucose in interstitial fluid are also available.

[0156] Such a standard CGM device may form part of an artificial pancreas and may provide measurements of the user's glucose levels to a controller of the artificial pancreas. In response to the measured glucose levels, the artificial pancreas regulates the glucose concentration in the user's body by controlling one or more doses of hormone (or other substance) to the user. The hormone(s) are typically administered subcutaneously or intraperitoneally, but may also be administered intravenously or intraarterially via lines connected to one or more corresponding hormone pumps containing reservoirs of hormone preparations. The artificial pancreas may be monohormonal (capable of administering only insulin) or bihormonal (capable of administering insulin as well as glucagon or another hormone or substance).

[0157] 2 is a flow chart illustrating a control loop for a conventional single hormone artificial pancreas. A single hormone artificial pancreas includes a glucose sensor (such as the CGM device of FIG. 1) at a subcutaneous or intraperitoneal site, a controller, and an insulin pump that administers insulin (under the control of the controller) at a site for insulin administration (e.g., via an infusion needle at a subcutaneous or intraperitoneal site). Typically, the glucose sensor and the site for insulin administration are separated on the user's body surface by at least 4-5 cm, and can be even further apart.

[0158] A CGM device typically measures the glucose level at the sensor site at a predetermined time interval, for example every 5 minutes. Each glucose measurement measured by the CGM device is received by the artificial pancreas controller, which compares the measured glucose level with an ideal glucose level and measures the deviation (difference) between the two values. Based on the measurement of the deviation of the measured glucose level from the ideal glucose level, the controller determines whether insulin should be administered. If the controller determines that insulin should be administered, the controller controls the insulin pump to administer insulin through an insulin line and an infusion needle placed at the site for insulin administration. Insulin absorption and metabolic processes that utilize insulin affect the glucose level in the plasma. Transport of glucose throughout the body means that changes in the glucose level in the plasma will correspondingly affect the glucose level (in the interstitial fluid) at the sensor site.

[0159] 3 is a flow chart showing the control loop for a conventional bihormonal artificial pancreas that uses insulin and glucagon. As mentioned above, conventional bihormonal artificial pancreases that administer insulin and hormones or other substances other than glucagon are also known, but this discussion will focus on conventional bihormonal artificial pancreases that administer insulin and glucagon.

[0160] The bi-hormonal artificial pancreas includes a glucose sensor (such as the CGM device of FIG. 1) at a subcutaneous or intraperitoneal site, a controller, an insulin pump (under control of the controller) at a site for insulin administration (e.g., via an infusion needle at a subcutaneous or intraperitoneal site) that administers insulin, and a glucagon pump (under control of the controller) at a site for glucagon administration (e.g., via an infusion needle at a subcutaneous or intraperitoneal site) that administers glucagon. Typically, the glucose sensor, the site for insulin administration, and the site for glucagon administration are each spaced at least 4-5 cm apart from one another on the user's body surface, and can be spaced even further apart.

[0161] A CGM device typically measures the glucose level at the sensor site at a predetermined time interval, for example, every 5 minutes. Each glucose measurement measured by the CGM device is sent to the artificial pancreas controller, which compares the measured glucose level with an ideal glucose level and measures the deviation (difference) between the two values. Based on the measurement of the deviation of the measured glucose level from the ideal glucose level, the controller determines whether insulin or glucagon should be administered. Here, any glucagon administered by a conventional bihormonal artificial pancreas is administered with the purpose of reversing the episode of hypoglycemia (i.e., a therapeutic dose is administered). If the controller determines that insulin or glucagon should be administered, the controller controls an insulin pump or glucagon pump, respectively, to administer insulin (via an insulin line and infusion needle placed at the site for insulin administration) or glucagon (via a glucagon line and infusion needle placed at the site for glucagon administration).

[0162] Absorption of insulin or glucagon and metabolic processes that utilize insulin or glucagon affect glucose levels in plasma. The transport of glucose throughout the body means that changes in glucose levels in plasma correspondingly affect glucose levels at the sensor site (in the interstitial fluid).

[0163] Conventional bihormonal artificial pancreases administer one or the other of insulin and glucagon at any one time, but there is no control mechanism by which insulin and glucagon can be administered simultaneously or synchronized in time. This is true because glucagon has opposing effects to insulin; glucagon is administered to raise glucose levels, whereas insulin is administered to lower glucose levels, and therefore are not conventionally administered at or near the same time points.

[0164] FIG. 4 shows a modified CGM device. The structure of the device is generally as set forth for the device shown in FIG. 1, except that the modified device shown in FIG. 4 further includes a subcutaneous sustained release glucagon "reservoir" 10. The reservoir 10 can take any form that allows for sustained release of glucagon, including, for example, a sustained release glucagon coating on the glucose sensor 5 located near (e.g., in close proximity, such as within 2 cm) the glucose sensor, or a sustained release glucagon depot implant or sustained release glucagon micro-ampoules (e.g., capsules that enclose or encapsulate a formulation of glucagon in a manner that allows for sustained release of glucagon through the walls of a capsule or pill, e.g., mixed with one or more other substances that facilitate sustained release of glucagon when placed in the body). Sustained release carriers and coatings and materials suitable for such use are known in the art and include, for example, a variety of polymeric materials.

[0165] A subcutaneous sustained release glucagon reservoir 10 is provided near, e.g., in close proximity (e.g., within 2 cm) to the sensing site of the glucose sensor 5, which is furthest from the skin surface 1 and near the end of the sensor. Due to the vasodilatory effects of glucagon, the sustained release of glucagon near (e.g., within 2 cm) the site where glucose concentration is measured may result in, for example, faster results or, more particularly, reduced delays, lag times or latency in sensing and / or more accurate results.

[0166] FIG. 5 also shows a CGM device that includes a sustained release glucagon reservoir. In this case, the glucagon reservoir is a transdermal sustained release glucagon patch 11. The transdermal sustained release glucagon patch 11 is adhered to the skin surface 1 within the housing 4 of the CGM device. In general, sustained release transdermal patches are known in the art (and can be modified as necessary to deliver glucagon), but in light of the inventors' findings, it is not known to include a sustained release transdermal glucagon patch as part of a CGM device. Due to the vasodilatory effect of glucagon, sustained release of glucagon near (proximate to, e.g., within 2 cm) the site where glucose concentration is measured results in faster sensing, e.g., faster results, or more specifically, reduced delay, lag or wait time for sensing and / or more accurate results.

[0167] Where a sustained release reservoir of glucagon is provided (e.g., as in Figures 4 and 5), the administration rate of glucagon is such that the dose of glucagon is typically lower than that administered to treat or counter hypoglycemia (i.e., a therapeutic dose is administered).

[0168] The CGM device of FIG. 6 has a structure similar to that shown in FIG. 1 (including a housing 4, a glucose sensor 5, and an adhesive patch 6). However, the device shown in FIG. 6 further includes a subcutaneous glucagon injection device including an infusion needle 7 in fluid communication with a glucagon infusion line 8. The infusion needle 7 is placed near or in close proximity (e.g., within 2 cm) to the glucose sensor 5. The glucagon infusion line 8 is in fluid communication with a glucagon pump (not shown) that includes a glucagon reservoir. The glucagon pump is placed outside the body. The provision of a glucagon pump (rather than a time-release glucagon reservoir) allows glucagon to be delivered in controlled doses at predetermined times. The administration of glucagon by the glucagon pump is under the control of a controller (not shown). The time at which glucagon is administered is synchronized in time with the sensing of glucose by the sensor. In particular, glucagon is administered at the same time as the time of sampling by the sensor or within at least 30 minutes before sampling occurs. Due to the vasodilatory effects of glucagon, administration of glucagon near (proximate, e.g., within 2 cm) the site where glucose concentration is measured results in faster sensing, e.g., faster results, or, more particularly, reduced delay, lag, or latency in sensing and / or more accurate results. The dose of each administration of glucagon is typically lower than the dose administered to treat or counter hypoglycemia.

[0169] FIG. 7 shows a schematic diagram of an artificial pancreas. The artificial pancreas of FIG. 7 includes a housing 4, a glucose sensor 5, an adhesive patch 6, and an infusion needle 7. The artificial pancreas further includes a glucagon infusion line 8 connected to a glucagon pump (not shown) and an insulin infusion line 9 in fluid communication with an insulin pump (not shown). The insulin pump includes an insulin reservoir and is located outside the body. The glucagon pump includes a glucagon reservoir and is located outside the body. In this embodiment, the insulin infusion line 9 merges with the glucagon infusion line 8 such that both insulin and glucagon can be delivered into the body via a single infusion needle 7. The infusion needle 7 is located near or in close proximity (e.g., within 2 cm) of the glucose sensor 5. The administration of glucagon and insulin is under the control of a controller (not shown).

[0170] The glucagon pump arrangement allows glucagon to be delivered in controlled amounts at predetermined times. The time at which glucagon is administered is synchronized in time with the sensing of glucose by the sensor and / or the administration of insulin. In particular, glucagon is administered immediately prior to the time of sampling by the sensor or at least 30 minutes before the sampling occurs. Furthermore, glucagon is administered simultaneously with the time of insulin administration or at least 30 minutes before insulin administration or within 1-2 hours after insulin administration. The dose of glucagon administered each time is typically lower than the dose administered to treat or counteract hypoglycemia.

[0171] As discussed above, due to the vasodilatory effect of glucagon, administration near (e.g., within 2 cm) the site where glucose concentration is measured results in faster sensing, e.g., faster results, or more specifically, reduced delay, lag, or wait time for sensing and / or more accurate results. Furthermore, due to the vasodilatory effect of glucagon, administration near (e.g., within 2 cm) the site where insulin is administered results in improved effects from insulin administration. Thus, improved insulin effects can be more rapid, more rapid, lower blood glucose levels, and faster onset of lowering blood glucose levels. Improved insulin effects can also result in more predictable absorption of insulin by reducing the day-to-day variability in insulin absorption observed with subcutaneous insulin injections, which can also result in more predictable effects on glucose levels.

[0172] In addition to administering glucagon to benefit from its vasodilatory effect (time-synchronized with insulin administration and / or glucose sensing), the glucagon pump can be controlled by the controller to administer a rescue glucagon dose (therapeutic dose) in the event that the controller determines that the user is suffering from hypoglycemia or is at risk for hypoglycemia in the near future.

[0173] As mentioned above, in a conventional bihormonal artificial pancreas, the site where glucose is sensed, insulin is administered, and glucagon is also administered, but are spatially separated from one another on the user's body surface. In light of the inventors' findings, it is not known to have all three sites together in close proximity as shown in FIG.

[0174] 8A and 8B show a subcutaneous glucagon injection device and a subcutaneous insulin injection device, respectively. Each device includes a housing 4 held against a skin surface 1 using an adhesive backing or adhesive pad 6. Each device further includes a glucagon infusion line 8 and an insulin infusion line 9. In FIG. 8A, two infusion needles 7 are provided (a first infusion needle is in fluid communication with the glucagon infusion line 8 and a second infusion needle is in fluid communication with the insulin infusion line 9). The two infusion needles are positioned near each other, e.g., close to each other (e.g., within 2 cm). By comparison, in the device shown in FIG. 8B, only one infusion needle 7 is provided, and this single infusion needle is in fluid communication with both the glucagon infusion line 8 and the insulin infusion line 9. 8A and 8B, the glucagon infusion line 8 is in fluid communication with a glucagon pump (not shown) that contains a glucagon reservoir, and the insulin infusion line 9 is in fluid communication with an insulin pump (not shown) that contains an insulin reservoir. The insulin pump and glucagon pump are located outside the body.

[0175] 8A and 8B include or are in communication with a controller that controls administration of glucagon and insulin in response to blood glucose level measurements from a separate CGM device. Glucagon may be administered to affect glucose levels in the body (i.e., glucagon may be administered to treat or combat hypoglycemia) and / or to enhance absorption of subcutaneous insulin from insulin infusion line 9 delivered by infusion needle 7.

[0176] The glucagon pump device allows glucagon to be delivered in controlled doses at a predetermined time. The time at which glucagon is administered is synchronized with the administration of insulin. In particular, glucagon is administered at the same time as insulin is administered, or at least 30 minutes before insulin is administered, or within 2 hours after insulin is administered.

[0177] Due to the vasodilatory effect of glucagon, administration near the site where insulin is administered (proximate, e.g., within 2 cm) results in improved effects from insulin administration. Thus, improved insulin effects can be more rapid, more rapid, lower blood glucose levels, and more rapid onset of lowering blood glucose levels. Improved insulin effects can also result in more predictable absorption of insulin by reducing the day-to-day variability in insulin absorption observed with subcutaneous insulin injections, which can also result in more predictable effects on glucose levels. The dose of glucagon administered each time is typically lower than the dose administered to treat or counter hypoglycemia.

[0178] Conventionally, the site where insulin is administered and the site where glucagon is administered are spatially separated on the user's body surface. In light of the present inventors' findings, it is not known to provide both sites integrally and in close proximity as shown in Figures 8A and 8B.

[0179] FIG. 9 shows a schematic of an insulin injection device including a housing 4 held against a skin surface 1 using an adhesive backing or adhesive pad 6. The device further includes an infusion needle 7 in fluid communication with an insulin infusion line 9 connected to an insulin pump (not shown) including an insulin reservoir. The insulin pump is placed outside the body. The insulin injection device of FIG. 9 further includes a transdermal sustained release glucagon patch 11. The transdermal sustained release glucagon patch 11 is adhered to the skin surface 1 within the housing 4 of the insulin injection device. In general, sustained release transdermal patches are known in the art, but in light of the inventors' findings, it is not known to include a sustained release transdermal glucagon patch as part of an insulin injection device.

[0180] FIG. 10 shows an insulin injection device similar to that shown in FIG. 9, except that in the device of FIG. 10, a subcutaneous sustained release glucagon reservoir 10 is provided rather than a transdermal sustained release glucagon patch 11. The sustained release glucagon reservoir 10 is provided proximate (proximate, e.g., within 2 cm) the site of insulin administration and proximate the end of the infusion needle 7. The reservoir 10 can take any form that allows for the sustained release of glucagon, including, for example, a sustained release glucagon coating on the infusion needle 7 or a sustained release glucagon depot implant or sustained release glucagon micro-ampoules disposed proximate (proximate, e.g., within 2 cm) the end of the infusion needle 7. Sustained release carriers and coatings and materials suitable for such use are known in the art and include, for example, a variety of polymeric materials.

[0181] For either of the insulin injection devices shown in Figures 9 and 10, the insulin injection device includes or is in communication with a controller that controls administration of insulin in response to blood glucose level measurements from the CGM device. Due to the vasodilatory effect of glucagon, administration of glucagon near (proximate, e.g., within 2 cm) the site where insulin is administered results in improved efficacy from insulin administration. The improved insulin effect may be more immediate, more rapid, lower blood glucose levels, or a more rapid onset of lowering blood glucose levels. Improved insulin effect may also result in more predictable absorption of insulin by reducing the day-to-day variability in insulin absorption observed with subcutaneous insulin injections, which may also result in more predictable effects on glucose levels.

[0182] Figures 11, 12 and 13 each show a schematic representation of an artificial pancreas. In each case, the artificial pancreas includes a housing 4 held against a surface of the skin 1 using an adhesive backing or adhesive pad 6. The artificial pancreas shown in each of Figures 11, 12 and 13 further includes a glucose sensor 5 that extends through the surface of the skin 1, into the subcutaneous tissue 2 and into the capillaries 3. As described above (with reference to the device shown in Figure 1), the glucose sensor 5 is a needle-like electrode electrically connected to an electronic circuit located within the housing 4.

[0183] The artificial pancreas shown in each of Figures 11, 12 and 13 further includes an infusion needle 7 in fluid communication with an insulin infusion line 9 that is connected to an insulin pump (not shown) that includes an insulin reservoir. The insulin pump is placed outside the body. As described in more detail below, each of the artificial pancreas shown in Figures 11, 12 and 13 further includes means for sustained release of glucagon near (proximately, e.g., within 2 cm of) the site where glucose concentration is measured by glucose sensor 5 and insulin is administered by infusion needle 7.

[0184] In the device shown in Figure 11, the means for sustained release of glucagon is a transdermal sustained release glucagon patch 11 (discussed above in connection with Figures 5 and 9). The transdermal sustained release glucagon patch 11 is adhered to the skin surface 1 within the housing 4 of the artificial pancreas.

[0185] In the devices shown in Figures 12 and 13, the means for sustained release of glucagon is a subcutaneous sustained release glucagon reservoir 10. In the device shown in Figure 12, the subcutaneous sustained release glucagon reservoir 10 is provided near (proximately, e.g., within 2 cm) the end of the glucose sensor 5 that is furthest from the skin surface 1 and near the actual glucose sensing point on the glucose sensor 5. In the device shown in Figure 13, the subcutaneous sustained release glucagon reservoir 10 is provided near (proximately, e.g., within 2 cm) the end of the infusion needle 7, close to the insulin administration site.

[0186] 12 and 13 can take any form that allows for the sustained release of glucagon, including, for example, a sustained release glucagon coating or a sustained release glucagon depot implant or a sustained release glucagon micro-ampoules. Sustained release carriers and coatings and materials suitable for such use are known in the art and include, for example, a variety of polymeric materials.

[0187] For all of the artificial pancreas shown in Figures 11, 12, and 13, the artificial pancreas includes a controller that controls the administration of insulin in response to blood glucose level measurements from a glucose sensor. The setups in Figures 11, 12, and 13 may also be used when glucose sensing and insulin delivery via an insulin pump are used as a stand-alone solution rather than as an integrated part of the artificial pancreas.

[0188] Due to the vasodilatory effect of glucagon, administration of glucagon near (e.g., within 2 cm) the site where insulin is administered results in improved effects from insulin administration. The improved insulin effect may be more rapid, may be a reduction in blood glucose levels, and may be a more rapid onset of reduction in blood glucose levels. Improved insulin effect may also result in more predictable absorption of insulin by reducing the day-to-day variability in insulin absorption observed with subcutaneous insulin injections, which may also result in more predictable effects on glucose levels. Furthermore, administration near (e.g., within 2 cm) the site where glucose concentration is measured results in faster sensing, e.g., faster results, or more specifically, reduced delays, lags, or wait times for sensing and / or more accurate results.

[0189] All of the devices shown in Figures 3-13 allow administration of glucagon near or adjacent to the location where glucose levels are sensed and / or near or adjacent to the location where insulin is administered (and absorbed). Near may mean, for example, within 3 cm or 2.5 cm. Near may be within 2 cm, for example, within 1.5 cm or within 1 cm. The administration of glucagon is highly localized such that while the dose of glucagon is typically lower than that administered as a therapeutic dose to treat or counter hypoglycemia, in the localized area near the site of glucagon administration, the concentration of glucagon may be higher than the corresponding concentration resulting from administration of a therapeutic dose of glucagon. If a conventional 1 mg therapeutic dose to counter or treat hypoglycemia were absorbed into the blood, this therapeutic dose would be diluted by approximately 5 liters of blood in an average patient. By comparison, the dose delivered by the device to dilate blood vessels was initially about 20 cm 3The subcutaneous tissue contains approximately 90% cells and approximately 10% interstitial fluid, so the amount of the subcutaneous tissue may be less than 20 cm. 3 In the subcutaneous volume of 100 mm, glucagon is secreted in only about 2 cm 3 is diluted by body fluids.

[0190] The invention will be described in further detail in the following examples. EXAMPLES

[0191] Example 1 Glucagon's effects on blood flow The experiment was carried out on two healthy human young adult volunteers. The effect of subcutaneous (hereinafter SC) injection on intradermal blood flow was examined six times in two subjects (four studies in male subjects and two studies in female subjects). Glucagon was administered by subcutaneous injection of 0.1 ml of 1 mg / ml glucagon (i.e., an injection containing 0.1 mg of glucagon) to sites on both sides of the subject's upper arm. Blood flow was measured by laser Doppler technology on the skin surface at the administration site. As a control, the same volume of saline (0.9%) was injected as a placebo at the same site.

[0192] The results of this experiment are presented in Figure 14 for both glucagon and placebo. The average of six trials is shown along with the 95% confidence interval. It can be seen that the effect of glucagon on local blood flow was enormous, with blood flow increasing by several hundred percent. Even after returning to "normal" values, blood flow was still increased compared to before glucagon injection. Injection of saline with the same volume had only a short-lived acute effect and no long-term effects.

[0193] This effect was further explored in a similar experiment with varying doses of glucagon. Again, the same two subjects were used, and subcutaneous injections of glucagon or placebo were administered six times (four trials in male subjects and two trials in female subjects). Glucagon was administered at sites on the sides of both upper arms in the amounts of 0.1 mg, 0.015 mg and 0.01 mg (0.1 ml of glucagon at concentrations of 0.1 mg / ml, 0.015 mg / ml and 0.01 mg / ml, respectively). Blood flow was measured by laser Doppler technology on the skin surface at the administration site. As a control, the same volume of saline (0.9%) was injected as a placebo at the same site.

[0194] The results of this experiment are presented in FIG. 15, which shows the average over six trials for each concentration of glucagon and placebo. Comparable results are also shown in FIG. 16, with the placebo effect subtracted. It can be seen that both 0.1 mg and 0.015 mg of glucagon produced a dramatic increase in local blood flow (400-450% of baseline reading). A similar, but less pronounced effect was also observed with 0.01 mg of glucagon. As in the first experiment, the increase in blood flow was found to remain constant once values ​​stabilized. This was seen for all glucagon doses, but not for placebo.

[0195] Further experiments were carried out to explore the effect of subcutaneous injection of glucagon on local blood flow in the abdomen. Again, the same two subjects were used, and subcutaneous injections of glucagon or placebo were administered six times (three tests in male subjects and three tests in female subjects). Glucagon was administered by subcutaneous injection of 0.1 ml of 1 mg / ml glucagon (i.e., injection containing 0.1 mg of glucagon) to sites on both sides of the abdomen of the subjects. Blood flow was measured by laser Doppler technology on the skin surface of the administration site. As a control, the same volume of saline (0.9%) was injected as a placebo at the same site.

[0196] The results of this experiment are presented in Figure 17 for both glucagon and placebo. The average of six trials is shown along with the 95% confidence interval. It can be seen that administration of 0.1 mg of glucagon resulted in a significant increase in local blood flow, which was slightly greater than the increase observed when saline was administered. The increase in local blood flow following administration of glucagon was also more sustained than that observed following administration of the control, although blood flow values ​​for both groups were approximately equivalent after approximately 30 minutes.

[0197] This effect was further explored in a similar experiment with varying doses of glucagon. Again, the same two subjects were used, and subcutaneous injections of glucagon or placebo were administered six times (three trials in male subjects and three trials in female subjects). Glucagon was administered at sites on both sides of the abdomen in the amounts of 0.1 mg, 0.05 mg and 0.015 mg (0.1 ml of glucagon at concentrations of 0.1 mg / ml, 0.05 mg / ml and 0.015 mg / ml, respectively). Blood flow was measured by laser Doppler technology on the skin surface at the administration site. As a control, the same volume of saline (0.9%) was injected as a placebo at the same site.

[0198] The results of this experiment are presented in FIG. 18, which shows the average of six trials for each concentration of glucagon and placebo. The equivalent results are also shown in FIG. 19, with the placebo effect subtracted. Glucagon was administered into the abdomen, and only 0.1 mg of glucagon produced an initial increase in local blood flow that was greater than the initial increase seen following administration of the same control. Administration of 0.05 mg of glucagon did not result in a significant increase in local blood flow initially, but the increase observed was more sustained than the effect of saline injection, such that after 15 minutes the local blood flow exceeded that observed at the same time point after injection of the control. Administration of 0.015 mg of glucagon into the abdomen did not appear to produce a significant effect on local blood flow compared to control injection.

[0199] Further experiments were carried out to explore the effect of subcutaneous injection of glucagon on local blood flow in the thigh. A single female subject was used, and seven subcutaneous injections of glucagon or placebo were administered. Glucagon was administered to a site on the subject's thigh by subcutaneous injection of 0.05mg glucagon (five subcutaneous injections of 0.1ml and two subcutaneous injections of 0.05ml). Blood flow was measured by laser Doppler technology on the skin surface at the administration site. As a control, 0.9% saline (five injections of 0.6ml and two injections of 0.03ml) was injected as a placebo at the same site.

[0200] The results of this experiment are presented in Figure 22 for both glucagon and placebo. The average of seven trials is shown along with the 95% confidence interval. It can be seen that administration of 0.05 mg of glucagon resulted in a significant increase in local blood flow that was slightly greater than the increase observed when saline was administered. The increase in local blood flow following administration of glucagon was also more sustained than that observed following administration of the control, although blood flow values ​​for both groups were approximately equivalent after approximately 30 minutes.

[0201] This effect was further explored in a similar experiment with varying doses of glucagon. Again, one female subject was used, and glucagon or placebo was injected subcutaneously seven times. Glucagon was administered to a site on the subject's thigh in the amounts of 0.05mg (0.1ml for 5 times, 0.05ml for 2 times), 0.03mg (0.06ml for 5 times, 0.03ml for 2 times) and 0.01mg (0.02ml for 5 times, 0.01ml for 2 times). Blood flow was measured by laser Doppler technology on the skin surface of the administration site. As a control, 0.9% saline was injected as a placebo (0.06ml for 5 times, 0.03ml for 2 times) at the same site.

[0202] The results of this experiment are presented in Figure 23, which shows the average over seven trials for each concentration of glucagon and placebo. Comparable results are also shown in Figure 24, with the placebo effect subtracted. Glucagon was administered into the thigh, with 0.03 mg of glucagon producing the greatest increase in local blood flow. Administration of 0.05 mg of glucagon also resulted in a significant increase in local blood flow that was slightly greater and significantly more sustained than the increase in local blood flow observed following administration of the saline control. Administration of 0.01 mg of glucagon into the thigh did not appear to produce a significant effect on local blood flow compared to the control injection.

[0203] This effect was further explored in a similar experiment to explore the effect of glucagon on CGM performance. Again, data from 12 meals in non-diabetic women and 11 meals in non-diabetic men using two subjects and collected by Dexcom G6 CGM are shown. Subjects had two CGMs placed in symmetrical positions on the sides of each upper arm. 1-3 minutes before the start of eating, 0.1 ml of glucagon (1 mg / ml) was injected into one CGM site and 0.1 ml of placebo (saline (0.9%)) was injected into the contralateral CGM site. Before each meal, the glucagon delivery site was measured with a new randomization.

[0204] The results of this experiment are presented in Figure 26. It shows that administration of glucagon at the CGM site results in a rapid and large increase in detected glucose levels compared to placebo. This effect was evident in one of the subjects at 10 minutes.

[0205] Example 2 Effect of injection technique on glucagon efficacy To observe the influence of the injection technique, and in particular the speed of the injection, on the effect induced by subcutaneous injection of glucagon, an experiment was carried out comparing two different injection techniques, one in which the injection lasted for 1-3 seconds (technique 1) and one in which the injection lasted for at least 10 seconds (technique 2). Six injections were administered by technique 1 and four injections by technique 2. In each case, 0.1 mg of glucagon (by injection of 0.1 ml) was injected subcutaneously into the abdomen of the subject. For each technique, half of the injections were administered to male subjects and half to female subjects. Blood flow was measured by the laser Doppler technique on the skin surface at the administration site.

[0206] The results of this experiment are presented in Figure 20. Additionally, Figure 21 shows the same results along with placebo injections of 0.1 ml of 0.9% saline using the same two techniques. For technique 1, six placebo injections were administered, and for technique 2, two placebo injections were administered. Again, half of the injections for each technique were administered in male subjects, and half in female subjects.

[0207] It can be seen that technique 2, in which the injection is given more slowly, results in a significantly greater increase in local blood flow. This effect was observed with both glucagon and placebo injections, but what is noteworthy is that the effect of the "slow" glucagon injection on local blood flow was more sustained than that of either of the other injections.

[0208] Example 3 Effect of probe placement on measurements of glucagon effect The influence of the placement of the laser Doppler probe on the measurement of the effect of glucagon injection on local blood flow was explored by administering injections at multiple sites at varying distances from the probe. The experiment involved subcutaneous injection of 0.015 mg glucagon (in 0.1 ml) or 0.1 ml of 0.9% saline as a control at sites on the lateral sides of both upper arms of the subjects. Injections were administered below the probe, 1.6 cm from the probe center, 3 cm from the probe center, or 5 cm from the probe center. In each case, six injections were administered, except at 1.6 cm from the probe center, where only four saline injections were administered. Four studies were conducted in male subjects and two studies were conducted in female subjects. In all cases, except below the probe, half of the injections were administered to male subjects and half to female subjects. Blood flow was measured by laser Doppler techniques on the skin surface.

[0209] The results of this experiment are presented in Figure 25, which shows the average of six glucagon injections, subtracting the average of the placebo injections. It can be seen that the greatest increase in local blood flow was observed when the injections were administered directly under the probe. When injections were administered at greater distances from the probe, the increase in local blood flow was less significant. There did not appear to be a significant difference between the results obtained when injections were administered 1.6 cm, 3 cm, or 5 cm from the center of the probe. However, except for the injection 5 cm from the probe, the effect was greater than placebo. [Explanation of symbols]

[0210] 1 Skin surface 2 Subcutaneous tissue 3 Capillaries 4. Chassis 5. Glucose Sensor 6 Adhesive backing or adhesive pad Adhesive Patch 7 Injection needle 8 Glucagon infusion line 9. Insulin Infusion Line 10. Subcutaneous sustained-release glucagon reservoir Reservoir 11 Transdermal sustained-release glucagon patch

Claims

A pharmaceutical composition comprising a compound having glucagon activity for use in the treatment and / or management of diabetes by co-administration with insulin, wherein in said use, the compound is administered to a subject at a dose of 0.05 mg or less, at a site within 1 cm of the insulin administration site, and such that the compound has a vasodilatory effect at the administration site during and / or upon absorption of insulin, in temporal synchronization with insulin administration; the compound and insulin are each administered subcutaneously, either alone or in admixture, the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the compound is administered at a dose of 0.01 mg or less.

3. The pharmaceutical composition according to claim 1, wherein the compound is administered at a dose of less than 0.01 mg.

4. The pharmaceutical composition for use according to claim 1, wherein the treatment and / or management of diabetes further comprises a separate administration of a therapeutic dose of a compound having glucagon activity to treat or prevent hypoglycemia in the subject or to increase glucose levels.

5. The pharmaceutical composition according to claim 4, wherein the therapeutic dose is administered at the same site as the temporally synchronized administration.

6. In said use, the pharmaceutical composition and the insulin are co-administered in conjunction with or in response to sensing of glucose by an in vivo glucose sensor, the pharmaceutical composition according to claim 1.

7. The pharmaceutical composition, wherein (i) is administered during administration of the insulin; or (ii) is administered within 30 minutes, within 15 minutes, or within 5 minutes of administration of the insulin; or (iii) is administered simultaneously with the insulin; and / or (iv) is administered at the same site as the insulin; and / or (v) is co-administered with insulin as a single composition or pre-mixed with insulin prior to administration or mixed in a delivery device and administered, the pharmaceutical composition according to claim 1.

8. The pharmaceutical composition and / or the insulin are each administered from (i) an integrated device comprising one or more delivery devices or delivery means for administration of the insulin and the pharmaceutical composition and one or more subcutaneous glucose sensors, a subcutaneous artificial pancreas; or ​ (ii) It may be an insulin pump or another pump, and is administered from an insulin pump and / or a pump for delivering the pharmaceutical composition; or, (iii) It is administered as part of a plan for multiple daily injections; or, (iv) The pharmaceutical composition is administered by continuous infusion at a site within 1 cm of the insulin administration site and optionally also within 1 cm of a glucose sensor; or, (v) The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered in the form of a sustained-release preparation. (ix) In the artificial pancreas of (i), further in conjunction with the measurement of glucose by a subcutaneous glucose sensor(s), at a site within 1 cm of the site of glucose sensing by the glucose sensor(s), the compound is subcutaneously administered at a dose of 0.05 mg or less, and is subcutaneously administered in temporal synchronization with glucose sensing such that the compound exerts a vasodilatory effect at the time of glucose sensing. The pharmaceutical composition according to claim 8. (x) (v) In the case of (v), the sustained-release preparation is a reservoir for administration at a site within 1 cm of the insulin administration site and optionally also within 1 cm of the glucose sensor; or, It is in the form of a coating at or towards the delivery end of the insulin delivery line; or, (viii) The pharmaceutical composition according to claim 8, which is a skin adhesive patch for application at a site within 1 cm of the insulin administration site and optionally also within 1 cm of the glucose sensor. (xi) In the artificial pancreas, a compound having glucagon activity is further subcutaneously administered separately, optionally at the same site, for the treatment or prevention of hypoglycemia or for raising the blood glucose level as needed. The pharmaceutical composition according to any one of claims 8 to 10. (xii) (xiii) A subcutaneous integrated system for controlling blood glucose levels in a subject with diabetes, (i) One or more subcutaneous glucose sensors configured to measure the blood glucose level of the subject and provide sensor data related to the blood glucose level; (ii) Compound delivery means configured subcutaneously to administer a compound having glucagon activity to the subject; (iii)an insulin delivery device configured to subcutaneously administer insulin to the subject; and (iv)a control system configured to receive sensor data from the glucose sensor, determine an insulin dosage to be administered to the subject based at least on the sensor data, and control the insulin delivery device to administer the insulin dosage comprising (a)the compound delivery means includes a sustained release reservoir of the compound configured to administer the compound at a dosage of 0.05 mg or less to a site within 1 cm of the insulin administration site; or (b)the compound delivery means is controllable to administer the compound to the subject, and the control system controls the compound delivery means to administer the compound at a dosage of 0.05 mg or less to a site within 1 cm of the insulin administration site in temporal synchronization with the administration of insulin, thereby configured to improve blood flow in the vicinity of the insulin administration site, an integrated system.

13. Further, (a)the sustained release reservoir is configured to administer the compound at a dosage of 0.05 mg or less to a site within 1 cm of the glucose sensor; or further (b)the control system controls the compound delivery means to administer the compound at a dosage of 0.05 mg or less to a site within 1 cm of the glucose sensor in temporal synchronization with the operation of the glucose sensor that measures blood glucose level, thereby configured to improve blood flow in the vicinity of the glucose sensor, the integrated system according to claim 12.

14. The control system is further configured to determine a therapeutic dosage of the compound to be administered to the subject to increase the blood glucose level of the subject based at least on the sensor data, administer the compound at the therapeutic dosage to the subject, and control the compound delivery means to counteract hypoglycemia or predicted hypoglycemia. The integrated system according to claim 12 or 13.

15. A subcutaneous insulin delivery system for administering insulin to a subject, comprising (i)compound delivery means configured subcutaneously to administer a compound having glucagon activity to the subject; (ii)a subcutaneous insulin delivery device configured to administer insulin to the subject; (iii)a control system configured to determine an insulin dose to be administered to the subject and control the insulin delivery device to administer the insulin dose comprising (a)the compound delivery means includes a sustained release reservoir of the compound configured to administer the compound at a dose of 0.05 mg or less to a site within 1 cm of the insulin administration site; or (b)the compound delivery means is controllable to administer the compound to the subject, and the control system is configured to control the compound delivery means to administer the compound at a dose of 0.05 mg or less to a site within 1 cm of the insulin administration site in temporal synchronization with the administration of insulin. An insulin delivery system. **Claim 16** Use of a compound having glucagon activity for the manufacture of a medicament for use in the treatment and / or management of diabetes in a subject by co-administration with insulin, wherein in said use, the compound is administered to the subject at a dose of 0.05 mg or less to a site within 1 cm of the insulin administration site, and the compound is administered to the subject in temporal synchronization with the administration of insulin such that the compound has a vasodilatory effect at the administration site during and / or upon absorption of insulin, wherein the compound and insulin are each administered subcutaneously, either alone or in admixture.

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