Self-inserting trocar-less analyte sensing cannula - Patent Application 20070122997

Abstract

The present disclosure describes devices and methods for inserting and delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations. The device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations may include: (a) a tube including a proximal end and a distal end, the proximal end being in fluid communication with a source of insulin or insulin analog formulation and the distal end being configured to subcutaneously deliver the insulin or insulin analog formulation; (b) a glucose sensor disposed along a central axis of the tube; and (c) a penetrator disposed along the central axis of the tube, the penetrator comprising a cross-sectional area equal to or less than the cross-sectional area of ​​the glucose sensor.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 439,480, filed January 17, 2023, which is incorporated herein by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Contract No. 2R44DK123766-02 awarded by the National Institutes of Health (under the National Institute of Diabetes and Digestive and Kidney Diseases). The government has certain rights in this invention. [Background technology]

[0003]

[0003] Subjects with diabetes may be at risk of developing complications, such as kidney disease, eye disease, cardiovascular disease, and foot / nerve disease. Subjects who require insulin treatment may have more difficulty controlling their glucose levels compared to subjects who do not. Subjects with type 1 diabetes (T1D) may require insulin, and many such subjects use a continuous pump to deliver insulin, which allows for precise and controlled delivery of insulin 24 hours a day. Summary of the Invention

[0004]

[0004] A valuable technology in the management of T1D is continuous glucose monitoring (CGM), in which a subcutaneously inserted sensor provides the user with interstitial glucose data every few minutes. For example, a JDRF-sponsored study showed that subjects of all ages who regularly used CGM experienced better glycemic control (e.g., as measured by hemoglobin A1C (A1C)) than non-users. However, many subjects may find CGM use troublesome, and many may only use CGM sporadically. Not surprisingly, CGM use may not result in better glycemic control when used sporadically or infrequently.

[0005] Daily life can be difficult for people who regularly use both an insulin pump and a CGM. Such individuals may be required to place two skin-penetrating devices, which can increase the risk of pain and infection and can adversely affect the operating characteristics of the device, such as the formation of a seal between the subject's subcutaneous tissue and the inserted insulin delivery cannula when inserting the CGM sensor and / or tissue damage and / or bleeding, which can interfere with the CGM device's sensors.

[0006]

[0006] To overcome the drawbacks of separate CGM sensor and insulin pump devices, advances in sensor material chemistry have made it possible to combine CGM sensors and insulin pumps in close proximity to each other and / or in a collinear or coaxial configuration, as described, for example, in U.S. Patent Nos. 10,780,222 and 11,135,369, each of which is incorporated herein by reference in its entirety.

[0007]

[0007] While such advances have reduced pain and risk of infection for subjects, for example, by reducing the number of insertion points for devices, there remains an unmet need for mechanisms to assist in the insertion of CGM sensors, insulin pump cannulae and / or combined devices into a subject's subcutaneous tissue to ensure proper device function.

[0008]

[0008] To address this unmet need, the disclosure provided herein provides devices and / or methods for inserting a CGM sensor, insulin delivery cannula and / or combined device to provide optimal device performance in the form of a proper seal and / or electrical connection between the CGM sensor and the surrounding subcutaneous tissue of the subject.

[0009]

[0009] In one aspect, the present disclosure provides a device for delivering insulin or insulin analog compounds and measuring subcutaneous glucose concentrations, the device comprising: (a) a tube having a proximal end and a distal end, the proximal end being in fluid communication with a source of insulin or insulin analog compounds and the distal end being configured to subcutaneously deliver the insulin or insulin analog compounds; (b) a glucose sensor positioned along a central axis of the tube; and (c) a penetrator positioned along the central axis of the tube, the penetrator having a cross-sectional area not larger than the cross-sectional area of ​​the glucose sensor.

[0010] In some embodiments, the penetrator comprises a cross-sectional area smaller than the cross-sectional area of ​​the glucose sensor. In some embodiments, the penetrator comprises a cross-sectional area substantially equal to the cross-sectional area of ​​the glucose sensor. In some embodiments, the cross-sectional area of ​​the penetrator is equal to or smaller than the cross-sectional area of ​​the tube. In some embodiments, the cross-sectional area of ​​the penetrator is smaller than the cross-sectional area of ​​the glucose sensor.

[0011] In some embodiments, the tube includes a tapered tip at its distal end. In some embodiments, the tapered tip of the tube includes a rounded taper or a planar taper. In some embodiments, the cross-sectional area of ​​the distal end of the tapered portion of the tube is equal to the cross-sectional area of ​​the penetrator.

[0012]

[0012] In some embodiments, the device further comprises a housing including an upper accessible surface and a lower surface configured to be adhered to a skin surface.

[0013] In some embodiments, the glucose sensor comprises an amperometric glucose sensor. In some embodiments, the glucose sensor is disposed on a second tube comprising a second distal end, wherein the second distal end is configured for subcutaneous insertion.

[0013]

[0014] In some embodiments, the tube comprises a taper in a direction toward the distal end of the tube. In some embodiments, the glucose sensor is disposed on a surface of the tube. In some embodiments, the glucose sensor comprises at least one electrode or at least two electrodes. In some embodiments, the at least two electrodes are electrically isolated when outside the subject.

[0014]

[0015] In some embodiments, at least one electrode or at least two electrodes comprise a thermoplastic material as a substrate. In some embodiments, at least one electrode or at least two electrodes are disposed on the surface of the penetrator. In some embodiments, at least one electrode or at least two electrodes are one or more layers of a glucose sensor. In some embodiments, at least one electrode or at least two electrodes comprise a gold, carbon, graphite, platinum, or iridium material. In some embodiments, at least one electrode or at least two electrodes are laminated on the surface of a thermoplastic substrate. In some embodiments, the surface of the thermoplastic substrate comprises at least two surfaces of the thermoplastic substrate. In some embodiments, the thermoplastic substrate is molded around the penetrator.

[0015]

[0016] In some embodiments, the glucose sensor includes a reference electrode. In some embodiments, the reference electrode includes a silver (Ag) or silver chloride (Ag / AgCl) reference electrode. In some embodiments, the glucose sensor further includes an insulating layer and a metal layer, wherein the insulating layer is bonded to the metal layer, and wherein the metal layer is bonded to an electrode layer including at least one electrode or at least two electrodes. In some embodiments, the insulating layer includes a polyimide or a liquid crystal polymer. In some embodiments, the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some embodiments, the metal layer includes a titanium, gold, or platinum material. In some embodiments, the electrode layer includes a film having a thickness of not more than about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In certain embodiments, the metal compound of the metal layer comprises a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0016]

[0017] In some embodiments, the penetrator comprises a proximal end and a distal end, and the distal end is tapered. In some embodiments, the penetrator comprises a stylet or sharp. In some embodiments, the penetrator comprises a lumen. In some embodiments, the penetrator comprises a beveled tip.

[0017]

[0018] In another aspect, the present disclosure provides a method for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations, the method comprising the following steps: (a) a device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations, wherein the device comprises: (i) a tube comprising a proximal end and a distal end, the proximal end in fluid communication with a source of insulin or insulin analog formulations and the distal end configured to subcutaneously deliver the insulin or insulin analog formulations; (ii) a glucose sensor disposed along a central axis of the tube; and (iii) a penetrator disposed along the central axis of the tube, the penetrator comprising a cross-sectional area no larger than a cross-sectional area of ​​the glucose sensor; (b) performing subcutaneous insertion of the distal end of the tube, the glucose sensor, and the penetrator into a subject; and (c) subcutaneously delivering insulin or insulin analog formulations to the subject or measuring the subcutaneous glucose concentration of the subject using the glucose sensor, or a combination thereof.

[0018]

[0019] In some embodiments, the penetrator comprises a cross-sectional area that is smaller than the cross-sectional area of ​​the glucose sensor. In some embodiments, the penetrator comprises a cross-sectional area that is substantially equal to the cross-sectional area of ​​the glucose sensor. In some embodiments, the cross-sectional area of ​​the penetrator is equal to or smaller than the cross-sectional area of ​​the tube. In some embodiments, the cross-sectional area of ​​the penetrator is smaller than the cross-sectional area of ​​the glucose sensor.

[0019]

[0020] In some embodiments, the tube comprises a tapered tip at its distal end. In some embodiments, the tapered tip of the tube comprises a rounded taper or a planar taper. In some embodiments, the cross-sectional area of ​​the distal end of the tapered portion of the tube is equal to the cross-sectional area of ​​the penetrator.

[0020]

[0021] In some embodiments, the device further comprises a housing including an upper accessible surface and a lower surface configured to be adhered to a skin surface.

[0022] In some embodiments, the glucose sensor comprises an amperometric glucose sensor. In some embodiments, the glucose sensor is disposed on a second tube comprising a second distal end, wherein the second distal end is configured for subcutaneous insertion.

[0021]

[0023] In some embodiments, the tube comprises a taper in a direction toward the distal end of the tube. In some embodiments, the glucose sensor is disposed on a surface of the tube. In some embodiments, the glucose sensor comprises at least one electrode or at least two electrodes. In some embodiments, the at least two electrodes are electrically isolated when outside the subject.

[0022]

[0024] In some embodiments, at least one electrode or at least two electrodes comprise a thermoplastic material as a substrate. In some embodiments, at least one electrode or at least two electrodes are disposed on the surface of the penetrator. In some embodiments, at least one electrode or at least two electrodes are one or more layers of a glucose sensor. In some embodiments, at least one electrode or at least two electrodes comprise a gold, carbon, graphite, platinum, or iridium material. In some embodiments, at least one electrode or at least two electrodes are laminated on the surface of a thermoplastic substrate. In some embodiments, the surface of the thermoplastic substrate comprises at least two surfaces of the thermoplastic substrate. In some embodiments, the thermoplastic substrate is molded around the penetrator.

[0023]

[0025] In some embodiments, the glucose sensor includes a reference electrode. In some embodiments, the reference electrode includes a silver (Ag) or silver chloride (Ag / AgCl) reference electrode. In some embodiments, the glucose sensor further includes an insulating layer and a metal layer, wherein the insulating layer is bonded to the metal layer, and wherein the metal layer is bonded to an electrode layer including at least one electrode or at least two electrodes. In some embodiments, the insulating layer includes a polyimide or a liquid crystal polymer. In some embodiments, the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some embodiments, the metal layer includes a titanium, gold, or platinum material. In some embodiments, the electrode layer includes a film having a thickness of not more than about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In certain embodiments, the metal compound of the metal layer comprises a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0024]

[0026] In some embodiments, the penetrator comprises a proximal end and a distal end, and the distal end is tapered. In some embodiments, the penetrator comprises a stylet or sharp. In some embodiments, the penetrator comprises a lumen. In some embodiments, the penetrator comprises a beveled tip.

[0025]

[0027] In another aspect, the present disclosure provides a device for delivery of insulin or insulin analog formulations and measurement of subcutaneous glucose concentrations, the device including: (a) a tube including a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or insulin analog formulations and wherein the distal end is configured to subcutaneously deliver the insulin or insulin analog formulations; (b) a glucose sensor disposed along a central axis of the tube; and (c) a penetrator disposed along the central axis of the tube, the penetrator configured to be at least partially inserted subcutaneously without the use of a trocar.

[0026]

[0028] In another aspect, the present disclosure provides a method for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations, the method comprising the following steps: (a) a device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations, wherein the device comprises: (i) a tube comprising a proximal end and a distal end, the proximal end in fluid communication with a source of insulin or insulin analog formulations and the distal end configured to subcutaneously deliver the insulin or insulin analog formulations; (ii) a glucose sensor disposed along a central axis of the tube; and (iii) a penetrator disposed along the central axis of the tube; (b) performing subcutaneous insertion of the distal end of the tube, the glucose sensor, and the penetrator into a subject without the use of a trocar; and (c) subcutaneously delivering insulin or insulin analog formulations to the subject, or measuring the subcutaneous glucose concentration of the subject using the glucose sensor, or a combination thereof.

[0027]

[0029] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0028] Incorporation by Reference

[0030] All publications, patents, and patent applications mentioned herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over any such conflicting material.

[0029]

[0031] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description and accompanying drawings (also referred to herein as "Figures" and "Figures") that set forth illustrative embodiments in which the principles of the invention are utilized: [Brief explanation of the drawings]

[0030] [Figure 1]

[0032] FIG. 1 shows a glucose sensor surrounded by a trocar that is used to penetrate a subject's skin to place the glucose sensor in the subject's subcutaneous tissue. [Figure 2]

[0033] FIG. 2 shows the combination of a glucose sensor and a round and / or curved insulin delivery tube and / or cannula having a deployed piercing member with a cross-sectional diameter equal to or less than the cross-sectional diameter of the insulin delivery tube and / or cannula. [Figure 3]

[0034] 3A-3B show a side perspective view (FIG. 3A) of a combination glucose sensor and a round and / or curved insulin delivery tube and / or cannula with a deployed piercing member, as well as a cross-sectional view (FIG. 3B) of the same. [Figure 4]

[0035] 4A-4B show a side perspective view of a glucose sensor and planar insulin delivery tube and / or cannula combination with a deployed piercing member (FIG. 4A) and a cross-sectional view of the same (FIG. 4B). [Figure 5]

[0036] FIG. 5 shows a flow diagram for a method for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations. DETAILED DESCRIPTION OF THE INVENTION

[0031]

[0037] While various aspects of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such aspects are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the aspects of the invention described herein may be utilized.

[0032]

[0038] Whenever the terms "at least," "greater than," or "equivalent to" precede the first number in a series of two or more numbers, the term "at least," "greater than," or "equivalent to" applies to every number in the series. For example, 1, 2, or 3 or more is equivalent to 1 or more, 2 or more, or 3 or more.

[0033]

[0039] Whenever the terms "not greater than," "less than," or "less than or equal to" precede the first number in a series of two or more numbers, the term "not greater than," "less than," or "less than or equal to" applies to each number in the series. For example, 3, 2, or 1 or less is equivalent to 3 or less, 2 or less, or 1 or less.

[0034]

[0040] As used herein, the term "cannula" refers to a hollow tube, generally fabricated using a material such as a polymer or metal, having an interior (e.g., inner) surface and an exterior (e.g., outer) surface and openings at both ends.

[0035]

[0041] As used herein, the term "sensing cannula" generally refers to a cannula having an analyte sensor (e.g., disposed on an interior or exterior surface) and one or more fluid delivery channels contained within the cannula.

[0036]

[0042] As used herein, the term "continuous glucose monitor (CGM)" generally refers to a system including electronic devices configured for continuous or near-continuous measurement of glucose levels from a subject (e.g., a human, animal, or mammal) and / or reporting of such measurements.

[0037]

[0043] As used herein, the term "CGM infusion set" generally refers to a device (e.g., a unified device) configured for use on the skin of a subject (e.g., a human, animal, or mammal) having a combination of sensor and cannula, which includes an electrical interface to signal acquisition electronics and a port for attachment of a fluid source, such as a pump or gravity-fed source.

[0038]

[0044] As used herein, the term "subject" generally refers to a person, individual, or patient. A subject may be a vertebrate, such as a mammal. Non-limiting examples of mammals include humans, monkeys, farm animals, sport animals, rodents, and pets. A subject may be a diabetic or a patient suspected of having diabetes. A subject may exhibit a symptom or symptoms indicative of a health or physiological state or condition of the subject, such as diabetes. Alternatively, a subject may be asymptomatic with respect to such a health or physiological state or condition.

[0039]

[0045] A valuable technology in managing type 1 diabetes is continuous glucose monitoring (CGM), in which a subcutaneously inserted sensor provides the user with interstitial glucose data every few minutes. For example, a JDRF-sponsored study may show that subjects of all ages who regularly used CGM experienced better glycemic control (e.g., as measured by hemoglobin A1C (A1C)) than non-users. Continuous subcutaneous insulin infusion devices (CSIIs, i.e., insulin pumps) and insulin infusion sets for use with minimally invasive CGM sensors share the need to be inserted through the skin into a subcutaneous sensor before use.

[0040]

[0046] For example, when inserting a subcutaneous insulin infusion device, e.g., an insulin infusion cannula, sharps and / or penetrators can be used to facilitate insertion of the insulin infusion cannula, as described elsewhere herein. In some cases, the insulin infusion cannula may comprise a soft and / or flexible material, such as silicone, or a hard or rigid material. In some cases, the cannula may not be sharp or rigid enough to puncture the skin on its own without buckling. Buckling of such plastic cannulas may occur due to forces generated during insertion (penetration of the skin and placement in the subcutaneous tissue). Buckling may not be the only way insertion can fail. A sensing cannula may be able to overcome insertion forces without buckling, yet not be fully inserted into the subcutaneous tissue. Skin is flexible and can relax to close relatively small wounds, such as those made by a cannula or hypodermic needle, after the subject has retracted. While the cannula remains in the skin and subcutaneous tissue, the tendency of the skin to relax can result in some pressure on the outer wall of the cannula, resulting in friction between the cannula and the surrounding tissue. This friction can result in the skin surface not relaxing to its pre-insertion state and remaining "wrinkled." A slight degree of skin wrinkling after insertion can resolve naturally while the device is worn, and slight stress from normal physical activity can help the skin relax. If the amount of wrinkling is too great, the skin may not relax or may be painful as it relaxes, and the device will slowly damage more tissue as it becomes more deeply embedded.

[0041]

[0047] Some characteristics that influence whether the skin remains wrinkled after insertion may include the energy / speed of insertion and friction at the exterior surface of the device.

[0048] In some cases, an insulin infusion cannula may include a lumen configured to receive a sharp and / or penetrator that can be deployed and / or extended to penetrate a subject's skin and then withdrawn to allow insertion of the insulin infusion cannula. Such a configuration and / or geometry of the sharp and / or penetrator can benefit from not creating a wound in the subject's tissue larger than the insulin infusion cannula itself. A wound with a cross-sectional area larger than the cross-sectional area of ​​the cannula increases the likelihood that an inserted cannula will cause infused fluid, such as insulin, to leak from the wound and not be absorbed into the tissue. The possibility of fluid leaking from the wound site poses a serious risk to users who require infused insulin to maintain their blood glucose levels, as they may not notice insulin leakage and the resulting reduced dosage. Elsewhere herein, embodiments of sharps and / or penetrators that penetrate a subject's tissue with a cross-sectional area that creates an insertion point for the cannula that prevents such leakage are described. For successful insertion of a soft cannula, it is important that its cross-sectional area does not exceed that of the stylet at the point where the cannula begins to penetrate the skin during insertion. For this reason, soft cannulas are often necked down to a smaller outer diameter at their tip. In some cases, the penetrator may comprise a stainless steel material. In some instances, the stainless steel may comprise 316L stainless steel. In some cases, the penetrator may comprise a lumen and / or be hollow.

[0042]

[0049] Although some cannulas may comprise a soft plastic material, it is not a requirement that the cannula be made from a soft material, even in devices intended for extended use. Some users prefer to use a rigid cannula. In some cases, using a cannula made from a sufficiently rigid material and having a sharp geometry may not require the use of an insertion aid. For example, an infusion set may use a stainless steel cannula (similar to a hypodermic needle) for the delivery of insulin. Although many users prefer a soft plastic cannula for various reasons, it is not a requirement that the cannula be made from a soft material, even in devices intended for extended use. Some users prefer to use a rigid cannula. Using a cannula made from a sufficiently rigid material and having a sharp geometry may not require the use of an insertion aid. For example, infusion sets using a stainless steel cannula (similar to a hypodermic needle) for the delivery of insulin are available and common on the market.

[0043]

[0050] For CGM sensors, it is generally assumed that smaller, more flexible sensors are desirable for user comfort. Because sensors are designed to be flexible, they also require insertion assistance similar to that of a soft plastic cannula infusion set.

[0044]

[0051] In contrast to separate devices for the CGM sensor and insulin infusion device, it may be possible to create and use a combination device in which the CGM sensor is integrated into the wall of the insulin infusion cannula. As taught in U.S. Patent Nos. 10,780,222 and 11,135,369, each of which is incorporated herein by reference in its entirety, such a combination device may require the use of specific CGM chemistry to avoid inaccurate glucose readings caused by compounds present in the insulin drug formulation. In the case of a CGM sensor / infusion cannula combination (sensing cannula), the use of a trocar is not appropriate because the risk of drug leakage / backflow due to the larger wound cross-section created by a trocar is unacceptable. If the cross-sectional area of ​​the sensing cannula does not exceed the cross-sectional area of ​​the stylet placed within it by a certain margin, the stylet is a viable insertion aid that can be used in the same manner as if the sensing cannula were simply a soft infusion cannula described above. The thickness of the cannula wall must be minimized to prevent the cross-sectional area of ​​the cannula material relative to its internal fluid path cross-sectional area from exceeding this margin.

[0045]

[0052] If the cannula wall is thick enough that a stylet is not suitable as an insertion aid, a sufficiently sharp and rigid cannula may be inserted by itself without a separate insertion aid.

[0046]

[0053] In some cases, the CGM sensor 100 can include a cross-sectional area less than that of an insulin infusion cannula and can include a flexible material, which is desirable for user comfort when inserted. In some cases, if the CGM sensor 100 includes a flexible material, the CGM sensor may require an insertion aid, such as a sharp and / or penetrator 102, similar to the cannula infusion sets described above. In some embodiments, the CGM sensor 100 can include a solid sensor, i.e., one that does not include a lumen, because the CGM sensor does not also function as an infusion cannula. In some examples, the insertion aid can include a rigid, sharp structure that pierces the skin during insertion 102 and surrounds the flexible sensor, as shown in FIG. 1 .

[0047]

[0054] In some cases, the rigid sharp structure may include a trocar. In some cases, as shown in FIG. 1, a sharp and / or penetrator 102 may surround the CGM sensor 100 and create a wound in the subject with a cross-sectional area larger than the sensor 100 itself. The larger wound can result in problems with excessive trauma to the subject's tissue, leading to reduced accuracy of the CGM sensor, which can be observed within one hour to one day after insertion using a sharp and / or penetrator that exceeds the cross-sectional area of ​​the CGM sensor. Such a large diameter wound is in contrast to the case of soft plastic injection cannulas, where a relatively small wound can be created with a stylet that is smaller in diameter than the cannula. Insertion trauma caused by a sharp and / or penetrator with a cross-sectional area that exceeds the cross-sectional area of ​​the CGM sensor can cause excessive bleeding and the addition of cellular debris to the environment surrounding the CGM sensor. In certain instances, sharps and / or penetrators with a cross-sectional area that exceeds that of the CGM sensor may alter the insertion area and / or location environment over the following hours, causing a subsequent inflammatory response that affects the sensor's response characteristics and accuracy. In certain cases, the insertion devices and methods for inserting glucose sensors described elsewhere herein provide glucose sensor response characteristics that are at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% stable for up to about two hours from initial insertion of the glucose sensor into a subject. A sensing cannula that uses a stylet or sharp with a smaller cross-sectional area than the cannula itself can minimize insertion trauma compared to the same sensor inserted using a trocar, likely resulting in less change in sensor response characteristics over the initial period after insertion and ultimately allowing for increased sensor accuracy during this time.

[0048]

[0055] Electrochemical and / or amperometric biosensors may include at least two electrodes that are electrically isolated from each other except during use when immersed in bodily fluids. Thermoplastic materials may be well suited to serve as a substrate for electrodes because they typically have low electrical conductivity. Thus, a thermoplastic cannula with electrodes on its surface may be an attractive design for a sensing cannula. The problem with thermoplastic materials is that they are typically not rigid enough to function in the same way as metals when acting as a needle, e.g., piercing the skin during insertion. A way to combine the qualities of both materials may be to surround a metal needle / sharp with an electrically insulating thermoplastic material onto which the sensing electrode can be laminated / deposited. The metal needle / sharp can be withdrawn after insertion of the sensing cannula, or it can be left in place, similar to a rigid metal needle injection cannula.

[0049]

[0056] The ability of a sensing cannula to be inserted without the use of an insertion aid (e.g., a stylet or trocar) depends in part on the following characteristics: the stiffness of the cannula / sensor material, the sharpness / geometry of the penetration tip, the overall size / geometry of the cannula / sensor, the lubricity / coefficient of friction of the cannula / sensor surface, and the speed / kinetic energy of the insertion motion. Other factors that affect insertion success may include the angle of insertion relative to the skin surface plane, the axial rotation of the object during insertion, and the orientation of the sharp geometry (tilt) relative to the insertion direction.

[0050]

[0057] Resistance to buckling due to insertion forces can depend on both the geometry and material properties of the cannula / sensor. Euler's critical load equation is a well-known method for determining the maximum static load a pillar will support without buckling. In this case, the cannula can be thought of as a pillar and the skin puncture force. The critical load can depend on the pillar's material stiffness, its area moment of inertia (cross-sectional geometry), length, and / or the way the pillar is allowed to move at its ends. A reduced area moment of inertia, increased length, and more degrees of freedom of movement at the pillar's ends all reduce the maximum static load the pillar can support.

[0051]

[0058] The cross section of the cannula can be kept to a minimum, as insertion generally becomes more painful as the cross section / needle diameter increases. The length of the cannula can be reduced to a point, but there is a minimum length required for successful drug infusion. The cannula can be sufficiently secured in place to leave the bottom surface of the medical device housing remaining on the skin surface. Remaining factors are the insertion speed, cannula sharp geometry (slope), surface friction / lubricity, and insertion angle.

[0052]

[0059] Recognizing the challenges encountered during insertion and interface of a CGM sensor and / or insulin infusion cannula with a subject's skin and / or subcutaneous tissue, the present disclosure, in certain embodiments, describes devices and / or methods that minimize trauma to a subject's tissue and ensure proper device interface and functionality when inserted into a subject's subcutaneous tissue.

[0053]

[0060] In one aspect, the present disclosure provides a device for delivering insulin analog formulations and measuring subcutaneous glucose concentrations, as shown in FIGS. 2, 3A-3B, and 4A-4B, comprising: (a) a tube (200, 212) including a proximal end (214, 216) and a distal end (218, 220), the proximal end being in fluid communication with a source of insulin and / or insulin analog formulation, and the distal end being configured to subcutaneously deliver the insulin and / or insulin analog formulation to a subject; (b) a glucose sensor disposed along the central axis of the tube (200, 212), for example, as shown in FIG. 2; and (c) a penetrator 210 disposed along the central axis of the tube (200, 212), the penetrator 210 comprising a cross-sectional area equal to the cross-sectional area of ​​the glucose sensor. In some cases, the cross-sectional area of ​​the penetrator 210 can include a cross-sectional area equal to or less than the cross-sectional area of ​​the tube (200, 212), as shown in Figures 2, 3A-3B, and 4A-4B. In some cases, the cross-sectional area of ​​the penetrator 210 can include a cross-sectional area less than the cross-sectional area of ​​the glucose sensor. In some cases, the cross-sectional area of ​​the penetrator less than the cross-sectional area of ​​the tube and / or glucose sensor can provide a penetration site in the subject's skin and / or subcutaneous tissue that prevents leakage of fluid flowing through the tube and reduces bleeding and / or cellular debris from interfering with the glucose sensor reading glucose in the subject's subcutaneous tissue, as described elsewhere herein.

[0054]

[0061] In some cases, the tubes (200, 212) can include a taper in a direction toward the distal ends (218, 220) of the tubes. In some cases, the tubes (200, 212) and / or the distal tapered tips (218, 220) can include a circular and / or curved geometric shape and / or shape (224), as shown in FIG. 3A, or a planar geometric shape and / or shape (222), as shown in FIG. 4A. In some cases, the cross-sectional area of ​​the distal portion of the distal tapered tips (218, 220) can include a cross-sectional area equal to or less than the cross-sectional area of ​​the penetrator 210. In some cases, the tubes (200, 212) can include a polymeric material. In some examples, the tube can be molded around the penetrator 210. In some cases, the tubes (200, 212) can include a polymeric molded or extruded component. In some cases, the device can further include a housing including an upper accessible surface and a lower surface configured to be adhered to a skin surface.

[0055]

[0062] In some cases, the glucose sensor may include an amperometric glucose sensor. In some cases, the glucose sensor may be disposed on a second tube including a second distal end, where the second distal end is configured to be subcutaneously inserted into a subject. In some cases, the glucose sensor 202 may be disposed on a surface of the tube (200, 212), as shown in FIG. 2. The glucose sensor 202 may be disposed on an inner surface of the tube (200, 212) or an outer surface of the tube (200, 212). In some examples, the glucose sensor 202 may include at least one electrode or at least two electrodes.

[0056]

[0063] In some cases, the at least two electrodes of the glucose sensor can be electrically insulated from each other when they are external to the subject. In some examples, at least one electrode and / or at least two electrodes can include a thermoplastic material as a substrate. In some cases, the thermoplastic material can include a planar thermoplastic material, which can be molded around a metal needle. In some cases, the planar thermoplastic material molded around the metal needle can be heated to conform to a circular cross section. In some examples, the at least one electrode and / or at least two electrodes can be disposed on a surface of the penetrator. In some examples, the at least one electrode and / or at least two electrodes can at least partially surround the penetrator.

[0057]

[0064] In some cases, at least one electrode and / or at least two electrodes can be laminated and / or deposited on the surface of a thermoplastic material deposited on the surface of the penetrator. In some examples, the tube can include a thermoplastic cannula. In some cases, the thermoplastic cannula can be molded with a lumen configured to receive a metal tube (e.g., a sharp metal tube) as described elsewhere herein. In some cases, at least one electrode and / or at least two electrodes can be deposited and / or laminated on two or more surfaces of the thermoplastic cannula, and then a sharp metal tube can be provided in the thermoplastic cannula lumen as a penetrator at the distal end of the thermoplastic cannula to facilitate a fluid pathway connection between the proximal and distal ends of the thermoplastic cannula. In some examples, the thermoplastic cannula can be molded with a lumen, where the lumen of the thermoplastic cannula can be configured as a fluid pathway. In some cases, the distal tip of the thermoplastic cannula can be molded into a sharp distal tip. In some cases, at least one electrode and / or at least two electrodes can be deposited and / or laminated onto two or more surfaces of a metal tube and / or a thermoplastic material molded around a solid metal mandrel.

[0058]

[0065] In some examples, after molding the thermoplastic material and laminating and / or depositing at least one electrode and / or at least two electrodes, the solid metal mandrel can be removed and replaced with one or more lengths of sharp metal tube. In some cases, the at least one electrode and / or at least two electrodes laminated and / or deposited on the surface of the thermoplastic material can be molded around multiple lengths of metal tube held straight by tension. In some cases, the at least one electrode and / or at least two electrodes laminated and / or deposited on the surface of the thermoplastic material molded on multiple lengths of metal tube can be cut into multiple segments of shorter length than the multiple lengths of metal tube. In some cases, the multiple segments of electrode(s) laminated and / or deposited on the thermoplastic material molded around the metal tube can be tapered toward the distal end of the thermoplastic material. In some examples, the at least one electrode and / or at least two electrodes laminated and / or deposited on the thermoplastic material can be molded around a solid and / or rounded mandrel and / or wire. After forming the at least one electrode and / or at least two electrodes laminated and / or deposited on the thermoplastic material, the solid and / or rounded mandrel and / or wire can be removed and replaced with a sharp object, for example a sharp metal tube.

[0059]

[0066] In some cases, at least one electrode and / or at least two electrodes can include one or more layers of a glucose sensor. In some cases, at least one electrode and / or at least two electrodes can include gold, carbon, graphite, platinum, or iridium materials. In some cases, at least one electrode and / or at least two electrodes can be laminated on the surface of a thermoplastic substrate. In some cases, the surface of the thermoplastic substrate can include at least two surfaces of the thermoplastic substrate. In some examples, the thermoplastic substrate can be molded around the penetrator.

[0060]

[0067] In some examples, the glucose sensor can include a reference electrode. In some cases, the reference electrode can include a silver (Ag) or silver chloride (AgCl) material. In some cases, the glucose sensor can further include an insulating layer and a metal layer, where the insulating layer can be bonded to the metal layer, and where the metal layer can be bonded to an electrode layer including at least one electrode and / or at least two electrodes. In some cases, the insulating layer can include a polyimide or a liquid crystal polymer. In some cases, the metal layer can include a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some cases, the metal layer can include a titanium, gold, or platinum material. In some examples, the electrode layer can include a film having a thickness of no more than about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In some cases, the metal compound of the metal layer may include a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0061]

[0068] In some cases, the penetrator 210 can include a proximal end 226 and a distal end 228. In certain instances, the distal end of the penetrator 228 can be tapered. In some cases, the penetrator can include a stylet or sharp (e.g., a needle or stainless steel tube that has been cut and / or ground to a point). In some cases, the penetrator can include a beveled tip 208. In some cases, the penetrator can include an internal lumen and / or be hollow.

[0062]

[0069] In some cases, the present disclosure describes a method for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations 300, as seen in FIG. 5, wherein the method includes the following steps: (a) providing a device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations, wherein the device includes: (i) a tube including a proximal end and a distal end, the proximal end being in fluid communication with a source of insulin or insulin analog formulations and the distal end being configured to subcutaneously deliver the insulin or insulin analog formulations; (ii) a glucose sensor disposed along a central axis of the tube; and (iii) a penetrator disposed along the central axis of the tube, the penetrator including a cross-sectional area equal to the cross-sectional area of ​​the glucose sensor 302; (b) performing subcutaneous insertion of the distal end of the tube, the glucose sensor, and the penetrator into a subject 304; and (c) subcutaneously delivering insulin or insulin analog formulations to the subject, measuring the subcutaneous glucose concentration of the subject using the glucose sensor, or a combination thereof 304. In some cases, the insertion further includes inserting the glucose sensor into the subject's tissue, where the subject's tissue includes the subject's skin, epidermis, dermis, subcutaneous tissue, or any combination thereof. In some cases, the cross-sectional area of ​​the penetrator can include a cross-sectional area equal to or less than the cross-sectional area of ​​the tube. In some cases, the cross-sectional area of ​​the penetrator can include a cross-sectional area smaller than the cross-sectional area of ​​the glucose sensor. In some cases, the cross-sectional area of ​​the penetrator below the tube and / or glucose sensor can provide a puncture site in the subject's skin and / or subcutaneous tissue, which prevents leakage of fluid flowing through the tube and reduces bleeding and / or cellular debris from interfering with the glucose sensor reading glucose in the subject's subcutaneous tissue, as described elsewhere herein. In some cases, the penetrator can include a stainless steel material. In some examples, the stainless steel can include 316L stainless steel. In some cases, the penetrator can include a lumen and / or be hollow.

[0063]

[0070] In some cases, the tube can include a taper in a direction toward the distal end of the tube. In some cases, the tube and / or the distal tapered tip can include a circular and / or curved geometric shape and / or shape, or a planar geometric shape and / or shape. In some cases, the cross-sectional area of ​​the distal portion of the distal tapered tip can include a cross-sectional area equal to or less than the cross-sectional area of ​​the penetrator. In some cases, the tube can include a polymeric material. In some examples, the tube can be molded around the penetrator. In some cases, the tube can include a polymeric molded or extruded component. In some cases, the device can further include a housing including an upper accessible surface and a lower surface configured to be adhered to a skin surface.

[0064]

[0071] In some cases, the glucose sensor can include an amperometric glucose sensor. In some cases, the glucose sensor can be disposed on a second tube including a second distal end, where the second distal end is configured to be subcutaneously inserted into a subject. In some cases, the glucose sensor can be disposed on a surface of the tube. In some examples, the glucose sensor can include at least one electrode or at least two electrodes. In some cases, the at least two electrodes of the glucose sensor can be electrically isolated from each other when external to the subject.

[0065]

[0072] In some cases, at least one electrode and / or at least two electrodes can include a thermoplastic material as a substrate. In some cases, the thermoplastic material can include a planar thermoplastic material that can be molded around a metal needle. In some cases, the planar thermoplastic material molded around the metal needle can be heated to conform to a circular cross section.

[0066]

[0073] In some instances, the at least one electrode and / or the at least two electrodes can be disposed on a surface of the penetrator. In some instances, the at least one electrode and / or the at least two electrodes can at least partially surround the penetrator. In some instances, the at least one electrode and / or the at least two electrodes can be laminated and / or deposited on a surface of a thermoplastic material that is deposited on the surface of the penetrator.

[0067]

[0074] In some cases, at least one electrode and / or at least two electrodes laminated and / or deposited on the surface of the thermoplastic material can be inserted into an object coupled to the penetrator, after which the penetrator is retracted leaving the laminated and / or deposited at least one and / or at least two electrodes in the object.

[0068]

[0075] In some cases, at least one electrode and / or at least two electrodes can include one or more layers of a glucose sensor. In some cases, at least one electrode and / or at least two electrodes can include gold, carbon, graphite, platinum, or iridium materials. In some cases, at least one electrode and / or at least two electrodes can be laminated on the surface of a thermoplastic substrate. In some cases, the surface of the thermoplastic substrate can include at least two surfaces of the thermoplastic substrate. In some examples, the thermoplastic substrate can be molded around the penetrator.

[0069]

[0076] In certain instances, the tube can include a thermoplastic cannula. In some cases, the thermoplastic cannula can be molded with a lumen configured to receive a metal tube (e.g., a sharp metal tube) as described elsewhere herein. In some cases, at least one electrode and / or at least two electrodes can be deposited and / or laminated on two or more surfaces of the thermoplastic cannula, after which a sharp metal tube can be provided at the distal end of the thermoplastic cannula into the thermoplastic cannula lumen as a penetrator as described elsewhere herein that facilitates a fluid pathway connection between the proximal and distal ends of the thermoplastic cannula.

[0070]

[0077] In some instances, a thermoplastic cannula can be molded with a lumen, where the lumen of the thermoplastic cannula can be configured as a fluid pathway. In some instances, the distal tip of the thermoplastic cannula can be molded into a sharpened distal tip. In some instances, at least one electrode and / or at least two electrodes can be deposited and / or laminated onto two or more surfaces of a thermoplastic material molded around a metal tube and / or a solid metal mandrel. In some instances, after molding the thermoplastic material and laminating and / or depositing the at least one electrode and / or at least two electrodes, the solid metal mandrel can be removed and replaced with one or more lengths of sharpened metal tube.

[0071]

[0078] In some cases, at least one electrode and / or at least two electrodes stacked and / or deposited on the surface of a thermoplastic material can be molded around multiple lengths of metal tube held straight by tension. In some cases, at least one electrode and / or at least two electrodes stacked and / or deposited on the surface of a thermoplastic material molded on multiple lengths of metal tube can be cut into multiple segments of shorter lengths than the multiple lengths of metal tube. In some cases, multiple segments of electrode(s) stacked and / or deposited on a thermoplastic material molded around a metal tube can be tapered toward the distal end of the thermoplastic material. In some examples, at least one electrode and / or at least two electrodes stacked and / or deposited on a thermoplastic material can be molded around a solid and / or rounded mandrel and / or wire. After molding at least one electrode and / or at least two electrodes stacked and / or deposited on a thermoplastic material, the solid and / or rounded mandrel and / or wire can be removed and replaced with a sharp object, such as a sharp metal tube.

[0072]

[0079] In some cases, the glucose sensor can include a reference electrode. In some cases, the reference electrode can include a silver (Ag) or silver chloride (AgCl) material. In some cases, the glucose sensor can further include an insulating layer and a metal layer, where the insulating layer can be bonded to the metal layer, and where the metal layer can be bonded to an electrode layer including at least one electrode and / or at least two electrodes. In some cases, the insulating layer can include a polyimide or a liquid crystal polymer. In some cases, the metal layer can include a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some cases, the metal layer can include a titanium, gold, or platinum material. In some examples, the electrode layer can include a film having a thickness of no more than about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In some cases, the metal compound of the metal layer may include a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0073]

[0080] In some cases, the penetrator can include a proximal end and a distal end. In certain instances, the distal end of the penetrator can be tapered. In some cases, the penetrator can include a stylet or sharp (e.g., a needle or stainless steel tube that has been cut and / or ground to a point). In some cases, the penetrator can include a beveled tip. In some cases, the penetrator can include an internal lumen and / or be hollow.

[0074]

[0081] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such aspects are provided by way of example only. The present invention is not intended to be limited by the specific examples provided herein. While the present invention has been described with reference to the foregoing specification, the description and illustration of aspects herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it is to be understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions set forth herein, which depend upon a variety of conditions and variables. It should be understood that various alternatives to the aspects of the invention described herein can be utilized in practicing the invention. Accordingly, it is contemplated that the present invention shall cover any and all such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby. [Explanation of symbols]

[0075] 100 CGM sensors 102 Penetrator 200 tubes 208 Beveled tip 210 Penetrator 212 tubes 214 Proximal end 216 Proximal end 218 Distal end 220 distal end 226 Proximal end 228 Distal end 300 Subcutaneous glucose concentration 302 Glucose Sensor 304 Target

Claims

1. 1. A device for the delivery of insulin or insulin analogue formulations and measurement of subcutaneous glucose concentrations, comprising: (a) a tube comprising a proximal end and a distal end, the proximal end in fluid communication with a source of the insulin or insulin analog formulation, and the distal end configured for subcutaneous delivery of the insulin or insulin analog formulation; (b) a glucose sensor disposed along the central axis of the tube; and (c) a penetrator disposed along a central axis of the tube, the penetrator comprising a cross-sectional area no greater than a cross-sectional area of ​​the glucose sensor; Devices containing:

2. 10. The device of claim 1, wherein the penetrator comprises a cross-sectional area that is smaller than the cross-sectional area of ​​the glucose sensor.

3. 10. The device of claim 1, wherein the penetrator comprises a cross-sectional area substantially equal to the cross-sectional area of ​​the glucose sensor.

4. 10. The device of claim 1, wherein the cross-sectional area of ​​the penetrator is less than or equal to the cross-sectional area of ​​the tube.

5. 10. The device of claim 1, wherein the cross-sectional area of ​​the penetrator is smaller than the cross-sectional area of ​​the glucose sensor.

6. The device of claim 1 , wherein the tube includes a tapered tip at the distal end.

7. 10. The device of claim 1, wherein the tapered tip of the tube comprises a rounded taper or a planar taper.

8. 7. The device of claim 6, wherein the cross-sectional area of ​​the distal end of the tapered portion of the tube is equal to the cross-sectional area of ​​the penetrator.

9. 10. The device of claim 1, further comprising a housing including an upper accessible surface and a lower surface configured to be adhered to a skin surface.

10. 10. The device of claim 1, wherein the glucose sensor comprises an amperometric glucose sensor.

11. 10. The device of claim 1, wherein the glucose sensor is disposed on a second tube including a second distal end, the second distal end configured for subcutaneous insertion.

12. The device of claim 1 , wherein the tube includes a taper in a direction toward the distal end of the tube.

13. 10. The device of claim 1, wherein the glucose sensor is disposed on a surface of the tube.

14. 10. The device of claim 1, wherein the glucose sensor comprises at least one electrode or at least two electrodes.

15. 15. The device of claim 14, wherein the at least two electrodes are electrically isolated when external to the subject.

16. 15. The device of claim 14, wherein the at least one electrode or the at least two electrodes comprises a thermoplastic material as a substrate.

17. 15. The device of claim 14, wherein the at least one electrode or the at least two electrodes are disposed on a surface of the penetrator.

18. 15. The device of claim 14, wherein the at least one electrode or the at least two electrodes are one or more layers of the glucose sensor.

19. 15. The device of claim 14, wherein the at least one electrode or the at least two electrodes comprise a material selected from the group consisting of gold, carbon, graphite, platinum, and iridium.

20. 15. The device of claim 14, wherein the at least one electrode or the at least two electrodes are laminated to a surface of a thermoplastic substrate.

21. 21. The device of claim 20, wherein the surfaces of the thermoplastic substrate comprise at least two surfaces of the thermoplastic substrate.

22. 21. The device of claim 20, wherein the thermoplastic substrate is molded around the penetrator.

23. 10. The device of claim 1, wherein the glucose sensor includes a reference electrode.

24. 24. The device of claim 23, wherein the reference electrode comprises a silver (Ag) or silver chloride (Ag / AgCl) reference electrode.

25. 15. The device of claim 14, wherein the glucose sensor further comprises an insulating layer and a metal layer, the insulating layer bonded to the metal layer, and the metal layer bonded to an electrode layer comprising the at least one electrode or the at least two electrodes.

26. 26. The device of claim 25, wherein the insulating layer comprises a polyimide or a liquid crystal polymer.

27. 26. The device of claim 25, wherein the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm.

28. 26. The device of claim 25, wherein the metal layer comprises a titanium, gold, or platinum material.

29. 26. The device of claim 25, wherein the electrode layer comprises a film having a thickness of no more than about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm.

30. 26. The device of claim 25, wherein the metal compound of the metal layer comprises a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

31. 10. The device of claim 1, wherein the penetrator includes a proximal end and a distal end, the distal end being tapered.

32. The device of claim 1 , wherein the penetrator comprises a stylet or sharp.

33. 10. The device of claim 1, wherein the penetrator comprises an internal lumen.

34. 10. The device of claim 1, wherein the penetrator includes a beveled tip.

35. 1. A method for delivering insulin or an insulin analog formulation and measuring subcutaneous glucose concentrations, comprising the steps of: (a) A device for the delivery of insulin or insulin analogue formulations and the measurement of subcutaneous glucose concentrations is provided, wherein the device comprises: (i) a tube comprising a proximal end and a distal end, the proximal end being in fluid communication with a source of the insulin or insulin analog formulation, and the distal end being configured to subcutaneously deliver the insulin or insulin analog formulation; (ii) a glucose sensor disposed along the central axis of the tube; and (iii) a penetrator disposed along a central axis of the tube, the penetrator comprising a cross-sectional area no greater than a cross-sectional area of ​​the glucose sensor; Including, (b) performing subcutaneous insertion of the distal end of the tube, the glucose sensor, and the penetrator into the subject; and (c) subcutaneously delivering said insulin or insulin analog formulation to said subject, or measuring the subcutaneous glucose concentration of said subject with said glucose sensor, or a combination thereof.

36. 36. The method of claim 35, wherein the penetrator comprises a cross-sectional area that is smaller than the cross-sectional area of ​​the glucose sensor.

37. 36. The method of claim 35, wherein the penetrator comprises a cross-sectional area substantially equal to the cross-sectional area of ​​the glucose sensor.

38. 36. The method of claim 35, wherein the cross-sectional area of ​​the penetrator is less than or equal to the cross-sectional area of ​​the tube.

39. 36. The method of claim 35, wherein the cross-sectional area of ​​the penetrator is smaller than the cross-sectional area of ​​the glucose sensor.

40. 36. The method of claim 35, wherein the tube includes a tapered tip at the distal end.

41. 36. The method of claim 35, wherein the tapered tip of the tube comprises a rounded taper or a planar taper.

42. 36. The method of claim 35, wherein the cross-sectional area of ​​the distal end of the tapered portion of the tube is equal to the cross-sectional area of ​​the penetrator.

43. 36. The method of claim 35, wherein the device further comprises a housing including an upper accessible surface and a lower surface configured to be adhered to a skin surface.

44. 36. The method of claim 35, wherein the glucose sensor comprises an amperometric glucose sensor.

45. 36. The method of claim 35, wherein the glucose sensor is disposed on a second tube including a second distal end, the second distal end configured for subcutaneous insertion.

46. 36. The method of claim 35, wherein the tube includes a taper in a direction toward the distal end of the tube.

47. 36. The method of claim 35, wherein the glucose sensor is disposed on a surface of the tube.

48. 36. The method of claim 35, wherein the glucose sensor comprises at least one electrode or at least two electrodes.

49. 49. The method of claim 48, wherein the at least two electrodes are electrically isolated when external to the subject.

50. 49. The method of claim 48, wherein the at least one electrode or the at least two electrodes comprises a thermoplastic material as a substrate.

51. 49. The method of claim 48, wherein the at least one electrode or the at least two electrodes are disposed on a surface of the penetrator.

52. 49. The method of claim 48, wherein the at least one electrode or the at least two electrodes are one or more layers of the glucose sensor.

53. 49. The method of claim 48, wherein the at least one electrode or the at least two electrodes comprise a material of gold, carbon, graphite, platinum, or iridium.

54. 49. The method of claim 48, wherein the at least one electrode or the at least two electrodes are laminated to a surface of a thermoplastic substrate.

55. 55. The method of claim 54, wherein the surfaces of the thermoplastic substrate comprise at least two surfaces of the thermoplastic substrate.

56. 55. The method of claim 54, wherein the thermoplastic substrate is molded around the penetrator.

57. 36. The method of claim 35, wherein the glucose sensor comprises a reference electrode.

58. 58. The method of claim 57, wherein the reference electrode comprises a silver (Ag) or silver chloride (Ag / AgCl) reference electrode.

59. 49. The method of claim 48, wherein the glucose sensor further comprises an insulating layer and a metal layer, the insulating layer being bonded to the metal layer, and the metal layer being bonded to an electrode layer comprising the at least one electrode or the at least two electrodes.

60. 60. The method of claim 59, wherein the insulating layer comprises a polyimide or a liquid crystal polymer.

61. 60. The method of claim 59, wherein the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm.

62. 60. The method of claim 59, wherein the metal layer comprises a titanium, gold, or platinum material.

63. 60. The method of claim 59, wherein the electrode layer comprises a film having a thickness of no more than about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm.

64. 60. The method of claim 59, wherein the metal compound of the metal layer comprises a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

65. 36. The method of claim 35, wherein the penetrator includes a proximal end and a distal end, the distal end being tapered.

66. 36. The method of claim 35, wherein the penetrator comprises a stylet or sharp.

67. 36. The method of claim 35, wherein the penetrator comprises an internal lumen.

68. 36. The method of claim 35, wherein the penetrator includes a beveled tip.

69. 1. A device for the delivery of insulin or insulin analogue formulations and measurement of subcutaneous glucose concentrations, comprising: (a) a tube comprising a proximal end and a distal end, the proximal end in fluid communication with a source of the insulin or insulin analog formulation, and the distal end configured for subcutaneous delivery of the insulin or insulin analog formulation; (b) a glucose sensor disposed along the central axis of the tube; and (c) a penetrator disposed along a central axis of the tube, the penetrator configured to be inserted at least partially subcutaneously without the use of a trocar; Devices containing:

70. 1. A method for delivering insulin or an insulin analog formulation and measuring subcutaneous glucose concentrations, comprising the steps of: (a) A device for the delivery of insulin or insulin analogue formulations and the measurement of subcutaneous glucose concentrations is provided, wherein the device comprises: (i) a tube comprising a proximal end and a distal end, the proximal end in fluid communication with a source of the insulin or insulin analog formulation, and the distal end configured for subcutaneous delivery of the insulin or insulin analog formulation; (ii) a glucose sensor disposed along the central axis of the tube; and (iii) a penetrator disposed along the central axis of the tube; Including, (b) performing subcutaneous insertion of the distal end of the tube, the glucose sensor, and the penetrator into the subject without the use of a trocar; and (c) A method comprising subcutaneously delivering insulin or an insulin analog formulation to a subject, or measuring the subcutaneous glucose concentration of the subject using a glucose sensor, or a combination thereof.

Images