Extended administration time infusion system

Abstract

Describe an extended administration time infusion set / system suitable for the transdermal delivery of therapeutic fluids to a subject. This infusion set reduces and delays the formation of fibrous capsules on and around the infusion cannula, significantly extending the useful life of the infusion set. The infusion set includes a flexible therapy tank that "actively" diffuses insulin and eliminates the effects of FBR (foreign body reaction).

Description

Technical Field

[0001] The present invention relates to an infusion set. The present invention also relates to a method for transdermally infusing a fluid such as insulin or glucagon to a subject.

Background Art

[0002] A drug infusion set provides a method for delivering a drug transdermally to a subject. The infusion set includes a small infusion set cannula attached to a cannula housing attached to a patient's body (e.g., arm or abdomen), a pump for delivering the drug from a tank to the cannula for infusion, and associated tubing. The cannula is transdermally implanted into the subject. The cannula is typically part of a wearable device such as an infusion set or a patch-pump-device and can be used to deliver a drug to the subject continuously or at predetermined time intervals. These cannulas are commonly used for the delivery of insulin by subjects suffering from diabetes.

[0003] A problem commonly seen with current infusion sets is a foreign body reaction, which causes a fibrous layer or capsule to form on and around the infusion cannula, resulting in occlusion. Typically, this occlusion occurs within 4 days of implantation, and often the cannula must be removed and discarded prematurely, and a new cannula must be implanted at a different location. Such occlusion can also occur due to inappropriate insertion techniques that cause the cannula to kink. A further problem with these devices is that the pressure increases within the infusion cannula due to the fibrous capsule, resulting in a bolus administration of the drug. In the case of an insulin infusion set, such a bolus administration causes hypoglycemia in the subject. The inability to deliver insulin can cause hyperglycemia and ketoacidosis.

[0004] Some companies have attempted to passively eliminate the above reaction by increasing the number of diffusible holes in the cannula, thereby increasing the diffusion area. Such a method has shown a slight improvement in maintaining insulin diffusion over time. However, this method of increasing the number of holes is passive and limited in its ultimate effect of eliminating fibrous obstacles and enabling long-term effective drug diffusion.

[0005] An object of the present invention is to solve at least one of the above problems.

Summary of the Invention

[0006] To address the problems of the prior art, there is provided an infusion set comprising a bendable therapy tank that "actively" diffuses insulin and eliminates the influence of FBR (foreign body reaction). This bendable therapy tank, when compressed, pushes down the fluid (therapy) within the therapy tank along the length of the lumen of the connected cannula. Such compression of the therapy tank is controlled, for example, by adjusting the pressure of a second "actuating" tank, the ramp speed, and the actuation profile. The actuating tank enables multiple diffusion modes by using gas, fluid, or solid, and by bending the therapy tank, it can solve the influence of fibrous capsules that progress over time during drug diffusion. By eliminating such an influence of FBR, a consistent delivery of a specified amount of drug to the surrounding tissue can be achieved, the area of the tissue to which these drugs are delivered can be changed, and the position of the lumen of the cannula can be consistently corrected, for example, by eliminating the twist of the lumen when the lumen of the cannula is twisted. The lumen of the cannula may have holes defined along its length or may be entirely porous. By providing a drug tank with a fluidic deflector, it is possible to enable more finely adjusted and more responsive drug delivery from the cannula and to provide a more controllable actuating mechanism.

[0007] In a first aspect, there is provided an infusion set suitable for the transdermal delivery of a therapeutic fluid to a subject, the infusion set comprising: a small infusion set cannula having a hollow body defining a central lumen, a fluid inlet, and a plurality of infusion outlets (8) in fluid communication with the central lumen; a therapeutic fluid chamber having a fluid outlet in fluid communication with the fluid inlet of the small infusion set cannula and a fluid inlet; a therapeutic fluid supply tube in fluid communication with the fluid inlet of the therapeutic fluid chamber; a fluid flexor having an actuation chamber, an actuation fluid reservoir, an actuation fluid supply tube fluidly connecting the actuation fluid reservoir to the actuation chamber, and an actuation fluid pump operable to pump actuation fluid into the actuation chamber from the actuation fluid reservoir; an elastically deformable and bendable membrane separating the therapeutic fluid in the therapeutic fluid chamber from the actuation fluid in the actuation chamber; a controller operably connected to the actuation fluid pump and configured to control the operation of the fluid flexor upon operation of the actuation fluid pump.

[0008] Upon actuation, the fluid flexor bends an elastically deformable and bendable membrane to push the therapeutic fluid from the therapeutic fluid chamber into the central lumen of the small infusion set cannula and out through the infusion outlets.

[0009] The infusion set of the present invention enables the pumping of a drug from a tank into an implanted infusion set cannula at a predetermined rate, and by providing a fluid flexor that additionally "pushes" the drug at defined time intervals and pressures, it is possible to address the problem of the construction of fibrous capsules, and it has been found that this significantly reduces the rate of formation of fibrous capsules. Additionally, with the infusion set of the present invention, the fluid flexor can be positioned adjacent to the cannula, which is beneficial as it is within the range of the therapeutic flow in the infusion system.

[0010] In any embodiment, the infusion set further comprises a therapeutic fluid reservoir and a therapeutic fluid pump configured to pump the therapeutic fluid from the therapeutic fluid reservoir to the small infusion set cannula via a therapeutic fluid supply tube and a therapeutic fluid chamber.

[0011] In any embodiment, the therapeutic fluid chamber comprises an elastically deformable and bendable membrane.

[0012] In any embodiment, the therapeutic fluid chamber is housed within an actuation chamber.

[0013] In any embodiment, the therapeutic fluid chamber and the actuation chamber are connected to the proximal end of the small infusion set cannula.

[0014] In any embodiment, the therapeutic fluid chamber and the actuation chamber are configured to be disposed on the skin surface.

[0015] In any embodiment, the elastically deformable and bendable membrane has a convex shape before fluid bending.

[0016] In any embodiment, the small infusion set cannula has an axial length of 5 - 20 mm.

[0017] In any embodiment, the controller is configured to control the parameters of the operation of the fluid bender selected from the operating frequency of the fluid bender, the pressure in the therapeutic fluid chamber during the operation of the fluid bender, the ramp rate of the pressure in the therapeutic fluid chamber during operation, and the operation profile / wavelength.

[0018] In any embodiment, the controller is pre - programmed to operate the fluid bender at predetermined time intervals during the delivery of a predetermined amount of drug.

[0019] In any embodiment, the controller is pre-programmed to operate the fluidic actuator according to a square-wave actuation profile with an on-time of 4 to 8 seconds and an off-time of 4 to 8 seconds.

[0020] In any embodiment, the controller is pre-programmed to operate the fluidic actuator at an amplitude of 0.5 to 15, 2 to 12, or 4 to 8 psi.

[0021] In any embodiment, the infusion set (30) further comprises a body parameter sensor.

[0022] In any embodiment, the body parameter sensor is operably connected to the controller, and the controller is configured to operate the fluidic actuator in response to measurements received from the sensor.

[0023] In any embodiment, the plurality of infusion outlets are disposed along the length of the small infusion set cannula.

[0024] In any embodiment, the small infusion set cannula is flexible.

[0025] In any embodiment, the infusion set comprises a small infusion set cannula having a hollow body defining a central lumen and a plurality of infusion outlets in fluid communication with the central lumen; a therapeutic fluid chamber having a fluid outlet in fluid communication with an inlet of the central lumen of the small infusion set cannula; a therapeutic fluid reservoir; a therapeutic fluid supply tube providing fluid communication between the therapeutic fluid reservoir and a fluid inlet of the therapeutic fluid chamber; a therapeutic fluid pump configured to pump therapeutic fluid from the therapeutic fluid reservoir into the therapeutic fluid chamber via the therapeutic fluid supply tube; A fluid flexure device having an actuation chamber, an actuation fluid reservoir fluidly connected to the actuation chamber, and an actuation fluid pump operable to pump actuation fluid from the actuation fluid reservoir into the actuation chamber, and a controller operably connected to the actuation fluid pump and configured to control the operation of the actuation fluid pump.

[0026] Typically, the treatment fluid chamber comprises an elastically deformable and bendable membrane that separates the treatment fluid in the treatment fluid chamber from the actuation fluid in the actuation fluid chamber.

[0027] In any embodiment, the infusion set comprises a small infusion set cannula having a hollow body defining a central lumen and a plurality of infusion outlets fluidly communicating with the central lumen, a treatment fluid chamber having a fluid outlet fluidly communicating with an inlet of the central lumen of the small infusion set cannula, a treatment fluid supply tube fluidly communicating with the fluid inlet of the treatment fluid chamber, a fluid flexure device having an actuation chamber, an actuation fluid reservoir fluidly connected to the actuation chamber, and an actuation fluid pump operable to pump actuation fluid from the actuation fluid reservoir into the actuation chamber, an elastically deformable and bendable membrane separating the treatment fluid in the treatment fluid chamber from the actuation fluid in the actuation chamber, and a controller operably connected to the actuation fluid pump and configured to control the fluid flexure device by operation of the actuation fluid pump.

[0028] Typically, the controller is pre-programmed to operate the fluid flexure device at predetermined time intervals during delivery of a predetermined amount of drug.

[0029] In any embodiment, the infusion set comprises a small infusion set cannula having a hollow body defining a central lumen and a plurality of infusion outlets fluidly communicating with the central lumen, A treatment fluid chamber having a fluid outlet that is in fluid communication with an inlet of a central lumen of a small infusion set cannula, A treatment fluid supply tube that is in fluid communication with a fluid inlet of the treatment fluid chamber, A fluid flexure having an actuation chamber, an actuation fluid reservoir fluidly connected to the actuation chamber, and an actuation fluid pump operable to pump actuation fluid from the actuation fluid reservoir into the actuation chamber, An elastically deformable and bendable membrane that separates the treatment fluid in the treatment fluid chamber from the actuation fluid in the actuation chamber, A controller operably connected to the actuation fluid pump and configured to control the fluid flexure in response to actuation of the actuation fluid pump.

[0030] Typically, the controller is configured to operate the fluid flexure with a square wave actuation profile.

[0031] In another aspect, an infusion cannula set suitable for transdermal delivery of a treatment fluid to a subject is provided, the infusion cannula set comprising A small infusion set cannula having a hollow body defining a central lumen and a plurality of infusion outlets in fluid communication with the central lumen, A treatment fluid chamber at least partially defined by an elastically deformable and bendable membrane and having a fluid outlet in fluid communication with an inlet of the central lumen of the small infusion set cannula, A treatment fluid supply tube that is in fluid communication with a fluid inlet of the treatment fluid chamber, A fluid flexure having an actuation chamber configured to be pressurized pneumatically or hydraulically by an actuation fluid pump, A controller operably connected to the fluid flexure and operable to control the actuation of the fluid flexure.

[0032] Typically, the treatment fluid chamber is housed within the actuation chamber such that during use, upon pressurization of the actuation chamber, an elastically deformable and bendable membrane bends, forcing treatment fluid from the treatment fluid chamber into the hollow body of the small infusion set cannula and out through the infusion opening.

[0033] In another aspect, an infusion cannula set suitable for transdermal delivery of a treatment fluid to a subject is provided, the infusion cannula set comprising a small infusion set cannula having a hollow body defining a central lumen and a plurality of infusion outlets in fluid communication with the central lumen, a treatment fluid reservoir, a treatment fluid supply tube fluidly connecting the treatment fluid reservoir and the fluid inlet of the small infusion set cannula, an infusion cannula set comprising a treatment fluid pump (19) configured to pump treatment fluid from the treatment fluid reservoir (18) to the small infusion set cannula (6) via the treatment fluid supply tube (15), comprising an actuation module, the actuation module comprising a fluid flexor having an actuation chamber (11), an actuation fluid reservoir (20) fluidly connected to the actuation chamber (11), and an actuation fluid pump (21) operable to pressurize the actuation chamber (11) by pumping actuation fluid from the actuation fluid reservoir (20) to the actuation chamber (11), a compressible treatment fluid chamber (10) arranged in a row in the treatment fluid supply tube (15), a controller operably connected to the actuation fluid pump (21) and configured to control the operation of the actuation fluid pump (21), wherein by arranging the compressible treatment fluid chamber (10) within the actuation chamber, when the actuation chamber (11) is pressurized, the compressible treatment fluid chamber (10) is compressed, forcing treatment fluid from the treatment fluid chamber (10) into the hollow body of the small infusion set cannula (6) and out through the infusion opening (8).

[0034] In another aspect, an infusion set is provided that includes an infusion set cannula suitable for the transdermal delivery of a therapeutic fluid, such as a drug, to a subject. The term "therapeutic fluid" is intended to include fluids for clinical or diagnostic purposes. The infusion set typically has a hollow body (usually flexible) that defines a central lumen, has a distal end and a proximal end, and an infusion set cannula having a plurality of infusion openings that are in fluid communication with the central lumen, and a treatment fluid tank having a flexible membrane and in fluid communication with the central lumen of the flexible hollow body a treatment fluid supply tube in fluid communication with the treatment fluid tank, and a flexor that, by flexing the flexible membrane, pushes the treatment fluid from the treatment fluid tank into the flexible hollow body of the infusion cannula and out through the infusion openings.

[0035] Typically, the treatment fluid tank is disposed at the proximal end of the hollow tube. In these embodiments, the treatment fluid tank forms part of the implantable portion of the cannula. In other embodiments, the tank is remote from the hollow tube and is connected to the tube via a fluid tube. In these embodiments, the treatment fluid tank is typically located outside the body.

[0036] In any embodiment, the treatment fluid tank is an elastically deformable chamber. In any embodiment, the treatment fluid tank is a soft robotic capsule. In any embodiment, the flexible membrane is deformable and is typically elastically deformable.

[0037] In any embodiment, the cannula includes an actuation chamber and the treatment fluid tank is disposed within the actuation chamber.

[0038] In any embodiment, the flexor is a fluid flexor.

[0039] In any embodiment, the fluid flexure includes a flexure chamber, a flexure fluid supply tube fluidly connected to the flexure chamber, and a first pump operable to pump flexure fluid into the flexure chamber. The supply of flexure fluid to the flexure chamber causes the size of the flexure chamber to increase and effectively flexes the flexible membrane.

[0040] In any embodiment, the treatment fluid tank and the flexure chamber are separated by a flexible membrane.

[0041] In any embodiment, the flexure is configured to mechanically flex the flexible membrane.

[0042] In any embodiment, the flexure is configured to electrically flex the flexible membrane.

[0043] In any embodiment, the flexure is configured to magnetically flex the flexible membrane.

[0044] In any embodiment, the flexure is configured to thermally flex the flexible membrane (e.g., photothermal or electrothermal activation).

[0045] In any embodiment, the flexible membrane has a convex shape.

[0046] In any embodiment, the flexible membrane is bendable from a convex shape to a planar or concave shape.

[0047] In any embodiment, the flexible membrane is bendable from a planar shape to a concave shape.

[0048] In any embodiment, the treatment fluid supply tube includes a lumen disposed within the flexure fluid supply tube.

[0049] In any embodiment, the flexure fluid supply tube includes a lumen disposed within the treatment fluid supply tube.

[0050] In any embodiment, the plurality of infusion openings are arranged along the side wall of a flexible hollow body.

[0051] In any embodiment, the plurality of infusion openings are provided by forming at least a part of the hollow body from a material that is porous to the therapeutic fluid. The porous material may be formed, for example, by salt leaching.

[0052] In any embodiment, the infusion cannula is sized for percutaneous implantation for delivering a drug subcutaneously or into adipose tissue.

[0053] In any embodiment, the infusion cannula has an axial length of 5 - 20 mm, such as 5 - 10 mm, 10 - 20 mm, 10 - 15 mm, or 15 - 20 mm.

[0054] In any embodiment, the infusion cannula has an inner diameter of 0.1 - 1.0 mm or 0.1 - 0.5 mm.

[0055] In any embodiment, the system of the present invention is wearable.

[0056] In any embodiment, the system comprises a therapeutic fluid storage tank that is fluidly connected to the proximal end of the therapeutic fluid supply tube.

[0057] In any embodiment, the system comprises a second pump configured to pump the therapeutic fluid from the therapeutic fluid storage tank into a flexible therapeutic fluid tank during operation.

[0058] In any embodiment, the system comprises a controller operably connected to the flexor and operative to control the operation of the flexor. The controller is configured to control the actuation rate of the fluid flexor (e.g., how often it actuates). The controller may be configured to control the pressure in the treatment fluid tank during flexion, the ramp rate of the pressure, and the actuation profile / waveform (see FIG. 7E).

[0059] In one embodiment, the controller is pre-programmed to operate the flexor in accordance with a series of steps.

[0060] In any embodiment, at least two of the series of steps have different flexion waveforms.

[0061] In any embodiment, the controller is configured to perform the series of steps multiple times a day at predetermined time intervals.

[0062] In any embodiment, the system comprises a body parameter sensor. The body parameter sensor may be a blood or body fluid sensor. The sensor may be configured to detect body fluid parameters such as body temperature, pH, oxygen, or the level of a component in the body fluid, such as a metabolite like glucose.

[0063] In any embodiment, the sensor is operably connected to the controller, and the controller is configured to execute a series of steps in response to measurements received from the sensor.

[0064] In any embodiment, the sensor is a glucose sensor configured to measure glucose in the subject's blood or interstitial fluid. The glucose sensor is operably connected to the controller, and the controller is configured to execute a series of steps in response to the blood glucose measurement received from the sensor.

[0065] In any embodiment, the sensor is configured to manually operate the pump. This is suitable, for example, for a patient suffering from diabetes who wants to operate the system before a meal to bolus administer a fluid such as insulin.

[0066] The present invention also relates to delivering a fluid to a subject by means of a cannula infusion, typically transdermally, using the infusion set described herein.

[0067] The present invention also relates to a method of diffusing a fluid to a subject (in one embodiment, employing the infusion set of the present invention), the method comprising: implanting an infusion set cannula having an infusion outlet (e.g., transdermally) within the tissue of the subject; advancing a therapeutic fluid within a therapeutic fluid supply tube and flowing the therapeutic fluid into a therapeutic fluid chamber by operating a therapeutic fluid pump; flexing an elastically deformable and bendable membrane that is in fluid communication with the therapeutic fluid within the therapeutic fluid chamber by operating a fluid flexor by a controller, pushing the therapeutic fluid from the therapeutic fluid chamber into the infusion set cannula, and flowing it out through the infusion outlet.

[0068] In any embodiment, the infusion set cannula is implanted transdermally to the subject.

[0069] In any embodiment, the fluid flexor comprises an actuation chamber and means for fluidly flexing an elastically deformable and bendable membrane by fluidly pressurizing the actuation chamber with an actuation fluid, the method comprising fluidly pressurizing the actuation chamber by operating an actuation fluid pump.

[0070] In any embodiment, the method comprises delivering a predetermined amount of therapeutic fluid to the subject.

[0071] In any embodiment, the elastically deformable and bendable membrane forms part of a treatment fluid chamber, and the method includes implanting a treatment fluid chamber and an actuation chamber subcutaneously.

[0072] In any embodiment, the method includes changing at least one bending parameter of a fluid flexor during delivery of a predetermined amount of treatment fluid.

[0073] In any embodiment, the bending parameter is selected from the pressure in the treatment fluid chamber during operation of the fluid flexor, the ramp rate of the pressure in the treatment fluid chamber during operation, and the actuation profile / waveform.

[0074] In any embodiment, the method includes actuating a fluid flexor according to a series of steps, at least two of the series of steps having different bending parameter values. For example, if the parameter is the waveform of the fluid flexor, the first step may be a square actuation waveform, and the second step may be a triangular actuation waveform.

[0075] In any embodiment, the series of steps includes at least three steps, each step having a different actuation waveform.

[0076] In any embodiment, the method includes changing the ramp rate of the pressure in the treatment fluid chamber during operation and during delivery of a predetermined amount of treatment fluid.

[0077] In any embodiment, the infusion set is operably connected to an actuation fluid pump and includes a controller configured to control the operation of the actuation fluid pump during delivery of a predetermined amount of treatment fluid.

[0078] In any embodiment, the fluid includes a pharmaceutically active agent.

[0079] In any embodiment, the pharmaceutically active agent is insulin or glucagon.

[0080] In any embodiment, the inflation fluid is a gas such as air or a liquid such as physiological saline solution.

[0081] Other aspects and preferred embodiments of the present invention are defined and described in the other claims set forth below.

Brief Description of the Drawings

[0082]

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DETAILED DESCRIPTION OF THE INVENTION

[0083] All documents, patents, patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual document, patent, or patent application was specifically and individually incorporated by reference and its content was fully described.

[0084] Definitions and General Preferences Unless otherwise specified, the following terms used herein shall have the following meanings in addition to any broader (or narrower) meanings that these terms may have in the art.

[0085] Unless required by context, the use of the singular herein is construed to include the plural and vice versa. The terms "a" or "an" used in connection with an entity are construed to mean that there is one or more of that entity. Accordingly, the terms "a" (or "an"), "one or more", and "at least one" are used interchangeably herein.

[0086] As used herein, the term "comprise", or variations such as "comprises" or "comprising", are construed to mean the inclusion of any recited integer (e.g., a property, element, feature, characteristic, method / process step, or limitation) or group of integers (e.g., a property, element, feature, characteristic, method / process step, or limitation) but not the exclusion of any other integer or group of integers. Accordingly, the term "comprising" as used herein is inclusive or open-ended and does not exclude additional, unrecited integers or method / process steps.

[0087] As used herein, the term "disease" is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to include any disorder, disease, abnormality, medical condition, illness, state, or syndrome that impairs physiological function regardless of the nature of the etiology (or indeed whether there is any basis in the etiology for the disease). Accordingly, the term includes conditions resulting from infection, trauma, injury, surgery, radiation ablation, age, poisoning, or nutritional imbalance.

[0088] As used herein, the term "treatment" or "treating" refers to an intervention (e.g., administration of an agent to a subject) that cures, ameliorates, or alleviates the symptoms of a disease or removes (or reduces the effects of) its cause (e.g., an increase in the level of an adhesion protein). In this case, the term is used synonymously with the term "therapy".

[0089] In addition, the term "treatment" or "treating" refers to an intervention (e.g., administration of an agent to a subject) that prevents or delays the onset or progression of a disease or reduces (or eradicates) the occurrence of a disease in a treated population. In this case, the term "treatment" is used synonymously with the term "prevention".

[0090] As used herein, an effective amount of an agent or its therapeutically effective amount is an amount that can be administered to a subject without causing undue toxicity, inflammation, allergic reaction, or other problems or complications and that has a reasonable benefit-risk ratio, but that is an amount sufficient to obtain the desired effect, such as a permanent or temporary improvement in the condition of the subject, e.g., treatment or prevention. Such amount varies depending on the age and general condition of the individual, the method of administration, and other factors. Thus, it is not possible to specify an exact effective amount, but one of ordinary skill in the art can determine the appropriate "effective" amount in an individual case using routine experimentation and ancillary general knowledge. Treatment outcomes related thereto include eradication or alleviation of symptoms, reduction of pain or discomfort, extension of survival period, improvement of motor function, and other clinical improvement markers. Treatment outcomes do not necessarily have to be a complete cure. Improvement can be seen in biological / molecular markers or in clinical or observational improvements. In a preferred embodiment, the methods of the invention are applicable to humans, large competitive animals (horses, camels, dogs), and household pets (cats and dogs).

[0091] With respect to the treatment and effective amounts defined above, the term "subject" (which is to be construed as encompassing "individual", "animal", "patient" or "mammal" as the context may require) defines any subject to which treatment is indicated, particularly a mammal. A subject that is a mammal includes, but is not limited to, humans, domestic animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, donkeys, bison, cattle, and dairy cows, agricultural animals, zoo animals, sports animals, and pet animals, primates such as apes, monkeys, orangutans, and chimpanzees, canids such as dogs and wolves, felids such as cats, lions, and tigers, equids such as horses, zebras, and wild horses, food animals such as dairy cows, pigs, or sheep, ungulates such as deer and giraffes, and rodents such as mice, rats, hamsters, and guinea pigs. In a preferred embodiment, the subject is a human. As used herein, the term "equid" means equid mammals including horses, donkeys, Tibetan wild asses, and zebras.

[0092] An "infusion set cannula" refers to an implantable cannula having a hollow body with an infusion outlet configured to be able to send the liquid within the hollow body to the surrounding tissue where the cannula is embedded. The infusion cannula is typically a small infusion set cannula such as a transdermal infusion set cannula (for example, an axial length of less than 30 or 25 mm, and / or an inner diameter of less than 1.5, 1.0, 0.75, 0.5, or 0.3 mm), usually having a length of 6 - 20 mm and an inner diameter of 0.15 - 1.0 mm. In one embodiment, the cannula is a 25G cannula. The infusion set cannula is more likely to become blocked due to fibrotic encapsulation compared to larger cannulas such as central line cannulas. The infusion set cannula is usually flexible. The cannula can be formed from any suitable material, the details of which are known to those skilled in the art. Examples of such materials include silicone, polyurethane, polyethylene, polyvinyl chloride, PTFE, and nylon. In one embodiment, the infusion set cannula is not an intravenous cannula. The cannula is usually sized such that a stylet can advance axially through the lumen of the cannula during implantation of the infusion cannula and has an open distal end.

[0093] "Transdermal" as applied to an infusion set cannula means an infusion set cannula configured for administration through the skin, for implantation into the subcutaneous or subcutaneous fat layer. Transdermal infusion cannulas are often designed for self-implantation by the patient using an applicator (for example, the Medtronic MiniMed® infusion set), and a doctor is not required for the implantation.

[0094] "Infusion outlet" refers to an opening that enables the infusion of fluid from the lumen of the cannula into the surrounding tissue. The opening is typically a small hole formed in the side wall of the cannula, and these holes usually extend at least as far as the distal end and can extend up to the maximum length of the balloon. The opening is typically located on the side of the cannula and optionally also at the distal end of the cannula. In the illustrated embodiment, the cannula has a pair of openings consisting of four infusion openings axially arranged on both sides of the side wall of the cannula. It should be noted that the infusion openings may be provided in any number or arrangement. The opening may have a size in the range of 5 to 300 microns. The holes may be configured such that the cannula has a porosity in the range of 5 to 95% (i.e., the ratio of the area of the side wall of the cannula that is open due to the holes). The infusion opening may also be of any shape, such as a round hole or an elongated slit. The infusion opening may have the same inner diameter from the inside to the outside, may be conical with an inlet larger than the outlet, or vice versa. In some embodiments, the cannula may be formed from a material that is itself porous, and the infusion opening is formed by the pores. The porous cannula may be formed by porogen leaching techniques (Jeffery A. Coffer et al PSS Vol 202, Issue 8 June 2005). The porous cannula may be composed of silicone, Pebax, polyurethane, Teflon®, PTFE, nylon elastomer, dacron, and other thermoplastic elastomers.

[0095] "Therapeutic fluid chamber" refers to a chamber having a flexible membrane, an inlet fluidly connected to a therapeutic fluid supply tube, and an outlet fluidly connected to the lumen of an infusion set cannula. The chamber is typically disposed at the proximal end of the infusion set cannula, integrally formed with the infusion set cannula, and configured for embedding of the cannula. In other embodiments, the chamber is remote from the infusion set cannula and connected to the cannula via a single tube. The chamber typically has the shape of a soft robotic capsule with an elastically deformable and flexible membrane. The flexible membrane is convex and configured to be bent planar or concave by a fluid flexor.

[0096] "Fluid flexor" refers to a device configured to bend the flexible membrane of a therapeutic fluid tank during operation. Typically, the fluid flexor includes an actuating chamber fluidly connected to an actuating fluid supply tube. By pumping an actuating fluid, which is typically a liquid such as normal saline, into the chamber, the flexible membrane of the therapeutic fluid tank is bent to push the therapeutic fluid into the hollow tube of the infusion cannula. The flexible membrane is convex and may be, for example, dome-shaped. The flexible membrane may be bendable from convex to planar or concave (or a shape with a reduced degree of convexity). The actuating chamber may include an actuating fluid tank fluidly connected to the actuating fluid supply tube and configured to have resistance to the flexible membrane when the actuating fluid is pumped into the actuating fluid tank. In other embodiments, the flexor may be an electrical or electromechanical device configured to bend the flexible membrane during operation. In other embodiments, the flexor may form part of the flexible membrane and bend the membrane by being actuated by electrical, magnetic, acoustic, or thermal (photo-thermal or electro-thermal) means. In one embodiment, the flexible membrane comprises a dielectric elastomer or a piezoelectric material.

[0097] "Fluid" refers to air, gas, liquid, or a combination thereof. When the flexor is a fluid flexor, the fluid is usually a liquid such as physiological saline, but may also be air. The therapeutic fluid is usually a drug, but is, for example, a self-administered drug such as insulin or a diagnostic reagent. Other drugs that can be self-administered are anti-inflammatory agents, antibacterial agents, analgesics, and chemotherapeutic agents. Drugs are usually fluids and may be solutions or suspensions.

[0098] "Controller" refers to a device that is operably connected to a working fluid pump and configured to control the operation of the pump. The system typically includes a pump for the working fluid supply pipe (working fluid pump) and a separate pump for the treatment fluid supply pipe (treatment fluid pump). The controller may be configured to replenish an emptied treatment fluid tank by operating the pump. The controller may be configured to push treatment fluid into the infusion set cannula by operating the working fluid pump. The controller may be configured to control one or more of the following operating parameters: operating time, operating frequency, operating ramp speed, maximum operating pressure (Pmax), and time at pmax. In one embodiment, the controller is configured to perform a series of operating steps by operating the working fluid pump. Typically, at least two (preferably all) of the operating steps have different operating profiles. The operating profiles of the operating steps have different operating waveforms (see Figure 5E) and can be selected from square, triangular, and trapezoidal. The controller may be programmed to operate the system a predetermined number of times, such as once a day, several times a day, or a number of times set by the user. Additionally, the operating parameters may be controlled by the controller, for example, controlling the amount of drug delivered, drug infusion time, drug delivery pressure, and the period between balloon expansion and balloon contraction. The controller typically includes a processor that is operably connected to the controller. The processor may be pre-programmed. The controller may include a graphic display. The controller may include a user interface. The controller and the processor may be housed in the same housing. The controller is typically wearable. The controller may include a wireless communication module configured to communicate with an independent processor. The independent processor may include a portable communication device having software for instructing the processor to control the operation of the controller. The software may be downloadable software (e.g., a portable communication "app").The software may be configured to graphically display data related to the operation of the system on the screen of a controller or a mobile communication device.

[0099] "Sensor" refers to a device capable of measuring physical parameters such as, for example, pH or the presence or absence of a certain element (e.g., drug or metabolite) in a body fluid such as inside the body, particularly blood or interstitial fluid. The sensor may be implantable. For example, sensors that detect the level of metabolites in body fluids such as blood or interstitial fluid, such as glucose sensors, etc., can be mentioned. The system of the present invention may be provided with a sensor or configured to be operably connected to a sensor. The controller forming part of the system of the present invention may be operably connected to the sensor and operate the system according to the data received from the sensor. The controller may be configured to operate the system of the present invention when the level of the metabolite reaches a threshold value. For example, when the system of the present invention is for insulin infusion, the system may be configured to operate according to sensor data indicating that the glucose level has reached a specified threshold value.

[0100] Embodiments The present invention will be described below with reference to specific embodiments. These embodiments are for illustrative purposes only and do not limit the scope of the present invention and its claims in any way. These embodiments are the best modes currently contemplated for practicing the present invention.

[0101] Referring to the drawings, in the first FIGS. 1 to 3, an infusion set of the present invention used for transdermal infusion of insulin to a subject is shown, and the infusion set is generally denoted by reference numeral 1. The infusion set 1 includes an infusion set cannula 6, an actuation module 9, a drug supply module 4, an actuation fluid supply module 5, and a fluid supply tube 3.

[0102] The infusion set cannula 6 includes a flexible tube having a lumen 7 and an outlet opening 8. In this embodiment, the infusion set cannula 1 has a length of about 3 cm and a width of about 0.3 cm. Therefore, the cannula is described as a small infusion set cannula. The cannula is dimensioned to be implanted under the patient's skin and deliver drugs subcutaneously during operation.

[0103] The actuation module 9 is connected to the proximal end of the cannula 6 and includes an actuation chamber 11 and a drug chamber 10. The actuation chamber 11 is fluidly connected to an actuation fluid supply module 5 (described later). One end of the drug chamber 10 is fluidly connected to a drug supply module 4 (described later), and the other end is fluidly connected to the lumen 7 of the cannula 6. The drug chamber 10 is disposed in contact with the actuation chamber 11 and includes a dome-shaped (convex), elastically deformable and bendable membrane 13 that separates the drug in the drug chamber 10 from the actuation fluid in the actuation chamber 11. As shown in FIGS. 3A and 3B, when the actuation fluid flows into the actuation chamber 11 to pressurize the chamber, the elastically deformable membrane 13 is bent from a convex shape (FIG. 3A) to a concave shape (FIG. 3B) by the pressure. Thereby, as shown in FIG. 3B, an effect of pushing the drug from the drug chamber into the cannula 6 is obtained.

[0104] Referring particularly to FIG. 1A, the fluid supply tube 3 connects the infusion set cannula 6 (which is located subcutaneously during use) to the other parts of the system (which are disposed outside the body). The tube 3 includes a drug supply tube 15 that fluidly connects the drug chamber 10 to the drug supply module 4 and an actuation fluid supply tube 16 that fluidly connects the actuation chamber 11 to the actuation fluid supply module 5. The drug supply module 4 includes a drug storage tank 18 and a drug pump 19 configured to pump the drug from the storage chamber 18 to the cannula 6 via the drug tank 10 during operation. The actuation fluid supply module 5 includes an actuation fluid storage tank 20 and an actuation fluid pump 21 configured to pump the actuation fluid from the storage tank 20 to the actuation chamber 11 during operation.

[0105] Referring to FIGS. 2 and 3, in use, when the chemical pump 19 is activated, chemicals are pumped from the storage chamber 18 into the chemical tank 10, filling the tank as shown in FIG. 2C. Although not shown, the chemicals then continue to flow into the cannula 6 and out of the outlet 8. The pump 19 is configured to deliver chemicals to the cannula 6 at a defined flow rate until a predetermined amount is delivered. Subsequently, when the working fluid pump 21 is activated, the working fluid is pumped into the working chamber 11, thereby pressurizing the chamber and bending the membrane 13 that can be bent from the dome shape shown in FIG. 3A to the concave shape in FIG. 3B. This forces the chemicals into the cannula 6 and out of the infusion outlet 8. During the delivery of a predetermined amount of chemicals, the working chamber is intermittently pressurized at a defined frequency, amplitude (chamber pressure), and waveform by periodically activating the pump. For example, in one embodiment, the working chamber is pressurized according to a square waveform with an amplitude of 6 psi (e.g., the pressure within the working chamber). Note that as the pressurization profile of the working chamber, different amplitudes, as well as different waveforms and frequencies, may be employed according to the degree of occlusion of the cannula and other parameters such as, for example, the infusion rate of the chemicals or the size of the infusion area. The pressurization profile of the working chamber may be controlled by a controller that is operably connected to the working fluid pump 21 and is configured to operate the pump by selecting one or more preset operating frequencies, operating waveforms, and operating amplitudes.

[0106] FIG. 4 shows different embodiments of the infusion set of the present invention, in which (A) a fluid flexor for a bendable membrane, (B) an electrical, magnetic, or acoustic flexor for a bendable membrane, (C) a mechanical flexor for a bendable membrane, (D) a photothermal flexor for a bendable membrane, and (E) an electrothermal flexor for a bendable membrane are shown.

[0107] Fig. 5 generally shows the infusion set of the present invention, denoted by reference numeral 30, and the same parts as those described in the foregoing embodiments are denoted by the same reference numerals. The system includes the above-described infusion set 1, a wearable glucose sensor 31 configured to measure the glucose level in the subject's blood, and a controller 32 configured to wirelessly receive data from the sensor and operate the infusion set 1 based on the received data. In this embodiment, the controller 32 is implemented in a mobile phone while running control software on the device. The software may be downloadable software (e.g., an "app"). The software may have program instructions for operating the actuating pump according to a pre-programmed process by instructing the device to wirelessly communicate with the sensor and the two pumps 19, 21 of the infusion set 11. The sequence selected by the controller may be determined according to the data received from the sensor or the drug to be delivered. The controller may control the operation of the infusion cannula, such as when to operate (e.g., at what time, how many times a day), and how to operate (e.g., the operation profile). The controller may be wearable. The system of the present invention may be wearable. For example, the controller may be configured to operate the infusion cannula in a series of operating steps, such as 2 to 100 consecutive operating steps. The series of steps may be performed over a period of, for example, 1 to 60 minutes. At least two (or most or all) of the operating steps have different operating profiles, such as square, triangular, or trapezoidal.

[0108] Equivalents In the above description, preferred embodiments of the present invention have been described in detail. In practice, in view of these descriptions, numerous modifications and variations can be conceived by those skilled in the art. These modifications and variations are within the scope of the appended claims.

Description of Reference Numerals

[0109] 1 Infusion set / Infusion cannula set 3 Fluid supply tube 4 Drug supply module 5 Actuating fluid supply module 6 Infusion set cannula / Miniature infusion set cannula 7 Lumen / Central lumen 8 Outlet opening / Infusion outlet 9 Actuating module 10 Drug tank / Drug chamber / Therapeutic fluid chamber 11 Actuating chamber / Infusion set 13 Flexible membrane / Elastically deformable and flexible membrane 15 Drug supply tube / Therapeutic fluid supply tube 16 Actuating fluid supply tube 18 Drug storage tank / Storage chamber / Therapeutic fluid storage tank 19 Drug pump / Therapeutic fluid pump 20 Actuating fluid storage tank 21 Actuating fluid pump 30 Infusion set 31 Glucose sensor / Body parameter sensor 32 Controller

Claims

Claim 1 An infusion set (1) suitable for percutaneous delivery of a therapeutic fluid to a subject, comprising: a small infusion set cannula (6) having a hollow body defining a central lumen (7), a fluid inlet, and a plurality of infusion outlets (8) in fluid communication with the central lumen; a therapeutic fluid chamber (10) having a fluid outlet in fluid communication with the fluid inlet of the small infusion set cannula (6) and a fluid inlet; a therapeutic fluid supply tube (15) in fluid communication with the fluid inlet of the therapeutic fluid chamber (10); a fluid flexure device having an actuation chamber (11), an actuation fluid storage tank (20), an actuation fluid supply tube (16) fluidly connecting the actuation fluid storage tank (20) to the actuation chamber (11), and an actuation fluid pump (21) operable to pump actuation fluid from the actuation fluid storage tank (20) into the actuation chamber (11); an elastically deformable and bendable membrane (13) separating the therapeutic fluid in the therapeutic fluid chamber (10) from the actuation fluid in the actuation chamber (11); a controller operably connected to the actuation fluid pump (21) and configured to control the operation of the fluid flexure device upon operation of the actuation fluid pump (21); The fluid flexure device is configured to push the therapeutic fluid from the therapeutic fluid chamber (10) into the central lumen (7) of the small infusion set cannula (6) by bending the elastically deformable and bendable membrane (13) during operation, and to cause the therapeutic fluid to flow out from the infusion outlet (8). An infusion set (1). Claim 2 The infusion set according to claim 1, further comprising a therapeutic fluid storage tank (18) and a therapeutic fluid pump (19) configured to pump the therapeutic fluid from the therapeutic fluid storage tank (18) to the small infusion set cannula (6) via the therapeutic fluid supply tube (15) and the therapeutic fluid chamber (10). Claim 3 The infusion set according to claim 1 or 2, wherein the therapeutic fluid chamber (10) comprises the elastically deformable and bendable membrane (13). Claim 4 The infusion set according to any one of claims 1 to 3, wherein the therapeutic fluid chamber (10) is housed within the actuation chamber (11). Claim 5 The infusion set according to any one of claims 1 to 4, wherein the therapeutic fluid chamber (10) and the actuation chamber (11) are connected to the proximal end of the small infusion set cannula (6).

6. The infusion set according to claim 5, wherein the treatment fluid chamber (10) and the actuating chamber (11) are configured to be arranged on the skin surface when the small infusion set cannula (6) is implanted under the skin.

7. The infusion set according to any one of claims 1 to 6, wherein the elastically deformable and bendable membrane (13) has a convex shape before fluid bending.

8. The infusion set according to any one of claims 1 to 7, wherein the small infusion set cannula (6) has an axial length of 5 to 20 mm.

9. The infusion set according to any one of claims 1 to 8, wherein the controller is configured to control parameters of the operation of the fluid flexor selected from the operating frequency of the fluid flexor, the pressure in the treatment fluid chamber during operation of the fluid flexor, the ramp speed of the pressure in the treatment fluid chamber during operation, and the operating profile / wavelength.

10. The infusion set according to any one of claims 1 to 9, wherein the controller is pre-programmed to operate the fluid flexor at predetermined time intervals during delivery of the predetermined amount of drug.

11. The infusion set according to claim 10, wherein the controller is pre-programmed to operate the fluid flexor according to a square wave operating profile with an on-time of 4 to 8 seconds and an off-time of 4 to 8 seconds.

12. The infusion set according to claim 10, wherein the controller is pre-programmed to operate the fluid flexor with an amplitude of 4 to 8 psi.

13. The infusion set (30) according to any one of claims 1 to 12, further comprising a body parameter sensor (31).

14. The infusion set according to claim 13, wherein the body parameter sensor (31) is operably connected to the controller (32), and the controller is configured to operate the fluid flexor according to a measurement received from the sensor.

15. The infusion set according to any one of claims 1 to 14, wherein the plurality of infusion outlets (8) are arranged along the length of the small infusion set cannula.

16. The infusion set according to any one of claims 1 to 15, wherein the small infusion set cannula is connected to the treatment fluid chamber (10) and the actuating chamber (11) using a flexible or rigid fluid tube.

17. A small infusion set cannula (6) having a hollow body defining a central lumen (7) and having a plurality of infusion outlets (8) in fluid communication with the central lumen (7); A treatment fluid chamber (10) having a fluid outlet in fluid communication with an inlet of the central lumen of the small infusion set cannula (6); A treatment fluid storage tank (18); A treatment fluid supply pipe (15) fluidly connecting the treatment fluid storage tank (16) and a fluid inlet of the treatment fluid chamber (10); A treatment fluid pump (19) configured to pump a treatment fluid from the treatment fluid storage tank (18) into the treatment fluid chamber (10) via the treatment fluid supply pipe; A fluid flexure device having an actuation chamber (11), an actuation fluid storage tank (20) fluidly connected to the actuation chamber (11), and an actuation fluid pump (21) operable to pump an actuation fluid from the actuation fluid storage tank (20) into the actuation chamber (11); A controller operably connected to the actuation fluid pump (21) and configured to control the operation of the actuation fluid pump (21); The infusion set (1) according to claim 1, wherein the treatment fluid chamber (10) comprises an elastically deformable and bendable membrane (13) separating the treatment fluid in the treatment fluid chamber from the actuation fluid in the actuation fluid chamber (11).

18. A small infusion set cannula (6) having a hollow body defining a central lumen (7) and having a plurality of infusion outlets (8) in fluid communication with the central lumen; A treatment fluid chamber (10) having a fluid outlet in fluid communication with an inlet of the central lumen (7) of the small infusion set cannula (6); A treatment fluid supply pipe (15) fluidly communicating with a fluid inlet of the treatment fluid chamber (10); A fluid flexure device having an actuation chamber (11), an actuation fluid storage tank (20) fluidly connected to the actuation chamber (11), and an actuation fluid pump (21) operable to pump an actuation fluid from the actuation fluid storage tank (20) into the actuation chamber (11); An elastically deformable and bendable membrane (13) separating the treatment fluid in the treatment fluid chamber (10) from the actuation fluid in the actuation chamber (11); A controller operably connected to the working fluid pump (21) and configured to control the fluid flexure device by the operation of the working fluid pump (21). The controller of the infusion set according to claim 1, which is pre-programmed to operate the fluid flexure device at predetermined time intervals during the delivery of the predetermined amount of the drug.

19. A small infusion set cannula (6) having a hollow body defining a central lumen and a plurality of infusion outlets (8) in fluid communication with the central lumen, A therapeutic fluid chamber (10) having a fluid outlet in fluid communication with the inlet of the central lumen of the small infusion set cannula (6), A therapeutic fluid supply pipe (15) in fluid communication with the fluid inlet of the therapeutic fluid chamber (10), A fluid flexure device having an actuating chamber (11), an actuating fluid storage tank (20) fluidly connected to the actuating chamber (11), and an actuating fluid pump (21) operable to pump actuating fluid from the actuating fluid storage tank (20) into the actuating chamber (11), An elastically deformable and bendable membrane (13) separating the therapeutic fluid in the therapeutic fluid chamber (10) from the actuating fluid in the actuating chamber (11), A controller operably connected to the working fluid pump (21) and configured to control the fluid flexure device by the operation of the working fluid pump (21). The controller of the infusion set according to claim 1, which is configured to operate the fluid flexure device with a square-wave actuation profile.

20. An infusion cannula set (1) suitable for transdermal delivery of a therapeutic fluid to a subject, A small infusion set cannula (6) having a hollow body defining a central lumen and a plurality of infusion outlets (8) in fluid communication with the central lumen, A therapeutic fluid chamber (10) at least partially defined by an elastically deformable and bendable membrane (13) and having a fluid outlet in fluid communication with the inlet of the central lumen of the small infusion set cannula (6), A therapeutic fluid supply pipe (15) in fluid communication with the fluid inlet of the therapeutic fluid chamber (10), A fluid flexure device having an actuating chamber (11) configured to be pressurized pneumatically or hydraulically by an actuating fluid pump (21). A controller operably connected to the fluid flexure device and operable to control the operation of the fluid flexure device. The treatment fluid chamber (10) is housed within the actuation chamber (11) such that, in use, pressurization of the actuation chamber (11) causes the elastically deformable and bendable membrane (13) to bend, forcing treatment fluid from the treatment fluid chamber (10) into the hollow body of the small infusion set cannula (6) and out through the infusion outlet (8). **Claim 21** A small infusion set cannula (6) having a hollow body defining a central lumen (7) and a plurality of infusion outlets (8) in fluid communication with the central lumen; A treatment fluid reservoir tank (18); A treatment fluid supply tube (15) fluidly connecting the treatment fluid reservoir tank (16) to the fluid inlet of the small infusion set cannula (6), the treatment fluid supply tube (15); An infusion set comprising, via the treatment fluid supply tube (15), a treatment fluid pump (19) configured to pump treatment fluid from the treatment fluid reservoir tank (18) to the small infusion set cannula (6); Comprising an actuation module; The actuation module; A fluid flexure device having an actuation chamber (11), an actuation fluid reservoir tank (20) fluidly connected to the actuation chamber (11), and an actuation fluid pump (21) operable to pressurize the actuation chamber (11) by pumping actuation fluid from the actuation fluid reservoir tank (20) into the actuation chamber (11); A compressible treatment fluid chamber (10) disposed in the treatment fluid supply tube (15); A controller operably connected to the actuation fluid pump (21) and configured to control the operation of the actuation fluid pump (21); The infusion set (1) according to claim 1, wherein by disposing the compressible treatment fluid chamber (10) within the actuation chamber, when the actuation chamber (11) is pressurized, the compressible treatment fluid chamber (10) is compressed, forcing treatment fluid from the treatment fluid chamber (10) into the hollow body of the small infusion set cannula (6) and out through the infusion outlet (8).

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