PFAS-free infusion cannula

Abstract

The present disclosure relates to the use of a PFAS-free cannula in delivering a fluid drug, such as insulin, to a subcutaneous site. The cannula comprises a polycarbonate polyurethane polysiloxane (PC-PU-PS), wherein the cannula is configured for subcutaneous insertion into a tissue of an individual in need thereof. The present disclosure includes methods for administering insulin using the cannula and infusion devices including the cannula.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 641,349, filed May 1, 2024, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0003] The present technology relates generally to medical devices, and more particularly to PFAS-free infusion cannulas for administering a drug to an individual, such as administering insulin to a diabetic patient. BACKGROUND

[0004] Millions of individuals with diabetes require insulin therapy to control uncontrolled blood glucose levels (i.e., blood glucose levels). As an alternative to multiple daily injections (syringes or pen-injection), many people rely on small, wearable insulin infusion devices to manage their blood glucose. Typically, an infusion device includes a pump (which includes controls, a processing module, and a battery), a reservoir containing a fluid medicament (e.g., insulin), and an infusion set / subsystem. The infusion set / subsystem includes a cannula configured for subcutaneous insertion into the individual and a tubing system connecting the reservoir to the cannula. When the tubing in the infusion subsystem is minimal and the pump is adhered to the skin, the pump system is wearable and is referred to as a patch pump. The cannula and tubing are part of the infusion subsystem in a patch pump. Infusion devices in which the pump is not worn against the skin but is tethered by a longer tubing are referred to as tethered pumps, and the cannula and tubing are referred to as an infusion set. In either a patch pump or a tethered pump, the cannula is inserted subcutaneously and remains at the infusion site for multiple days to enable delivery of the fluid medicament. The cannula provides a passageway for subcutaneous delivery of the medicament to the individual.

[0005] The most popular and widely used cannula is made of polytetrafluoroethylene (PTFE) and fluorinated ethylene propylene (FEP). These biocompatible polymers are lubricious and allow for easy manufacturing. Cannulas made of these polymers can reliably deliver insulin to an individual for multiple days before performance degradation, and the cannula must be removed and replaced.

[0006] However, one drawback of using PTFE and FEP polymers is that they are composed of per- and poly-fluoroalkyl substances (PFAS), which are long-lasting chemicals associated with adverse effects on human health and are difficult to break down. Because PFAS do not degrade easily, they can accumulate over time and build up in the body and the environment. Studies have shown correlations between exposure to certain PFAS and adverse effects on reproductive capacity, childhood developmental delays, increased risk of cancer, reduced immune system in the body to fight infection, interference with the body’s natural hormones, and increased cholesterol levels and risk of obesity.

[0007] There is a need for a biocompatible cannula composed of PFAS-free materials that is suitable for conventional manufacturing processes and can deliver insulin to an individual's tissue in a matter of days while maintaining good performance. PFAS-free cannulas are not only beneficial to the millions of diabetic patients who require subcutaneous infusion of insulin, but also to any individual who requires subcutaneous infusion of fluid medication. SUMMARY

[0008] The present disclosure provides a method for subcutaneously administering insulin to a diabetic patient via a PFAS-free cannula configured for subcutaneous insertion. Additionally, cannulas and infusion devices are disclosed herein.

[0009] In one aspect, the present disclosure provides a cannula for delivering insulin to an individual in need thereof, wherein: the cannula comprises a copolymer, and the copolymer is polycarbonate polyurethane polysiloxane (PC-PU-PS); and the cannula is configured for subcutaneous insertion into tissue of the individual in need thereof.

[0010] In another aspect, the present disclosure provides a method of administering insulin to an individual in need thereof, the method comprising: providing a cannula, wherein the cannula comprises a copolymer, and the copolymer is polycarbonate polyurethane polysiloxane (PC-PU-PS), wherein the cannula is configured for subcutaneous insertion into tissue of the individual in need thereof; inserting the cannula into the individual; and delivering insulin to the individual in need thereof via the cannula.

[0011] In yet another aspect, the present disclosure provides an infusion device, the infusion device comprising: a housing configured to be positioned at a patient's skin at an infusion site; a reservoir configured to store a fluid medication, the reservoir configured to be received by the housing; and a cannula configured for subcutaneous insertion into tissue of the patient at the infusion site.

[0012] The various embodiments disclosed herein are provided by way of example, and not limitation, and do not limit the subject technology. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 Certain general aspects of example cannulas shown as flared onto a hub or needle guide are summarized.

[0014] Figure 2 An example of the entire cannula and optional cannula tip manufacturing process is illustrated.

[0015] Figure 3 A photograph of an example cannula with a needle inside the tip cannula.

[0016] Figure 4is a plot of the elastic stiffness of three different materials as a function of temperature as measured by dynamic mechanical analysis (DMA) at a cyclic rate of 0.8 Hz.

[0017] Figure 5 is a plot of the storage modulus and loss modulus and tan delta of polycarbonate polyurethane polysiloxane (PC-PU-PS) Figure 5A ) and PTFE Figure 5B ) as measured by dynamic mechanical analysis (DMA) at a cyclic rate of 0.8 Hz.

[0018] Figure 6 is a graphical overview of the TDD of insulin delivered to a diabetic pig over nine days for each cannula material test group (EIS, ARCS-95A, ARCS-70D, ARCS-55D).

[0019] Figure 7 is a drawing of a cannula example, where the size ranges are provided in the examples section. DETAILED DESCRIPTION

[0020] I. Cannula Overview

[0021] Cannulas are a critical component of infusion therapy and serve as the junction between an infusion device and a patient's subcutaneous tissue. Cannulas provide the ability to deliver a fluid medication, such as insulin, to a target location (i.e., infusion site) on an individual's body over a period of days (e.g., 1 to 2 days, 2 to 3 days, up to 6 to 7 days). Some cannulas are used for subcutaneous insertion and can be 22 to 30 gauge. Some cannulas are made of synthetic polymers and can also be referred to as plastic catheters.

[0022] Figure 1 is an illustration of a cannula mated with a hub that can be used as a needle guide. The hub connects the cannula to the rest of the infusion device. The hub and cannula together serve to provide a sealed fluid delivery path for a medication (e.g., insulin) into a patient's (e.g., diabetic patient's) subcutaneous tissue.

[0023] A. Foreign body response and cannula-related complications

[0024] Implantation of a cannula in human tissue elicits an immune response known as a foreign body reaction. This reaction manifests as an acute inflammatory response at the site of insertion and can encompass the epidermis, dermis, and subcutaneous adipose tissue. In addition to the immune response, the insertion process itself can induce mechanical trauma. This trauma can affect cells and connective tissue along the cannula path, potentially damaging the basement membrane, extracellular matrix, and structural proteins. Disruption of the vascular network, including lymphatic vessels, arterioles, capillaries, and venules, can further compromise the tissue microenvironment and lead to fluid accumulation and potential blood clotting.

[0025] Another complication associated with cannula implantation is infusion site loss or site reduction. This phenomenon is thought to be mediated in part by encapsulation of the cannula by fibrous tissue and quality of insulin infusion, which can be affected by temperature and the interaction of insulin with materials it comes into contact with (e.g., reservoirs and fluid paths contacted during storage, filling, and delivery). The encapsulation process can result in inconsistent and unreliable drug delivery. In the case of inconsistent insulin, the individual can experience blood glucose fluctuations. The exact mechanism of site loss / reduction is still unclear, but can involve complex interactions between factors such as local inflammation, intraluminal clotting within the cannula, and progressive fibrotic tissue proliferation. Additionally, movement of the cannula during daily activities can exacerbate the host response and contribute to continued tissue irritation.

[0026] The above immunological responses, tissue trauma, and infusion site loss result in cannula failure, loss of effective insulin delivery, and ultimately uncontrolled blood glucose levels. To effectively deliver insulin and control blood glucose levels, the infusion set is replaced, which involves removal of the failed cannula and insertion of a new cannula, typically at a different infusion site. One way to extend the life of the cannula is to reduce or minimize the foreign body response, mechanical trauma, and infusion site loss by optimizing the cannula material and performance.

[0027] B. Elastic stiffness

[0028] The material of the cannula is stiff to facilitate penetration and insertion into the patient tissue and to resist bending or kinking that can obstruct insulin flow. The cannula material is sufficiently compliant to expand and conform to the hub or needle guide, but yet resilient enough to form a fluid-tight seal around the hub or needle guide. The cannula material does not react with the patient tissue.

[0029] A cannula whose stiffness varies as a function of temperature can reduce mechanical trauma due to the individual's micro-movements over time. Such a cannula is sufficiently rigid at room temperature to penetrate and insert into the patient tissue, but when the cannula is in contact with the patient tissue and raised to body temperature, the cannula softens and becomes more flexible after being implanted in the body. This flexibility enables the cannula to bend or otherwise accommodate any movement or micro-movements and / or deformations due to the individual's tissue pressure. The flexibility of the implanted cannula reduces tissue damage or trauma compared to a more rigid material, thereby reducing inflammation, occlusion, and infusion site loss, which extends the useful life of the implanted cannula. Reducing these negative effects in the patient increases the duration of effective delivery of the fluid medicament (e.g., insulin) and increases the length of time before the infusion set (e.g., cannula) needs to be replaced with a new set. Reducing the number of cannula insertions that the patient must perform enhances the patient's experience with the infusion therapy, which in some cases can be a lifelong therapy.

[0030] The stiffness or flexibility of a cannula can be assessed by measuring the elastic stiffness of the cannula material. One way to measure elastic stiffness is by dynamic mechanical analysis (DMA), which is known to those of ordinary skill in the art. Analysis by DMA can provide parameters such as storage modulus, loss modulus, tan delta, and elastic modulus, which give an indication of the physical characteristics of the material. The DMA test method calculates the relevant properties using the following equations:

[0031]

[0032] In the above equations, E' is the storage modulus, E" is the loss modulus, and delta is the phase shift. The raw data from DMA output (E', E", and delta) is used to calculate the elastic modulus, E.

[0033] Elastic stiffness is a function of the material used to make the cannula (e.g., PC-PU-PS). In some embodiments, elastic stiffness is a measure of the elastic modulus of the material. In a stress-strain curve, the elastic modulus is calculated from the slope of the linear region (elastic deformation) before permanent deformation of the material, which is stress / strain. Changes in the physical properties of the cannula material as a function of temperature can be assessed by subjecting the material to DMA over a range of temperatures. For example, the storage modulus and loss modulus, and tan delta data for polycarbonate polyurethane polysiloxane (PC-PU-PS) and PTFE cannulas can be measured over a range of temperatures as discussed in the Examples section. The performance of cannulas made from different materials can be compared by plotting their elastic stiffness (elastic modulus) over a range of temperatures. The Examples section also includes a comparison of the elastic stiffness of FEP, PTFE, and PC-PU-PS from 25 °C to about 60 °C.

[0034] Other methods of obtaining measurements related to elasticity include uniaxial tensile testing on an Instron at each temperature of interest, which is a method known to those of ordinary skill in the art.

[0035] The in vivo performance of a cannula is also affected by its surface microstructure. A smooth surface reduces protein adhesion to the cannula, potential occlusion, and minimizes the inflammatory response. A smooth surface also reduces friction during insertion, which helps to reduce insertion force and tissue trauma. A smoother cannula surface compared to a rougher surface can prolong consistent delivery of insulin and avoid infusion site loss for a longer period of time. The smoothness of the surface can be checked by visual observation using a microscope, SEM, and the like.

[0036] The quality of the cannula tip is critical for the penetration and longevity of the in vivo cannula. The tip geometry of the cannula is optimized for minimal penetration force and minimal pain to the patient. To increase the longevity of the in vivo cannula, the tip needs to strike a balance between sharp and blunt. A sharp tip reduces the force required to pierce the tissue, thereby minimizing discomfort during insertion. After the cannula is inserted into the tissue, a certain degree of bluntness in the tip will help reduce tissue damage during any subsequent movement of the cannula tip in vivo. The longevity of the cannula can be increased by including an optional silicone oil coating to reduce the effects of micro-movement of the cannula in vivo.

[0037] The opening of the cannula is large enough to deliver fluid medication (e.g., insulin) without creating an obstruction and narrow enough to minimize trauma to the patient tissue during insertion and placement at the infusion site. Additionally, the fill volume of the cannula is minimized to reduce the amount of insulin wasted after disposal of the used cannula.

[0038] C. General manufacturing process

[0039] An overview of the conventional cannula manufacturing process and optional tip forming process is shown in Figure 2 The conventional cannula manufacturing process begins with the addition of the raw material (i.e., copolymer) into the feed hopper of a screw extruder. The screw is rotated at a predetermined speed and a temperature controller is connected to the heating / cooling elements on the barrel to maintain the temperature at the set point temperature. The extrudate exits the die, which can be set to the desired shape or the shape of the extrudate can be changed, then set, and the resulting catheter is cooled. The term "catheter" is interchangeable with "cannula" as used herein. The catheter can be extruded on conventional manufacturing equipment and the specific processing parameters associated with a particular resin can be obtained from the supplier. The extruded catheter is then cut to length and flared onto a bushing that is fitted with a mandrel by an interference fit (also known as a friction fit or press fit). The distal end of the catheter is then tip formed using a heated and lubricated die. The tip forming process requires a heated die, which is typically lubricated to prevent the tubing from sticking. Finally, the tip cannula can be treated with a lubricant.

[0040] A tip-forming mold determines the geometry of the distal portion of the cannula, such as a round tip or a conical shaped feature. The mold is designed to provide an optimized tip catheter where the shape and size facilitate insertion into the body and reduce tissue trauma. The tip-forming process requires pre-heating the tip-forming mold to a predetermined temperature in order to reflow the resin of the tubing and force the tip of the tubing to conform to the shape of the mold. A silicone / siloxane lubricant is applied to the mold surface prior to tip-forming. The distal end of the cannula, also referred to as a catheter tubing, is forced and pressed into the mold. During tip formation, a mandrel is used to hold, guide, and center the cannula with the mold. The distal end is held in the mold for a predetermined dwell time to allow the distal end of the cannula to contact the mold to reflow and conform to the size of the mold. After the predetermined dwell time is complete, the cannula is withdrawn from the mold. A successfully formed tip will have a smooth surface while also conforming to the size of the molded surface.

[0041] In some embodiments, the cannula is a tipped cannula. In some embodiments, the cannula is not tipped.

[0042] D. PFAS-free cannula alternatives

[0043] Polytetrafluoroethylene (PTFE) and fluorinated ethylene propylene (FEP) have been the material of choice for cannula formation. PTFE can be reflowed when heated and is more lubricious than other resins, conforming to the shape of the mold and reducing the chance of sticking to the molded surface. Despite the lubricity of PTFE, the mold surface is typically lubricated during manufacturing to facilitate tip-forming and reduce the sticking of the tubing to the mold.

[0044] PTFE and FEP belong to a group of several hundred chemicals classified as per- and poly-fluoroalkyl substances (PFAS). PFAS are characterized by a chain of carbon atoms bonded to fluorine atoms and are referred to as “forever chemicals” due to their persistence and resistance to degradation. There is a growing awareness of the accumulation of PFAS in soil, water, and living organisms. The extent of the adverse effects of forever chemicals on human health and the environment is the subject of ongoing research. At the same time, the present disclosure provides an alternative to currently marketed PTFE and FEP cannulas. In some embodiments, the cannula described herein is PFAS-free.

[0045] Suitable alternatives to PFAS-free materials are not readily apparent and there are many manufacturing and mechanical reasons why one material can not be suitable for use in infusion cannulae. As a result, PTFE and FEP cannulae and catheters have become popular. Unlike PTFE and FEP, many other resins do not reflow well or become very “sticky” and adhere to the molding surface when heated. Resins that lack sufficient reflow result in cannula tip that take the form of the mold improperly and have poor quality characteristics. The term “reflow” refers to a process in which the cannula material melts and conforms to the dimensions of the mold during the tip forming process and then solidifies when cooled. Some materials are inferior because they do not have sufficient stiffness and will cause kinking or buckling within the cannula during insertion, damaging the cannula. Some materials can not be soft enough, which can result in tissue trauma and inflammation due to movement of the cannula when implanted in the body. Other resins can not be biocompatible and can react with the patient’s tissues.

[0046] E. Copolymers

[0047] In some embodiments, the present disclosure provides a cannula comprising a PFAS-free copolymer, wherein the cannula is configured for subcutaneous insertion into the tissue of an individual in need thereof. The copolymer is compatible with conventional manufacturing processes, has sufficient stiffness to withstand insertion forces without bending or kinking, is soft enough to reduce tissue trauma and inflammation, and is biocompatible.

[0048] The term “copolymer” refers to any polymer formed from two or more monomers. An example of a copolymer includes polycarbonate polyurethane polysiloxane (PC-PU-PS). The polycarbonate component of the copolymer is known to be a rigid, hard, and stiff material. Polycarbonate is commonly selected for its durability in the construction and automotive industries and is used in items such as roof panels, headlamp covers, and windows. The incorporation of this component in a PC-PU-PS copolymer for use as a cannula material is a surprising and unusual choice. It would not be possible for one of ordinary skill in the art to select polycarbonate as a component of a cannula material because of its inflexibility and hardness have the potential to cause patient discomfort and tissue damage, leading to adverse events such as inflammation, foreign body reactions, and infusion site breakdown.

[0049] In one embodiment, the raw material used to make the cannula is a PC-PU-PS resin. PC-PU-PS resins are available under the trade name Quadrasil TM ARCS is available from the manufacturer Biomerics, Inc. Quadrasil TM ARCS is a family of aromatic polycarbonate polyurethane polysiloxane copolymers. These copolymers can also be described as aromatic polycarbonate silicone TPU. A list of nine Quadrasil TMARCS copolymers and their physical properties.

[0050] Table 1.

[0051]

[0052] PC-PU-PS copolymers such as Quadrasil TM ARCS have measurable physical properties such as hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage, as listed in Table 1. These properties can be measured by standardized tests, for example, by those developed by ASTM International. Table 1. Physical properties of ARCS copolymers.

[0053] In some embodiments, the polycarbonate polyurethane polysiloxane copolymer is Quadrasil TM ARCS, which are available from commercial suppliers such as Biomerics, Inc. as resins. In some embodiments, the polycarbonate polyurethane polysiloxane copolymer is selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, or combinations thereof. In some embodiments, the polycarbonate polyurethane polysiloxane copolymer is selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, or combinations thereof. In some embodiments, the polycarbonate polyurethane polysiloxane copolymer is selected from the group consisting of ARCS-95A and ARCS-70D, or combinations thereof.

[0054] In some embodiments, the polycarbonate polyurethane polysiloxane copolymers disclosed herein have a physical property profile comprising two or more physical properties (e.g., hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage) listed in Table 1, wherein the physical property profile is equivalent to that of Quadrasil TM Physical property profiles of ARCS polycarbonate polyurethane polysiloxane copolymers.

[0055] In some embodiments, the copolymers disclosed herein have a physical property profile comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage, wherein the physical property profile is equivalent to that of ARCS copolymers described in Table 1.

[0056] In some embodiments, the copolymers disclosed herein have a physical property profile comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flex modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage, wherein the physical property profile is equivalent to the physical property profile of an ARCS copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D. In some embodiments, the physical property profile consists of three or more, four or more, five or more, six or more, or seven or more of the aforementioned physical properties.

[0057] In some embodiments, the copolymers disclosed herein can have a physical property profile equivalent to the physical property profile of ARCS-95A or ARCS-70D. For example, in some embodiments, the copolymer has two or more physical properties selected from the group consisting of: a durometer hardness of 95A, a specific gravity of about 1.17, a flex modulus of about 10000 psi, an ultimate tensile of about 6000 psi, an ultimate elongation of about 380%, a tensile at 100% of about 2400 psi, a tensile at 300% of about 4500 psi, and a molding shrinkage of about 0.008 in / in to 0.012 in / in. In some embodiments, the copolymer has two or more physical properties selected from the group consisting of: a durometer hardness of about 70D, a specific gravity of about 1.20, a flex modulus of about 55000 psi, an ultimate tensile of about 7300 psi, an ultimate elongation of about 200%, a tensile at 100% of about 3900 psi, and a molding shrinkage of about 0.008 in / in to 0.012 in / in. In some embodiments, the copolymer has three or more, four or more, five or more, six or more, or seven or more of the aforementioned physical properties.

[0058] As used herein, the term “equivalent” is plus or minus 0.1% to 20%, plus or minus 0.1% to 10%, plus or minus 0.1% to 5%, or plus or minus 0.1% to 2% of the value listed in Table 1.

[0059] F. Cannula configured with a needle

[0060] A needle can optionally be used to facilitate insertion of the cannula by piercing tissue (e.g., skin) of an individual so as to allow the cannula to be inserted and positioned at the intended site. The cannula can be configured to surround an outer surface of the needle. For example, Figure 3 A photograph showing a needle positioned inside a lumen of a tip cannula is shown. Alternatively, the needle can be configured to surround an outer surface of the cannula.

[0061] In some embodiments, the cannula further comprises a needle located within the cannula. In some embodiments, the cannula further comprises a needle located on the exterior of the cannula. In embodiments where the cannula further comprises a needle located on the exterior of the cannula, the cannula is not a sharp cannula. In some embodiments, the cannula further comprises a needle located within the cannula, and the cannula is a sharp cannula. In some embodiments, the cannula is configured for subcutaneous insertion into the tissue of a diabetic patient. In some embodiments, the cannula is part of an infusion set / subsystem.

[0062] In some embodiments, the cannula for delivering insulin to an individual in need thereof, wherein: the cannula comprises a copolymer, and the copolymer is a polycarbonate polyurethane polysiloxane (PC-PU-PS); the cannula is configured for subcutaneous insertion into the tissue of an individual in need thereof; the difference in elastic stiffness of the cannula at 25 °C and 37 °C is at least 150 MPa, as measured by DMA at a cyclic rate of 0.8 Hz; and the copolymer has physical property characteristics equivalent to the physical property characteristics of an ARCS copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D; and the physical property characteristics of the ARCS copolymer are listed in Table 1.

[0063] In some embodiments, the cannula for delivering insulin to an individual in need thereof, wherein: the cannula comprises a polycarbonate polyurethane polysiloxane copolymer (PC-PU-PS); the cannula is configured for subcutaneous insertion into the tissue of an individual in need thereof; and the difference in elastic stiffness of the cannula at 25 °C and 37 °C is at least 150 MPa, as measured by DMA at a cyclic rate of 0.8 Hz.

[0064] In some embodiments, the cannula for delivering insulin to an individual in need thereof, wherein: the cannula comprises a polycarbonate polyurethane polysiloxane copolymer (PC-PU-PS); the cannula is configured for subcutaneous insertion into the tissue of an individual in need thereof; and the elastic stiffness of the cannula at 25 °C is at least 50% greater than the elastic stiffness of the copolymer at 37 °C, as measured by DMA at a cyclic rate of 0.8 Hz.

[0065] In some embodiments, the cannula is for delivering insulin to an individual in need thereof, wherein: the cannula comprises a polycarbonate polyurethane polysiloxane copolymer (PC-PU-PS); the cannula is configured for subcutaneous insertion into tissue of an individual in need thereof; the difference in elastic stiffness of the cannula at 25 °C and 37 °C is at least 150 MPa, as measured by DMA at a cyclic rate of 0.8 Hz; and the copolymer has a physical property profile comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage; and the physical property profile is equivalent to that of a copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, as described in Table 1.

[0066] In some embodiments, the cannula is for delivering insulin to an individual in need thereof, wherein: the cannula comprises a polycarbonate polyurethane polysiloxane copolymer (PC-PU-PS); the cannula is configured for subcutaneous insertion into tissue of an individual in need thereof; the elastic stiffness of the cannula at 25 °C is at least 50% greater than the elastic stiffness of the copolymer at 37 °C, and the copolymer has a physical property profile comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage; and the physical property profile is equivalent to that of a copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, as described in Table 1.

[0067] II. Methods of using cannula to deliver fluidic drugs

[0068] The present disclosure provides methods of administering a fluid medicament to an individual in need thereof using the cannula described herein. An individual in need thereof refers to a subject in need of subcutaneous infusion of a fluid medicament (e.g., insulin), and includes humans, pigs, dogs.

[0069] The fluid medicament can be any medicament that requires subcutaneous delivery. Examples of subcutaneous administration include insulin, growth hormone, epinephrine, opioids, heparin, and allergy medications. Medicaments that require long-term delivery to an individual over a period of days can benefit from the use of a cannula.

[0070] Administration of fluid medicaments can be performed with infusion devices that include a cannula. Infusion devices include a pump (which includes controls, a processing module, and a battery), a reservoir containing a fluid medicament (e.g., insulin), and an infusion set / subsystem for subcutaneous insertion into an individual (which includes a cannula as described herein), and a tubing system connecting the reservoir to the cannula. Infusion sets refer to both external infusion sets, which connect a tethered pump to a cannula via a long tubing, and internal infusion sets, such as within a body worn patch pump (i.e., the pump, cannula, and tubing are all within the patch device).

[0071] In some embodiments, the present disclosure provides a method of administering insulin to an individual in need thereof, the method comprising: providing a cannula as described herein; inserting the cannula into the individual; and delivering insulin into the individual in need thereof via the cannula.

[0072] The cannula is inserted subcutaneously at an infusion site on the abdomen, thigh, hip, upper arm, lower back, or buttocks of an individual in need. During insertion into the individual in need, the cannula resists bunching or kinking. Insertion results in the cannula being implanted into the individual. During the period of implantation, the individual can continue to "wear" the cannula. The term "wear" as used herein means that the cannula is implanted into the individual after insertion.

[0073] Once implanted, the cannula is in contact with the individual in need (i.e., implanted in the body) for at least 3 consecutive days, at least 4 consecutive days, at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, or at least 10 consecutive days before the cannula is replaced or removed. Implantation of the cannula is maintained as long as the flow of fluid medicament (e.g., insulin) is sufficient to facilitate administration of the medicament to the individual. In individuals with diabetes, beneficial administration of insulin results in effective control of blood glucose levels. When a foreign body reaction, an inflammatory reaction, coagulation, or any other adverse reaction occurs resulting in failure of the infusion site, blood glucose levels will rise despite administration of larger doses of insulin. This is a signal that the individual is no longer benefiting from infusion therapy and the cannula should be removed with insertion of a new cannula at a different infusion site. Currently, manufacturers recommend removal of the cannula every 3 days and insertion of the cannula at a different site on the body, and some cannula insertions are for up to 7 days. Beyond this time increases the chance of tissue damage, infection, scarring, and elevated blood glucose.

[0074] In some embodiments, the individual in need is a human. In some embodiments, the individual is a human with diabetes. In some embodiments, the individual is a human with diabetes. In some embodiments, the individual is a pig with diabetes.

[0075] In some embodiments, the distal end of the cannula comprises a tip configured to penetrate the skin of an individual in need thereof. In some embodiments, the cannula is configured to be worn (i.e., implanted) at a single site on a diabetic patient for at least 2 days, at least 3 days, or at least 3 days. In some embodiments, the cannula is in contact with an individual in need thereof for at least 3 consecutive days, at least 4 consecutive days, at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, or at least 10 consecutive days prior to replacement or removal of the cannula.

[0076] In some embodiments, the cannula is used to deliver a fluid medicament to an individual in need thereof. In some embodiments, the cannula is used to deliver insulin. In some embodiments, the cannula is a fluid conduit for a fluid medicament. In some embodiments, the cannula is used to deliver insulin to a diabetic subject at a single infusion site over a period of time (e.g., 1 to 2 days, 2 to 3 days, at least 6 to 7 days, at least 10 days).

[0077] In some embodiments, the disclosure provides a method of administering insulin to an individual in need thereof, the method comprising: providing a cannula, wherein the cannula comprises a copolymer, and the copolymer is a polycarbonate polyurethane polysiloxane (PC-PU-PS), wherein the cannula is configured for subcutaneous insertion into tissue of the individual in need thereof; inserting the cannula into the individual; and delivering insulin to the individual in need thereof via the cannula; wherein the cannula is implanted in the individual in need thereof for at least 3 consecutive days prior to replacement or removal of the cannula.

[0078] In some embodiments, the disclosure provides a method of administering insulin to an individual in need thereof, the method comprising: providing a cannula, wherein the cannula comprises a copolymer, and the copolymer is a polycarbonate polyurethane polysiloxane (PC-PU-PS), wherein the cannula is configured for subcutaneous insertion into tissue of the individual in need thereof; inserting the cannula into the individual; and delivering insulin to the individual in need thereof via the cannula; wherein the cannula is implanted in the individual in need thereof for at least 3 consecutive days prior to replacement or removal of the cannula, and the average total daily dose (TDD) of insulin delivered to the individual in need thereof over the period of at least 3 consecutive days is about or less than the average TDD of insulin delivered via a similar cannula comprising PTFE or FEP.

[0079] The term“about” in reference to a value of a dimension indicates a value that is slightly outside the recited value, e.g., plus or minus 0.1% to 10%, plus or minus 0.1% to 5%, or plus or minus 0.1% to 2%. In some embodiments, the term“about” indicates a value that is plus or minus 10% of the recited value. In some embodiments, the term“about” indicates a value that is plus or minus 5% of the recited value. In some embodiments, the term“about” indicates a value that is plus or minus 2% of the recited value. In some embodiments, the term“about” indicates a value that is plus or minus 1% of the recited value.

[0080] III. Evaluating cannula performance

[0081] Examples of assessing cannula performance include monitoring the total daily dose (TDD) of insulin and determining the level of comfort of the patient during cannula insertion or during insulin infusion.

[0082] The TDD is the amount of insulin needed to maintain an individual’s blood glucose at a desired level. Foreign body reactions, tissue damage, and infusion site depletion due to the use of infusion devices (i.e., cannula implantation and insulin infusion) can reduce the effective delivery of insulin. As the body begins to react at the insertion site, the amount of insulin needed to maintain the patient’s normal blood glucose levels will begin to increase. Eventually, the amount of insulin will not lower the glucose level, at which point the infusion set must be removed and a new infusion site is needed. Thus, monitoring the TDD of insulin can be used to assess the performance of the implanted cannula.

[0083] The subjective level of comfort and discomfort of cannula insertion can be assessed by providing a questionnaire to the test subjects. Immediately after each cannula insertion, each study participant can be presented with a comfort / discomfort Likert scale (very uncomfortable, uncomfortable, neutral, comfortable, and very comfortable). The patient indicates which level is closest to the level perceived during cannula penetration, and the response is recorded. The word“pain” is not used to avoid influencing the study participant’s perception. At the end of the test, the data is tabulated and analyzed by means of Software paired analysis (“regular technique” vs.“emergency technique”.

[0084] The singular terms or plural terms can also include the plural terms or singular terms, respectively, as context permits. Although specific embodiments and examples of the technology are described above for illustrative purposes, those of ordinary skill in the relevant art will appreciate that various equivalent modifications are possible within the scope of the technology.

[0085] As used herein, the terms “overall,” “substantially,” “about,” and similar terms are used as approximating terms and not as terms of degree, and are intended to account for the inherent deviations in measured or calculated values that would be recognized by those of ordinary skill in the art. As used herein, the term “about” is used synonymously with the term “approximately.”

[0086] Further, unless the word “or” is explicitly defined in the description of a claim as being the only item that is intended to be covered by that claim, the use of “or” in such a claim should be interpreted to be inclusive of either the item preceding or following the term “or” in that claim. Additionally, the term “comprising” is used throughout the specification to mean “including but not limited to.”

[0087] IV. Example embodiments

[0088] Some embodiments of the present disclosure relate to Embodiment I, as follows:

[0089] Embodiment I-1. A cannula for delivering insulin to an individual in need thereof, wherein: the cannula comprises a copolymer, and the copolymer is a polycarbonate polyurethane polysiloxane (PC-PU-PS); and the cannula is configured for subcutaneous insertion into tissue of the individual in need thereof.

[0090] Embodiment I-2. The cannula of Embodiment I-1, wherein the elastic stiffness of the cannula at 25 °C is higher than the elastic stiffness at 37 °C.

[0091] Embodiment I-3. The cannula of Embodiment I-1, wherein the difference in elastic stiffness of the cannula at 25 °C and 37 °C is at least 25 MPa, at least 50 MPa, at least 75 MPa, at least 100 MPa, at least 150 MPa, at least 200 MPa, at least 250 MPa, at least 300 MPa, or at least 400 MPa, as measured by dynamic mechanical analysis (DMA) at a cyclic rate of 0.8 Hz.

[0092] Embodiment I-4. The cannula of any one of embodiments I-l to I-3, wherein the difference in elastic stiffness of the cannula at 25 °C and 37 °C is 300 MPa to 400 MPa, 250 MPa to 350 MPa, 200 MPa to 300 MPa, 100 MPa to 200 MPa, 50 MPa to 100 MPa, or 25 MPa to 75 MPa, as measured by DMA at a cyclic rate of 0.8 Hz.

[0093] Embodiment I-5. The cannula of any one of embodiments I-l to I-4, wherein the difference in elastic stiffness of the cannula at 25 °C and 37 °C is greater than the difference in elastic stiffness of PTFE at 25 °C and 37 °C, as measured by DMA at a cyclic rate of 0.8 Hz.

[0094] Embodiment I-6. The cannula of any one of embodiments I-l to I-5, wherein the elastic stiffness of the cannula at 25 °C is at least 20%, at least 50%, at least 75%, at least 100%, at least 125%, or at least 150% greater than the elastic stiffness of the copolymer at 37 °C, as measured by DMA at a cyclic rate of 0.8 Hz.

[0095] Embodiment I-7. The cannula of any one of embodiments I-l to I-6, wherein the cannula exhibits a tan delta peak between 30 °C and 50 °C, as measured by DMA at a cyclic rate of 0.8 Hz.

[0096] Embodiment I-8. The cannula of any one of embodiments I-l to I-7, wherein the tan delta peak of the cannula has an inflection point between 30 °C and 50 °C, as measured by DMA at a cyclic rate of 0.8 Hz.

[0097] Embodiment I-9. The cannula of any one of embodiments I-l to I-8, wherein the cannula further comprises a needle positioned within the cannula.

[0098] Embodiment I-10. The cannula of any one of embodiments I-l to I-8, wherein the cannula further comprises a needle positioned on the exterior of the cannula.

[0099] Embodiment I-11. The cannula of any one of embodiments I-l to I-10, wherein the cannula is free of polyfluoroalkyl substances (PFAS).

[0100] Embodiment I-12. The cannula of any one of embodiments I-l to I-11, wherein the cannula does not comprise a plasticizer additive.

[0101] Embodiment I-13. The cannula of any one of embodiments I-1 to I-12, wherein the individual in need thereof is a diabetic.

[0102] Embodiment I-14. The cannula of any one of embodiments I-1 to I-14, wherein the copolymer is selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, or combinations thereof.

[0103] Embodiment I-15. The cannula of any one of embodiments I-1 to I-14, wherein the copolymer is selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, or combinations thereof.

[0104] Embodiment I-16. The cannula of any one of embodiments I-1 to I-15, wherein the copolymer has physical property characteristics equivalent to those of an ARCS copolymer selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, wherein the physical property characteristics of the ARCS copolymers are listed in Table 1.

[0105] Embodiment I-17. The cannula of any one of embodiments I-1 to I-15, wherein: the copolymer has physical property characteristics equivalent to those of an ARCS copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D; and the physical property characteristics of the ARCS copolymers are listed in Table 1.

[0106] Embodiment I-18. The cannula of any one of embodiments I-1 to I-15, wherein: the copolymer has physical property characteristics comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flex modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage; and the physical property characteristics are equivalent to those of an ARCS copolymer described in Table 1.

[0107] Embodiment I-19. The cannula according to any one of embodiments I-1 to I-15, wherein: the copolymer has a physical property profile comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molding shrinkage; and the physical property profile is equivalent to the physical property profile of a copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D as described in Table 1.

[0108] Embodiment I-20. The cannula according to any one of embodiments I-1 to I-19, wherein the distal end of the cannula comprises a tip capable of penetrating the skin of the individual in need thereof.

[0109] Embodiment I-21. The cannula according to any one of embodiments I-1 to I-20, wherein two or more, three or more, or four or more of the dimensions of the cannula are proportional to the dimensions of the cannula described in Table 4.

[0110] Embodiment I-22. The cannula according to any one of embodiments I-1 to I-21, wherein two or more, three or more, or four or more of the dimensions of the cannula are about the dimensions of the cannula described in Table 4.

[0111] Embodiment I-23. A method of administering insulin to an individual in need thereof, the method comprising: providing a cannula, wherein the cannula comprises a copolymer and the copolymer is a polycarbonate polyurethane polysiloxane (PC-PU-PS), wherein the cannula is configured for subcutaneous insertion into tissue of the individual in need thereof; inserting the cannula into the individual; and delivering insulin into the individual in need thereof via the cannula.

[0112] Embodiment I-24. The method according to embodiment I-23, wherein the cannula is inserted into subcutaneous tissue on the abdomen, thigh, hip, upper arm, lower back, or buttocks of the individual in need thereof.

[0113] Embodiment I-25. The method according to embodiment I-23 or I-24, wherein the cannula resists bunching or kinking during insertion into the individual in need thereof.

[0114] Embodiment I-26. The method of any one of embodiments I-23 to I-25, wherein the cannula is implanted in the individual in need thereof for at least 3 consecutive days, at least 4 consecutive days, at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, or at least 10 consecutive days prior to replacement or removal of the cannula.

[0115] Embodiment I-27. The method of any one of embodiments I-23 to I-26, wherein the individual in need thereof experiences greater comfort, reduced inflammation, or reduced foreign body reaction compared to a similar cannula comprising PTFE or FEP.

[0116] Embodiment I-28. The method of embodiment I-27, wherein the greater comfort, reduced inflammation, or reduced foreign body reaction compared to a similar cannula comprising PTFE or FEP is associated with reduced stiffness of the cannula at body temperature.

[0117] Embodiment I-29. The method of any one of embodiments I-23 to I-28, wherein the average total daily dose (TDD) of insulin delivered to the individual in need thereof is about or less than the average TDD of insulin delivered via a similar cannula comprising PTFE or FEP over a period of at least 3 consecutive days, at least 4 consecutive days, at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, or at least 10 consecutive days.

[0118] Embodiment I-30. The method of any one of embodiments I-23 to I-29, wherein the average TDD of insulin delivered to the individual in need thereof is about or less than the average TDD of insulin delivered to the individual in need thereof via a similar cannula comprising PTFE or FEP over a period of up to 10 consecutive days.

[0119] Embodiment I-31. The method of any one of embodiments I-23 to I-30, wherein the TDD of insulin delivered to the individual in need thereof does not increase by more than at least 25% over the average TDD over a period of up to 10 consecutive days.

[0120] Embodiment I-32. The method of any one of embodiments I-23 to I-31, wherein the cannula is in fluid connection with an insulin infusion device.

[0121] Embodiment I-33. The method of any one of embodiments I-23 to I-32, wherein the elastic stiffness of the cannula at 25 °C is higher than the elastic stiffness at 37 °C.

[0122] Embodiment I-34. The method according to any one of embodiments I-23 to I-33, wherein the difference in elastic stiffness of the cannula at 25°C and 37°C is at least 25 MPa, at least 50 MPa, at least 75 MPa, at least 100 MPa, at least 150 MPa, at least 200 MPa, at least 250 MPa, at least 300 MPa, or at least 400 MPa, as measured by DMA at a cycling rate of 0.8 Hz.

[0123] Embodiment I-35. The method according to any one of embodiments I-23 to I-34, wherein the difference in elastic stiffness of the cannula at 25°C and 37°C is from 300 MPa to 400 MPa, from 250 MPa to 350 MPa, from 200 MPa to 300 MPa, from 100 MPa to 200 MPa, from 50 MPa to 100 MPa, or from 25 MPa to 75 MPa, as measured by DMA at a cycling rate of 0.8 Hz.

[0124] Embodiment I-36. The method according to any one of embodiments I-23 to I-35, wherein the difference in elastic stiffness of the cannula at 25°C and 37°C is greater than the difference in elastic stiffness of PTFE at 25°C and 37°C.

[0125] Embodiment I-37. The method according to any one of embodiments I-23 to I-36, wherein the elastic stiffness of the cannula at 25°C is at least 20%, at least 50%, at least 75%, at least 100%, at least 125%, or at least 150% greater than the elastic stiffness of the copolymer at 37°C.

[0126] Embodiment I-38. The method according to any one of embodiments I-23 to I-37, wherein the cannula exhibits a tan delta peak between 30°C and 50°C, as measured by DMA at a cycling rate of 0.8 Hz.

[0127] Embodiment I-39. The method according to any one of embodiments I-23 to I-38, wherein the tan delta peak of the cannula has an inflection point between 30°C and 50°C, as measured by DMA at a cycling rate of 0.8 Hz.

[0128] Embodiment I-40. The method according to any one of embodiments I-23 to I-39, wherein the cannula further comprises a needle positioned within the cannula.

[0129] Embodiment I-41. The method according to any one of embodiments I-23 to I-39, wherein the cannula further comprises a needle positioned on the exterior of the cannula.

[0130] Embodiment I-42. The method of any one of embodiments I-23 to I-41, wherein the cannula is free of polyfluoroalkyl substances (PFAS).

[0131] Embodiment I-43. The method of any one of embodiments I-23 to I-42, wherein the cannula does not comprise a plasticizer additive.

[0132] Embodiment I-44. The method of any one of embodiments I-23 to I-43, wherein the individual in need thereof is a diabetic.

[0133] Embodiment I-45. The method of any one of embodiments I-23 to I-44, wherein the copolymer is selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, or combinations thereof.

[0134] Embodiment I-46. The method of any one of embodiments I-23 to I-44, wherein the copolymer is selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, or combinations thereof.

[0135] Embodiment I-47. The method of any one of embodiments I-23 to I-46, wherein the copolymer has physical property characteristics equivalent to those of an ARCS copolymer selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D, wherein the physical property characteristics of the ARCS copolymer are listed in Table 1.

[0136] Embodiment I-48. The method of any one of embodiments I-23 to I-46, wherein: the copolymer has physical property characteristics equivalent to those of an ARCS copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D; and the physical property characteristics of the ARCS copolymer are listed in Table 1.

[0137] Embodiment I-49. The method of any one of embodiments I-23 to I-46, wherein: the copolymer has a physical property profile comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molded shrinkage; and the physical property profile is equivalent to a physical property profile of an ARCS copolymer described in Table 1.

[0138] Embodiment I-50. The method of any one of embodiments I-23 to I-46, wherein: the copolymer has a physical property profile comprising two or more physical properties selected from the group consisting of durometer hardness, specific gravity, flexural modulus, ultimate tensile, ultimate elongation, tensile at 100%, tensile at 300%, and molded shrinkage; and the physical property profile is equivalent to a physical property profile of a copolymer selected from the group consisting of ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D, and ARCS-70D as described in Table 1.

[0139] Embodiment I-51. The method of any one of embodiments I-23 to I-50, wherein the distal end of the cannula comprises a sharp tip capable of penetrating the skin of the individual in need thereof.

[0140] Embodiment I-52. The method of any one of embodiments I-23 to I-51, wherein two or more, three or more, or four or more of the dimensions of the cannula are proportional to the dimensions of the cannula described in Table 4.

[0141] Embodiment I-53. The method of any one of embodiments I-23 to I-52, wherein two or more, three or more, or four or more of the dimensions of the cannula are about the dimensions of the cannula described in Table 4.

[0142] Embodiment I-54. An infusion device comprising: a housing configured to be positioned at the skin of a patient at an infusion site; a reservoir configured to store a fluid medicament, the reservoir configured to be received by the housing; and a cannula configured for subcutaneous insertion into the tissue of the patient at an infusion site, wherein the cannula is the cannula of any one of embodiments I-1 to I-22.

[0143] V. Examples

[0144] The following specific examples are to be understood as merely illustrative, and not limitative of the remainder of the disclosure in any way.

[0145] Example 1: General process for making cannula

[0146] This example describes the general process for making the cannula described herein.

[0147] Quadrasil TM ARCS resin (PC-PU-PS) and added to the feed hopper of a screw extruder. The conduit is extruded on conventional equipment and the specific processing parameters associated with the specific resin are obtained from the supplier. The extruded conduit is cut to length and swaged onto a bushing mounted on a mandrel by an interference fit. The distal end of the conduit is then tip shaped using a heated and lubricated mold. This process requires the tip shaping mold to be preheated to a predetermined temperature in order to cause the resin to reflow and force the tip of the conduit to conform to the shape of the mold. A silicone / siloxane lubricant is applied to the heated mold surface just prior to tip shaping. The distal end of the conduit is forced and pressed into the heated mold. In the tip shaping process, a mandrel is used to hold, guide, and center the cannula with the heated mold. The distal end is held in the mold for a predetermined dwell time to allow the distal end of the cannula in contact with the mold to reflow and conform to the dimensions of the mold. Upon completion of the predetermined dwell time, the cannula is withdrawn from the mold.

[0148] Example 2: Comparison of elastic stiffness of various cannula materials

[0149] This example compares the elastic stiffness of three different materials at temperatures from 25°C to 60°C.

[0150] PTFE, FEP, and Quadrasil TM ARCS resin (PC-PU-PS) samples were DMAed at a cycle rate of 0.8 Hz while the temperature of the sample was ramped from 25°C to 60°C. The elastic stiffness (MPa) was calculated for each sample and the elastic stiffness was plotted as a function of temperature as shown in Figure 4

[0151] FEP has an elastic stiffness of about 525 MPa at 25°C, which represents room temperature, and does not fluctuate significantly at 37°C, which represents body temperature. PTFE has an elastic stiffness of about 325 MPa at 25°C and decreases to just below 300 MPa at 37°C. The higher elastic stiffness value of FEP indicates that it is stiffer than PTFE. It is noted that FEP does not perform as well as PTFE in the body, which can be due to the stiffness of FEP at body temperature.

[0152] ​The elastic stiffness curve of the PC-PU-PS material is significantly different than both PFAS polymers. At room temperature, PC-PU-PS has an elastic stiffness of about 550 MPa, which is higher than the elastic stiffness of both FEP and PTFE. At body temperature, the stiffness value decreases to 200 MPa, which is about 100 MPa lower than PTFE. This indicates that PC-PU-PS is stiffer than PTFE and FEP at room temperature, but softer than PTFE and FEP at body temperature. The high mechanical stiffness of PC-PU-PS at room temperature can help minimize failure due to bunching or kinking of the cannula during insertion. The softer and more flexible nature of the implanted cannula can increase patient comfort, reduce inflammation, and foreign body reaction to the cannula. As a result of reduced inflammation and foreign body reaction, the implanted cannula can have a longer survival, meaning the patient can wear the cannula for a longer period of time before replacing it with a new cannula.

[0153] Based on the results above, the mechanical properties of the PC-PU-PS copolymer are superior to PTFE and FEP polymers currently used as infusion cannulae.

[0154] Example 3: Comparison of PTFE and PC-PU-PS

[0155] This example compares the mechanical properties of PC-PU-PS and PTFE cannula materials.

[0156] Samples of PC-PU-PS and PTFE cannula materials were obtained and DMA was performed at a cycling rate of 0.8 Hz. The storage modulus, loss modulus, and tan delta were calculated based on the DMA measurements and plotted as a function of temperature. Figure 5A A plot of the data for PC-PU-PS is shown. The tan delta reaches a peak around 40 °C, which is very close to the body temperature of 37 °C.

[0157] The increased tan delta indicates greater elastic energy dissipation and lower elasticity, which is desirable for an implanted cannula. The greater the tan delta means the material is less likely to "spring back" when deformed and bent in the body. This flexibility and reduced elasticity can improve comfort and reduce inflammatory or foreign body reactions, which in turn leads to longer wear times for the patient and fewer times the cannula needs to be replaced.

[0158] Figure 5B A plot of the data for PTFE is shown, which does not exhibit a tan delta peak or inflection point around body temperature. This means that the PTFE material will be less likely to deform and flex with the body's movements. Stiff implanted cannulae potentially increase the risk of tissue trauma, inflammation, and foreign body reaction; events that reduce the life of the cannula and infusion site.

[0159] The tan delta profile of PC-PU-PS is surprising, especially since the copolymer contains a polycarbonate component, which is known to be a rigid, stiff material. The tan delta peak of PC-PU-PS indicates superior mechanical properties compared to PTFE for the purpose of a subcutaneous infusion cannula that is rigid upon insertion and then softens at body temperature.

[0160] Example 3: Preclinical testing of cannula in a diabetic pig model

[0161] Three types of PTFE-free cannula were tested for performance in a diabetic pig model over a 10-day period and compared to a conventional PTFE cannula. A commercially available infusion device was modified to accommodate the test cannula. The test cannula without PFAS was made from ARCS-95A (n=4), ARCS-70D (n=4), or ARCS-55 (n=4), where n indicates the number of pig subjects tested. The cannula made from PTFE (n=4) was a commercially available Medtronic Extended TM part of an infusion set (EIS).

[0162] Animal subjects were fasted for 12 hours or more prior to testing. On day 0, pigs were fed a standard diet at prescribed times. While the subjects were under general anesthesia, the cannula was placed subcutaneously into the abdominal tissue. A glucose sensor was also implanted at least 5 cm from the cannula. Additionally, blood glucose levels were measured 5 times per day at prescribed times (i.e., 07:30, 09:30, 11:30, 14:30, and 16:30). The infusion device was used to deliver Novolog insulin into the subjects.

[0163] A basal delivery rate was established on day 0, which represented the basal delivery rate needed to maintain blood glucose concentrations within the range of 100 mg / dL to 400 mg / dL. The infusion device delivered bolus amounts of insulin as needed, for example, after meals when blood glucose concentrations increased beyond the desired range. The infusion set was considered to have failed when blood glucose concentrations did not respond to changes in insulin dosage, for example, when giving an increased amount of insulin failed to lower or control blood glucose concentrations.

[0164] The amount of insulin administered over a 24-hour period, the total daily dose (TDD), was calculated for a nine-day period or until the infusion set failed. Table 2 summarizes the TDD for each test group from day 1 to day 9 and the p-value for the test groups compared to the PTFE group. Figure 6 is a graphical summary of the TDD for each test group over nine days. The experiment ended on day 10.

[0165] Table 2.

[0166]

[0167]

[0168] All subjects in each test group survived the 10-day study. For each test group, the average TDD did not change significantly during the experiment, indicating that there was no appreciable deterioration of the infusion site. The cannulas made from PTFE, ARCS-95A, ARCS-55D, and ARCS-70D successfully delivered insulin at a rate that maintained the desired blood glucose concentration throughout the test period. This indicates that there was very little inflammation, no occlusion, or infusion site loss as a result of the insulin infusion therapy. Furthermore, there were no statistically significant differences in TDD between the three test cannulas and PTFE. This data demonstrates that the cannula made from PC-PU-PS performed as well as the PTFE cannula in vivo over a nine-day period.

[0169] As previously noted, polycarbonate is known to be a hard, stiff, and rigid material. Surprisingly, the incorporation of polycarbonate in the PC-PU-PS copolymer did not hinder the performance of the test cannula.

[0170] The average TDD change from day 0 to day 9 for the PTFE, ARCS-95A, ARCS-55D, and ARCS-70D cannulas is summarized in Table 3.

[0171] Table 3.

[0172] Cannula materials Mean TDD change from day 0 to day 9 PTFE -4％ ACRS 95A cannula +2％ ACRS 55D cannula -2％ ACRS 70D cannula -15％

[0173] Example 4: Example cannula specifications

[0174] This example provides dimensional descriptions of the example cannulas disclosed herein. Table 4 provides the dimensions of various parameters for the cannula shown in FIG. 1. Figure 7 Feature 1 shows the proximal end of the cannula flared onto the needle guide / bush labeled Feature 2, which provides the cannula with a fluid inlet.

[0175] Table 4.

[0176]

[0177] In some embodiments, the present disclosure provides a cannula having two or more, three or more, four or more, five or more, six or more, or seven or more dimensional features comprising dimensions within the ranges of dimensions provided in Table 4. In some embodiments, the cannula has dimensions falling within all of the ranges of dimensions provided in Table 4.

[0178] Conclusion

[0179] While embodiments of the present disclosure have been shown and described herein, it will be understood by those skilled in the art that such embodiments are provided by way of example. Numerous changes, substitutions and alterations can be made herein without departing from the application. It should be understood that various alternatives to the embodiments of the application described herein can be employed in practicing the application. For example, although steps are presented in a given order, alternative embodiments can perform steps in a different order. Various embodiments described herein can also be combined to provide further embodiments. It is intended that the following claims define the scope of the application and that the methods and structures within the scope of these claims and their equivalents be covered thereby.

[0180] It will also be appreciated that specific embodiments have been described herein for illustrative purposes, but that various modifications are possible without departing from the technology. In addition, although advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments can also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the disclosure and associated technology can encompass other embodiments that are not expressly shown or described herein.

Claims

1. A cannula for delivering insulin to an individual in need, wherein: The cannula comprises a copolymer, and the copolymer is polycarbonate polyurethane polysiloxane (PC-PU-PS); and The cannula is configured for subcutaneous insertion into the tissues of the individual in need.

2. The cannula according to claim 1, wherein the elastic stiffness of the cannula at 25°C is higher than that at 37°C.

3. The cannula according to claim 1, wherein the difference in elastic stiffness between 25°C and 37°C is at least 25 MPa, at least 50 MPa, at least 75 MPa, at least 100 MPa, at least 150 MPa, at least 200 MPa, at least 250 MPa, at least 300 MPa, or at least 400 MPa, as measured by dynamic mechanical analysis (DMA) at a cycle rate of 0.8 Hz.

4. The cannula according to claim 1, wherein the elastic stiffness of the cannula at 25°C is at least 20%, at least 50%, at least 75%, at least 100%, at least 125%, or at least 150% greater than the elastic stiffness of the copolymer at 37°C, as measured by DMA at a cycling rate of 0.8 Hz.

5. The cannula according to claim 1, wherein the cannula does not contain polyfluoroalkyl substances (PFAS).

6. The cannula according to claim 1, wherein the copolymer is selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D and ARCS-70D or combinations thereof.

7. The cannula according to claim 1, wherein the copolymer has physical properties equivalent to those of an ARCS copolymer selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D and ARCS-70D, wherein the physical properties of the ARCS copolymer are listed in Table 1.

8. The cannulation according to claim 1, wherein: The copolymer has physical properties comprising two or more physical properties selected from the group consisting of hardness, specific gravity, flexural modulus, ultimate tensile strength, ultimate elongation, tensile strength at 100%, tensile strength at 300%, and molding shrinkage; and the physical properties are equivalent to those of the ARCS copolymers described in Table 1.

9. The cannula of claim 1, wherein two or more, three or more, or four or more of the dimensions of the cannula are approximately the dimensions of the cannula described in Table 4.

10. A method for administering insulin to an individual in need, the method comprising: A cannula is provided, wherein the cannula comprises a copolymer, and the copolymer is polycarbonate polyurethane polysiloxane (PC-PU-PS), wherein the cannula is configured for subcutaneous insertion into the tissue of the individual in need; Insert the cannula into the individual's body; and Insulin is delivered to the individual in need via the cannula.

11. The method of claim 10, wherein the average total daily dose (TDD) of insulin delivered to the individual in need is about or less than the average TDD of insulin delivered via a similar cannula comprising PTFE or FEP over a period of at least 3 consecutive days, at least 4 consecutive days, at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, or at least 10 consecutive days.

12. The method of claim 10, wherein the elastic stiffness of the cannula at 25°C is higher than that at 37°C.

13. The method of claim 10, wherein the difference in elastic stiffness of the cannula at 25°C and 37°C is at least 25 MPa, at least 50 MPa, at least 75 MPa, at least 100 MPa, at least 150 MPa, at least 200 MPa, at least 250 MPa, at least 300 MPa, or at least 400 MPa, as measured by DMA at a cycle rate of 0.8 Hz.

14. The method of claim 10, wherein the elastic stiffness of the cannula at 25°C is at least 20%, at least 50%, at least 75%, at least 100%, at least 125%, or at least 150% greater than the elastic stiffness of the copolymer at 37°C.

15. The method of claim 10, wherein the cannula exhibits a tanδ peak between 30°C and 50°C, as measured by DMA at a cycle rate of 0.8 Hz.

16. The method of claim 10, wherein the cannula does not contain polyfluoroalkyl substances (PFAS).

17. The method of claim 10, wherein the copolymer is selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D and ARCS-70D or combinations thereof.

18. The method of claim 10, wherein the copolymer has physical properties equivalent to those of an ARCS copolymer selected from the group consisting of ARCS-70A, ARCS-75A, ARCS-80A, ARCS-85A, ARCS-90A, ARCS-95A, ARCS-55D, ARCS-60D and ARCS-70D, wherein the physical properties of the ARCS copolymer are listed in Table 1.

19. The method of claim 10, wherein two or more, three or more, or four or more of the dimensions of the cannula are approximately the dimensions of the cannula described in Table 4.

20. An infusion device, the infusion device comprising: A housing configured to be positioned on the patient's skin at the infusion site; A reservoir configured to store a fluid drug, the reservoir being configured to be received by the housing; as well as An intubation cannula configured for subcutaneous insertion into the patient's tissue at the infusion site, wherein the intubation cannula is the intubation cannula according to claim 1.

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