THERAPEUTIC AGENT DELIVERY SYSTEMS HAVING IMPROVED POWDER CONSISTENCY

The present embodiments provide systems and methods suitable for delivering a therapeutic agent to a target site. In some embodiments, the system comprises a container for holding the therapeutic agent, a pressure source, and a catheter in fluid communication with the container. In one embodiment, the system further comprises a first inlet tube disposed at least partially within the container, and a second inlet tube disposed at least partially within the container at a location different than the first inlet tube. Pressurized fluid from the pressure source flows into the container via each of the first inlet tube and the second inlet tube. In other embodiments, a plate is disposed with the container, wherein the plate is able to move vertically within the container during delivery of the therapeutic agent.

BACKGROUND

The present embodiments relate generally to medical devices, and more particularly, to systems and methods for delivering therapeutic agents to a target site.

There are several instances in which it may become desirable to introduce therapeutic agents into the human or animal body. For example, therapeutic drugs or bioactive materials may be introduced to achieve a biological effect. The biological effect may include an array of targeted results, such as inducing hemostasis, sealing perforations, reducing restenosis likelihood, or treating cancerous tumors or other diseases.

Many of such therapeutic agents are injected using an intravenous (IV) technique and via oral medicine. While such techniques permit the general introduction of medicine, in many instances it may be desirable to provide localized or targeted delivery of therapeutic agents, which may allow for the guided and precise delivery of agents to selected target sites. For example, localized delivery of therapeutic agents to a tumor may reduce the exposure of the therapeutic agents to normal, healthy tissues, which may reduce potentially harmful side effects.

Localized delivery of therapeutic agents has been performed using catheters and similar introducer devices. By way of example, a catheter may be advanced towards a target site within the patient, then the therapeutic agent may be injected through a lumen of the catheter to the target site. Typically, a syringe or similar device may be used to inject the therapeutic agent into the lumen of the catheter. However, such a delivery technique may result in a relatively weak stream of the injected therapeutic agent.

Moreover, it may be difficult or impossible to deliver therapeutic agents in a targeted manner in certain forms, such as a powder form, to a desired site. For example, if a therapeutic powder is held within a syringe or other container, it may not be easily delivered through a catheter to a target site in a localized manner that may also reduce potentially harmful side effects.

Further, there may be challenges associated with delivering consistent doses of powder from a reservoir of the container, such as dense packing of particles, clogging, haphazard or poor settling of the powder after preceding delivery bursts, and other instances where the powder may be difficult to settle or otherwise advance from the container.

SUMMARY

The present embodiments provide systems and methods suitable for delivering a therapeutic agent to a target site. In various embodiments, the system comprises a container for holding the therapeutic agent, a pressure source in selective fluid communication with at least a portion of the container, and a catheter in fluid communication with the container and having a lumen sized for delivery of the therapeutic agent to a target site.

In one embodiment, the system comprises a first inlet tube disposed at least partially within the container, the first inlet tube having a first end that is upstream relative to a second end of the first inlet tube. Further, the system comprises a second inlet tube disposed at least partially within the container at a location different than the first inlet tube, the second inlet tube having a first end that is upstream relative to a second end of the second inlet tube. Pressurized fluid from the pressure source flows into the container via each of the first inlet tube and the second inlet tube.

In other embodiments, a system suitable for delivering a therapeutic agent to a target site comprises a plate disposed with the container, wherein the plate is able to move vertically within the container during delivery of the therapeutic agent.

Other systems, methods, features and advantages of the invention will be, or will become, apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be within the scope of the invention, and be encompassed by the following claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present application, the term “proximal” refers to a direction that is generally towards a physician during a medical procedure, while the term “distal” refers to a direction that is generally towards a target site within a patient's anatomy during a medical procedure.

Referring now toFIGS.1-3, a first embodiment of a system suitable for delivering one or more therapeutic agents is shown. In this embodiment, the system20comprises a container30that is configured to hold a therapeutic agent38, and further comprises at least one pressure source68that is configured to be placed in selective fluid communication with at least a portion of the container30, to deliver the therapeutic agent38through a catheter90to a target site within the patient, as explained more fully below.

The system20further comprises a housing22, which is suitable for securely holding, engaging and/or covering the container30, pressure source68, catheter90, and other components described below. Preferably, the housing22comprises an upright section24that may be grasped by a user and a section25for engaging the container30. Actuators26and28may be engaged by a user and selectively operated to perform the functions described below.

The container30may comprise any suitable size and shape for holding the therapeutic agent38. InFIGS.1-3, the container30comprises a generally tube-shaped configuration having a first region31, a second region32, and a reservoir33defined by an interior of the container30. A platform35may be positioned within the container30above a curved end region34, as best seen inFIG.3.

The platform35preferably forms a substantially fluid tight seal with an inner surface of the container30, thereby preventing the therapeutic agent38that is disposed in the reservoir33from reaching an inner portion of the curved end region34, as shown inFIG.3. In this embodiment, the platform35comprises an opening36though which fluid from the pressure source68is directed via a u-shaped tube37disposed within the curved end region34, as shown inFIG.3and explained in further detail below.

The container30may further comprise an inlet tube40, an outlet tube50, and a cap60, wherein the cap60is configured to be secured to the first region31of the container30, as depicted inFIG.3. The inlet tube40has first and second ends41and42with a lumen43extending therebetween, while the outlet tube50has first and second ends51and52with a lumen53extending therebetween. The first end41of the inlet tube40is placed in fluid communication with an inlet port61formed in the cap60, while the first end51of the outlet tube50is placed in fluid communication with an outlet port62formed in the cap60, as shown inFIG.3.

The second end42of the inlet tube40extends towards the platform35, and may be coupled to an adapter44, which may be integral with the platform35or secured thereto. The adapter44places the second end42of the inlet tube40in fluid communication with a first end45of the u-shaped tube37, which is disposed within the curved end region34, as shown inFIG.3. A second end46of the u-shaped tube37is in fluid communication with the opening36in the platform35.

Accordingly, fluid passed through the inlet port61of the cap60is directed through the inlet tube40, through the u-shaped tube37, and into the reservoir33via the opening36. Notably, the u-shaped tube37effectively changes the direction of the fluid flow by approximately 180 degrees, such that the fluid originally flows in a direction from the first region31of the container30towards the second region32, and then from the second region32back towards the first region31. In the embodiment ofFIGS.1-3, the first region31of the container30is disposed vertically above the second region32of the container30during use, however, it is possible to have different placements of the first and second regions31and32relative to one another, such that they are disposed at least partially horizontally adjacent to one another.

The second end52of the outlet tube50may terminate a predetermined distance above the platform35, as shown inFIGS.1-3. While the second end52is shown relatively close to the platform35in this embodiment, any suitable predetermined distance may be provided. For example, the outlet tube50may be shorter in length, e.g., about half of the length shown inFIGS.1-3, and therefore, the second end52may be spaced apart further from the platform35. In a presently preferred embodiment, the second end52of the outlet tube50is radially aligned with the opening36in the platform35, as depicted inFIGS.1-3. Accordingly, as will be explained further below, when fluid from the pressure source68is directed through the opening36in the platform35, the fluid and the therapeutic agent38within the reservoir33may be directed through the outlet tube50, through the outlet port62, and towards a target site. Alternatively, the outlet tube50may be omitted and the therapeutic agent38may flow directly from the reservoir33into the outlet port62. Other variations on the container30and the outlet port62may be found in U.S. Pat. No. 8,118,777 (hereafter “the '777 patent”), which is hereby incorporated by reference in its entirety.

The cap60may comprise any suitable configuration for sealingly engaging the first region31of the container30. In one example, an O-ring65is held in place around a circumference of the cap60to hold the therapeutic agent38within the reservoir33. Further, the cap60may comprise one or more flanges63that permit a secure, removable engagement with a complementary internal region of the section25of the housing22. For example, by rotating the container30, the flange63of the cap60may lock in place within the section25.

The inlet and outlet tubes40and50may be held in place within the container30by one or more support members. In the example shown, a first support member48is secured around the inlet and outlet tubes40and50near their respective first ends41and51, as shown inFIG.3. The first support member48may be permanently secured around the inlet and outlet tubes40and50, and may maintain a desired spacing between the tubes. Similarly, a second support member49may be secured around the inlet and outlet tubes40and50near their respective second ends42and52, as shown inFIGS.1-3. As will be apparent, greater or fewer support members may be provided to hold the inlet and outlet tubes40and50in a desired orientation within the container30. For example, in one embodiment, the second support member49may be omitted and just the first support member48may be provided, or greater than two support members may be used.

In a loading technique, the inlet and outlet tubes40and50may be securely coupled to the first support member48, the second support member49, the platform35and the u-shaped tube37. The platform35may be advanced towards the second region32of the empty container30until the platform rests on a step47above the curved end region35of the container30, as shown inFIG.3. In a next step, a desired quantity of the therapeutic agent38may be loaded through slits57formed adjacent to, or within, the first support member48, as depicted inFIG.3. Notably, the container30also may comprise measurement indicia39, which allow a user to determine a quantity of the therapeutic agent38that is loaded within the reservoir33as measured, for example, from the top of the platform35. With the therapeutic agent38loaded into the reservoir33, the cap60may be securely coupled to the first region31of the container30, and the container30then is securely coupled to the section25of the handle22as described above.

The pressure source68may comprise one or more components capable of producing or furnishing a fluid having a desired pressure. In one embodiment, the pressure source68may comprise a pressurized fluid, such as a liquid or gas. For example, as shown inFIG.2, the pressure source68may comprise a pressurized fluid cartridge of a selected gas or liquid, such as carbon dioxide, nitrogen, or any other suitable gas or liquid that may be compatible with the human body. The pressurized fluid cartridge may contain the gas or liquid at a relatively high, first predetermined pressure, for example, around 1,800 psi inside of the cartridge. The pressure source68optionally may comprise one or more commercially available components. The pressure source68therefore may comprise original or retrofitted components capable of providing a fluid or gas at an original pressure.

The fluid may flow from the pressure source68through a pressure regulator, such as regulator valve70having a pressure outlet72, as depicted inFIG.2, which may reduce the pressure to a lower, second predetermined pressure. Examples of suitable second predetermined pressures are provided below.

The actuator26may be actuated to release the fluid from the pressure source68. For example, a user may rotate the actuator26, which translates into linear motion via a threaded engagement29between the actuator26and the housing22, as shown inFIG.2. When the linear advancement is imparted to the pressure source68, the regulator valve70may pierce through a seal of the pressure cartridge to release the high pressure fluid. After the regulator valve70reduces the pressure, the fluid may flow from the pressure outlet72to an actuation valve80via tubing75.

The actuation valve80comprises an inlet port81and an outlet port82. The actuator28, which may be in the form of a depressible button, may selectively engage the actuation valve80to selectively permit fluid to pass from the inlet port81to the outlet port82. For example, the actuation valve80may comprise a piston having a bore formed therein that permits fluid flow towards the outlet port82when the actuator28engages the actuation valve80. Fluid that flows through the outlet port82is directed into the inlet port61of the cap60via tubing85, and subsequently is directed into the container30, as explained above. It will be appreciated that any suitable coupling mechanisms may be employed to secure the various pieces of tubing to the various valves and ports.

The system20further may comprise one or more tube members for delivering the therapeutic agent38to a target site. For example, the tube member may comprise a catheter90having a proximal end that may be placed in fluid communication with the outlet port62. The catheter90further comprises a distal end that may facilitate delivery of the therapeutic agent38to a target site. The catheter90may comprise a flexible, tubular member that may be formed from one or more semi-rigid polymers. For example, the catheter may be manufactured from polyurethane, polyethylene, tetrafluoroethylene, polytetrafluoroethylene, fluorinated ethylene propylene, nylon, PEBAX or the like. Further details of a suitable tube member are described in U.S. patent Ser. No. 12/435,574 (hereafter “the '574 patent”), the disclosure of which is hereby incorporated by reference in its entirety. As explained further in the '574 patent, a needle suitable for penetrating tissue may be coupled to the distal end of the catheter90to form a sharp, distal region configured to pierce through a portion of a patient's tissue, or through a lumen wall to perform a translumenal procedure.

In operation, the distal end of the catheter90may be positioned in relatively close proximity to the target site. The catheter90may be advanced to the target site using an open technique, a laparoscopic technique, an intraluminal technique, using a gastroenterology technique through the mouth, colon, or using any other suitable technique. The catheter90may comprise one or more markers configured to be visualized under fluoroscopy or other imaging techniques to facilitate location of the distal end of the catheter90. If desired, the catheter90may be advanced through a working lumen of an endoscope.

When the catheter90is positioned at the desired target site, the pressure source68may be actuated by engaging the actuator26. As noted above, the pressurized fluid may flow from the pressure source68through a regulator valve70and be brought to a desired pressure and rate. The fluid then flows through the tubing75, and when the actuator28is selectively depressed, the fluid flows through the valve80and through the tubing85towards the container30. The fluid is then directed through the inlet port62, through the inlet tube40within the container30, and through the u-shaped tube37. At this point, the u-shaped tube effectively changes the direction of the fluid flow. Regulated fluid then flows through the opening36in the platform35and urges the therapeutic agent38through the outlet tube50. The fluid and the therapeutic agent38then exit through the first end51of the outlet tube50, through the outlet port62of the cap60, and through the catheter90, thereby delivering the therapeutic agent38to the target site at a desired pressure.

Optionally, a control mechanism may be coupled to the system20to variably permit fluid flow into and/or out of the container30at a desired time interval, for example, a predetermined quantity of fluid per second. In this manner, pressurized fluid may periodically flow into or out of the container30periodically to deliver the therapeutic agent38to a target site at a predetermined interval or otherwise periodic basis.

The system20may be used to deliver the therapeutic agent38in a wide range of procedures and the therapeutic agent38may be chosen to perform a desired function upon ejection from the distal end of the catheter90. Solely by way of example, and without limitation, the provision of the therapeutic agent38may be used for providing hemostasis, closing perforations, performing lithotripsy, treating tumors and cancers, treat renal dialysis fistulae stenosis, vascular graft stenosis, and the like. The therapeutic agent38can be delivered during procedures such as coronary artery angioplasty, renal artery angioplasty and carotid artery surgery, or may be used generally for treating various other cardiovascular, respiratory, gastroenterology or other conditions. The above-mentioned systems also may be used in transvaginal, umbilical, nasal, and bronchial/lung related applications.

For example, if used for purposes of hemostasis, thrombin, epinephrine, or a sclerosant may be provided to reduce localized bleeding. Similarly, if used for closing a perforation, a fibrin sealant may be delivered to a localized lesion. In addition to the hemostatic properties of the therapeutic agent38, it should be noted that the relatively high pressure of the fluid and therapeutic agent, by itself, may act as a mechanical tamponade by providing a compressive force, thereby reducing the time needed to achieve hemostasis.

The therapeutic agent38may be selected to perform one or more desired biological functions, for example, promoting the ingrowth of tissue from the interior wall of a body vessel, or alternatively, to mitigate or prevent undesired conditions in the vessel wall, such as restenosis. Many other types of therapeutic agents38may be used in conjunction with the system20.

The therapeutic agent38may be delivered in any suitable form. For example, the therapeutic agent38may comprise a powder, liquid, gel, aerosol, or other substance. Advantageously, the pressure source68may facilitate delivery of the therapeutic agent38in any one of these forms.

The therapeutic agent38employed also may comprise an antithrombogenic bioactive agent, e.g., any bioactive agent that inhibits or prevents thrombus formation within a body vessel. Types of antithrombotic bioactive agents include anticoagulants, antiplatelets, and fibrinolytics. Anticoagulants are bioactive materials which act on any of the factors, cofactors, activated factors, or activated cofactors in the biochemical cascade and inhibit the synthesis of fibrin. Antiplatelet bioactive agents inhibit the adhesion, activation, and aggregation of platelets, which are key components of thrombi and play an important role in thrombosis. Fibrinolytic bioactive agents enhance the fibrinolytic cascade or otherwise aid in dissolution of a thrombus. Examples of antithrombotics include but are not limited to anticoagulants such as thrombin, Factor Xa, Factor VIIa and tissue factor inhibitors; antiplatelets such as glycoprotein IIb/IIIa, thromboxane A2, ADP-induced glycoprotein IIb/IIIa, and phosphodiesterase inhibitors; and fibrinolytics such as plasminogen activators, thrombin activatable fibrinolysis inhibitor (TAFI) inhibitors, and other enzymes which cleave fibrin.

Additionally, or alternatively, the therapeutic agent38may include thrombolytic agents used to dissolve blood clots that may adversely affect blood flow in body vessels. A thrombolytic agent is any therapeutic agent that either digests fibrin fibers directly or activates the natural mechanisms for doing so. Examples of commercial thrombolytics, with the corresponding active agent in parenthesis, include, but are not limited to, Abbokinase (urokinase), Abbokinase Open-Cath (urokinase), Activase (alteplase, recombinant), Eminase (anitstreplase), Retavase (reteplase, recombinant), and Streptase (streptokinase). Other commonly used names are anisoylated plasminogen-streptokinase activator complex; APSAC; tissue-type plasminogen activator (recombinant); t-PA; rt-PA. The therapeutic agent38may comprise coating-forming agents to protect or assist in healing of lesions and/or wounds.

In one example, the therapeutic agent38comprises a hemostasis powder manufactured by TraumaCure, Inc. of Bethesda, MD. However, while a few exemplary therapeutic agents38have been described, it will be apparent that numerous other suitable therapeutic agents may be used in conjunction with the system20and delivered through the catheter90.

Advantageously, the system20permits localized delivery of a desired quantity of the therapeutic agent38at a desired, regulated pressure. Since the distal end of the catheter90may be placed in relatively close proximity to a target site, the system20provides significant advantages over therapeutic agents delivered orally or through an IV system and may reduce accumulation of the therapeutic agent38in healthy tissues, thereby reducing side effects. Moreover, the delivery of the therapeutic agent38to the target site is performed in a relatively fast manner due to the relatively high pressure of the fluid, thereby providing a prompt delivery to the target site compared to previous devices.

Further, if an optional needle is employed at the distal end of the catheter90, as explained in the '574 patent, the system20advantageously may be used to both perforate tissue at or near a target site, then deliver the therapeutic agent38at a desired pressure in the manner described above. For example, the needle may comprise an endoscopic ultrasound (EUS) needle. Accordingly, in one exemplary technique, a sharpened tip of the needle may be capable of puncturing through an organ or a gastrointestinal wall or tissue, so that the therapeutic agent38may be delivered at a predetermined pressure in various bodily locations that may be otherwise difficult to access. One or more delivery vehicles, such as an endoscope or sheath, may be employed to deliver the catheter90to a target site, particularly if the distal end of the catheter90comprises the optional needle.

The therapeutic agent38must have a specific range of properties that make it suitable for delivery through the catheter90, particularly when the catheter90is sized for delivery through a lumen of an endoscope. In particular, the mass of an individual particle of the therapeutic agent38should be within a specific range. If a particle of the therapeutic agent38is too heavy, it will require too much pressure to travel the length of the catheter90and can result in clogging of the catheter90. If the particle is too light, it will aerosolize within the patient's body, e.g., in the gastrointestinal space, instead of being propelled to a target site.

In addition to mass of an individual particle of the therapeutic agent38, the size of the particle is important for ensuring proper delivery through the catheter90. If the particle of the therapeutic agent38is too large in size, then it will be prone to clogging within the delivery catheter90. If the particle is too small, it may have a higher likelihood of being aerosolized instead of being propelled to the target site.

In one embodiment, it has been found beneficial to have particles of the therapeutic agent38comprise a diameter in the range of about 1 micron to about 925 microns, and preferably in the range of about 45 microns to about 400 microns. Further, it has been found highly beneficial to have the particles of the therapeutic agent38comprise a mass in the range of about 0.0001 mg to about 0.5 mg, and preferably in the range of about 0.0001 mg to about 0.25 mg. It has been determined through multiple testing exercises that such ranges have criticality in terms of significantly reducing the likelihood of clogging of the catheter90during delivery, and also significantly reducing the likelihood of having the particles aerosolize during delivery, and therefore be properly delivered to a target site in the correct dose.

Particles of the therapeutic agent38may be ground, compacted and/or sieved to produce the desired particle size and mass. As used herein, particle mass is dependent on the density of the material and the volume of the particle. Further, regarding size, an assumption can be made that the particles are spheres, in which case the diameter ranges noted herein apply. However, it will be appreciated that other particle shapes exist, especially for crystalline materials. If the particle is substantially non-spherical, then similar micron ranges listed herein for spherical particles may apply, but instead of referring to diameter the value may refer to average or maximum width of the particle.

With regard to dimensions of the catheter90, when used in endoscopic applications, it is clinically important to size the catheter90to be small enough to fit through a working lumen of the endoscope, yet be large enough to substantially avoid clogging when the therapeutic agent38is advanced through the catheter. In one embodiment, it has been found beneficial to have a ratio of catheter inner diameter to particle size diameter to be at least 4:1, and more preferably at least 7.5:1. The applicant has tested various embodiments, including a 400 micron particle being delivered through a 1.6 mm catheter (i.e., a 4:1 ratio) and determined that there is a risk of clogging. Accordingly, there is criticality in providing the ratio above 4:1, with any suitable size catheter that can be advanced through a lumen of an endoscope.

It should be noted that endoscopes are generally available with accessory channels up to 4.2 mm. Since a catheter inserted through this channel has a wall thickness of generally greater than 0.25 mm, the maximum projected inner diameter of the catheter for endoscopic delivery would be 3.7 mm. Based on a 4:1 ratio of catheter inner diameter to particle diameter, then the maximum acceptable particle diameter would be approximately 925 microns. Further, it is noted that spherical particles may be less susceptible to clogging than cuboid or flat particles. Accordingly, a ratio of closer to 4:1 may be acceptable for spherical particles, whereas a higher ratio (e.g., 7.5:1 or greater) is preferable for other particle shapes.

With regard to pressure, as noted above, the pressure source68may comprise a pressurized fluid cartridge of a selected gas or liquid, such as carbon dioxide, nitrogen, or any other suitable gas or liquid that may be compatible with the human body. The pressurized fluid cartridge may contain the gas or liquid at a relatively high, first predetermined pressure, for example, around 1,800 psi inside of the cartridge. The pressure source may be in a solid (dry ice), liquid or gas state. As further noted above, the fluid may flow from the pressure source68through a pressure regulator, such as regulator valve70having a pressure outlet72, which may reduce the pressure to a lower, second predetermined pressure (referred to here as a “delivery system pressure”). In one embodiment, it has been found beneficial to have a delivery system pressure in the range of about 0.01 psi to about 100 psi, and preferably in the range of about 0.5 psi to about 75 psi. It has been determined through multiple testing exercises that such ranges have criticality in terms of providing appropriate force to propel the therapeutic agent38through the catheter90, while significantly reducing the likelihood of clogging of the catheter90during delivery, and therefore properly delivering the therapeutic agent38to a target site in the correct dose. It should be noted that the applicant has also demonstrated delivery using a syringe filled with a powder and air that is manually compressed.

In view of Newton's Second Law (force equals mass times acceleration), acceleration of a particle of the therapeutic agent is dependent upon the particle mass and force applied to the particle. Therefore, a minimum force is necessary to overcome the force of gravity on the particles and to accelerate them to the desired velocity at the time at which they exit the distal end of the catheter90. It is noted that increases in pressure of the pressure source68will deliver the therapeutic agent38more quickly, however, too high of a pressure can cause too high of a particle velocity and subsequently aerosolization.

There is a relationship between particle size, particle mass, and delivery velocity, which can be described by the drag equation: FD=(½)(ρ)(v2)(CD)(A); and the gravitational force equation: FG=(m)(g). In these equations, ρ is the density of air (1.184 kg/m3), v is the velocity of the particles of the therapeutic agent38, CDis the drag coefficient (0.47 if the particles of the therapeutic agent38are assumed to be spherical), A is the cross-sectional area of a particle of the therapeutic agent38, m is the mass of a particle of the therapeutic agent38, and g is the acceleration due to gravity (9.81 m/s2).

Aerosolization occurs when the drag force exceeds the gravitational force on the particles of the therapeutic agent38. Therefore, if the powder delivery velocity is too high relative to the mass of the particles, aerosolization can occur. The shape of the particles and size of the particles also should be factored into account, with more cubic shaped particles and larger particles requiring a lower delivery velocity so they do not aerosolize. In essence, for a given delivery system, there is a minimum particle mass at which aerosolization will occur.

In a preferred embodiment, the system of the present embodiments has a gravitational force FGto drag force FDratio of preferably greater than 1:1. However, as the velocity of the particles of the therapeutic agent38rapidly decreases with drag force, systems with gravitational force FGto drag force FDratios as small as 0.001:1 will clear within less than a minute.

Further details of preferred parameters for successfully delivering powder particles to a target site using a pressure source and catheter are described in U.S. Pat. No. 9,867,931 (hereafter “the '931 patent”), which is hereby incorporated by reference in its entirety.

Referring now toFIGS.4A-7B, various alternative systems are shown and described, compared to the system ofFIGS.1-3. The systems ofFIGS.4A-7Bhave design features that may be particularly well-suited for preventing powder clogging in the catheter90, or may otherwise provide a more consistent delivery of powder to the target site, while overcoming challenges of the powder failing to flow in a smooth and predictable manner.

The embodiments ofFIGS.4A-7Bare similar in certain respects to the system20ofFIGS.1-3, with pertinent differences noted below. For ease of reference, certain parts inFIGS.4A-7Bare identified by like reference numbers to similar parts explained in detail inFIGS.1-3above; for example, container130with regions131and132is similar to container30with regions31and32, respectively, while platform135is similar to platform35, outlet tube150is similar to outlet tube50, and so forth for additional components.

Referring now toFIGS.4A-4B, select components of a system120for delivering a therapeutic agent, particularly a powder, to a target site are shown and described. It is noted that the catheter90and other select parts are omitted in the depiction of the system120inFIGS.4A-4B, but preferably are provided according to the catheter90and other parts discussed inFIGS.1-3, with key distinctions noted below.

The system120ofFIGS.4A-4Bcomprises a container130having an alternative design compared to the container30ofFIGS.1-3. Notably, the container130comprises a first inlet tube140aand a second inlet tube140b, each of which delivers pressurized fluid into a reservoir133of the container130.

As shown inFIGS.4A-4B, the first inlet tube140ahas first and second ends141aand142awith a lumen extending therebetween, while the second inlet tube140bhas first and second ends141band142bwith a lumen extending therebetween. The first inlet tube140aand the second inlet tube140bare spaced-apart relative to each other in at least two directions.

In one direction, the first and second inlet tubes140aand140bare spaced-apart in a circumferential direction relative to each other. In particular, the first inlet tube140ais depicted on the right side of the container130(from the viewpoint ofFIGS.4A-4B), while the second inlet tube140bis depicted on the left side of the container130. In one example, the spacing is approximately 180 degrees, although it will be appreciated that the spacing may range from about 60 to about 300 degrees, so long as the objectives described below can be achieved.

In a second direction, the second (or lower) ends of the first and second inlet tubes140aand140bare spaced-apart vertically relative to each other. In particular, the second end142aof the first inlet tube140ais depicted as vertically beneath the platform135, while the second end142bof the second inlet tube140bis depicted as vertically above the platform135, as shown inFIGS.4A-4B. It should be noted that the second end142bmay be disposed above the therapeutic agent138, or may be submerged within the therapeutic agent138.

In this example, as shown inFIG.4B, a flow splitter170may be provided upstream relative to the container130, and downstream relative to an actuation valve180. The actuation valve180may be similar to the actuation valve80described above, and comprises an inlet port181and outlet tubing185. An actuator128, which may be in the form of a depressible button, may engage the actuation valve180to selectively permit fluid to pass from the inlet port181to the outlet tubing185. For example, the actuation valve180may comprise a piston having a bore formed therein that permits fluid flow towards the outlet tubing185when the actuator128engages the actuation valve180, as described above inFIGS.1-3. However, in the example ofFIG.4B, fluid that flows through the outlet tubing185is directed into an inlet port171of the flow splitter170.

The flow splitter170is coupled to first and second outlet conduits172and173, such as ports and associated tubing. The first outlet conduit172of the flow splitter170is in fluid communication with the first end141aof the first inlet tube140a, while the second outlet conduit173of the flow splitter170is in fluid communication with the first end141bof the second inlet tube140b, as depicted inFIG.4B. In this manner, pressurized fluid from a single pressure source, such as source68ofFIGS.1-2, is directed through the valve180, then through the flow splitter170, and is ultimately routed to each of the first and second inlet tubes140aand140bsimultaneously. It should be noted that, in alternative embodiments, the flow splitter170may be positioned within the valve180, such that the first and second outlet conduits172and173effectively replace the outlet tubing185and a stand-alone flow splitter170is omitted.

During operation, the pressurized fluid that is routed through the first inlet tube140aflows beneath the platform135, in a first direction to a second direction, and then is re-directed through an opening136in the platform135and into the second end152of the outlet tube150. As described above with respect toFIGS.1-3, a combination of the pressurized fluid and the therapeutic agent then flows from the second end152towards the first end151of the outlet tube150, and towards the catheter90for delivery to the target site.

During this process, the pressurized fluid that is routed through the second inlet tube140bexits above the platform135, and this fluid routing helps “shake” particles of the therapeutic agent138free on a regular basis throughout the agent's delivery, which may reduce clogging in the container130. In other words, the particles of the therapeutic agent138are less likely to settle in a compressed, packed or otherwise static manner relative to one another, similar to cooking flour that has not been agitated for a period of time. Instead, the fluid routed to the second inlet tube140bprovides a gentle agitation to keep the particles looser (compared to no agitation at all) and therefore less likely to become static and clog.

As a further advantage, the provision of the two inlet tubes140aand140bin this arrangement may promote a more consistent dose of powder, particularly when a user is periodically pressing the button128to switch between “on” and “off” states of powder delivery. Specifically, pressurized fluid from the second inlet tube140bmay reduce aeration time between user-actuated sprays of the powder, as the flow shaking and agitation provided by the second inlet tube140bhelps the powder settle in a faster and more consistent manner.

It is noted that some powders have high “air retention” properties, and for such powders, the settling time can run into the hours. The agitation or vibration provided by the pressurized fluid from the second inlet tube140bcan speed up the settling time.

In one embodiment, the flow splitter170may evenly distribute flow to the first and second outlet conduits172and173. However, in alternative embodiments, the flow splitter170may distribute flow unequally, for example, by allowing a higher pressure to pass through the first outlet conduit172and into the first inlet tube140a. In one example, the flow splitter170may be configured such that the pressure of the fluid moving through the first outlet conduit172is about 1.2 to about 4.0 times greater than the fluid flowing through the second outlet conduit173, and more preferably, about 2.0 to about 3.0 greater. In this manner, the second inlet tube140bprovides slightly less pressure to shake the powder above the platform135in a relatively gentle manner (without causing too much disruption that can cause dilation of the therapeutic agent138instead of even settling above the platform135), while the first inlet tube140aprovides slightly higher pressure as the primary driver to move the therapeutic agent138the requisite speed through the outlet tube150and the catheter90.

Notably, inFIGS.4A-4B, the platform135is shown having a tapered or angled design, where an outer region135ais vertically above an inner region135bthat is closest to the opening136. This design may have advantages in terms of routing powder towards the opening136using gravity of the taper in the platform; however, it will be appreciated that the generally flat platform35depicted inFIGS.1-3may be used in the design ofFIGS.4A-4B.

Referring now toFIGS.5A-5B, a further alternative system220comprises a container230which is similar to the container30ofFIGS.1-3, but which comprises a plate260disposed within a reservoir233that holds a therapeutic agent238.

In one embodiment, the plate260comprises an upper surface262, a lower surface263, and an outer perimeter261having a diameter that is substantially the same, or slightly less, than an inner diameter of the container230. In this manner, the outer perimeter261of the plate260is substantially flush with the interior of the container230, as depicted inFIG.5A, and the plate260has an ability to move vertically within the container230(i.e., in a direction from a first region231towards a second region232, and vice versa).

In one embodiment, the plate260is centered around the outlet tube250, as shown inFIG.5A. The plate260may comprise a first ring266having a bore267(which may be centrally-located if the plate is circular), through which the outlet tube250extends, and further comprises a second ring268having a bore269through which the inlet tube240extends. The first and second bores267and269are dimensioned with a small clearance relative to the outlet tube250and the inlet tube240, respectively, such that vertical movement of the plate260is enabled.

In one example, the plate260may be porous by providing a mesh or gauze270, which may comprise metal or plastic. The mesh270may comprise multiple strands271extending in a first direction, and multiple strands272extending in a second direction, where the first and second directions are substantially perpendicular to one another. The mesh270may comprise a generally circular shape with an exterior perimeter that approximates the outer perimeter261of the plate260, and the mesh270may omit material in the region of the first and second bores267and269, as shown inFIG.5B, thereby allowing passage of the outlet tube250and the inlet tube240, respectively.

The size of the mesh270may be correlated to a minimum particle size of the therapeutic agent, such that powder is not able to escape into a free space234in the reservoir233through the plate's mesh size, but the plate260still allows some pressurized fluid through the mesh that contributes to powder compaction and reduced aeration. By way of one non-limiting example, if the particles of the therapeutic agent have a diameter of about 75 microns, then the openings in the mesh270will be 75 microns or less, thereby avoiding haphazard particle movement in the free space234.

During use, pressurized fluid flows in a manner generally described above, i.e., from the pressure source68ofFIGS.1-2, then from a first end241towards a second end242of an inlet tube240. The pressurized fluid flows beneath the platform235, in a first direction to a second direction, and then is re-directed through an opening236in the platform235, where it then flows from a second end252towards a first end251of an outlet tube250. As described above with respect toFIGS.1-3, a combination of the pressurized fluid and the therapeutic agent238then flows out of the outlet tube250, and towards the catheter90for delivery to the target site.

As therapeutic agent238is being delivered to the target site, the height of the powder within the container230is reduced, and consequently the plate260falls in height due to gravity. The provision of the plate260improves therapeutic agent flow because the weight of the plate260helps to continue compaction of the powder adjacent to the platform235, and may provide a more predictable dose of powder delivery with each actuation of the button28by a user. Further, the plate260reduces the ability of the powder to haphazardly compile within the free space234of the reservoir233, which can lead to an inconsistent delivery.

Advantageously, when the plate260comprises openings in the mesh270, the weight and porosity of the plate260is designed to prevent over-compression of the powder inside the container230, but still allows powder aeration. The plate260rests atop the powder and allows the pressurized fluid to flow through the powder bed, but without allowing excessive powder dilation (i.e., rising of the powder bed). In short, a plate260having mesh270can allow some desired movement or shaking of the powder bed, which is desirable, without excessive rising of the powder bed, which may cause drawbacks including inconsistent delivery.

Referring now toFIGS.6A-6B, a further alternative system320comprises a container330which is similar to the container30ofFIGS.1-3, but which comprises a plate360disposed within a reservoir333that holds a therapeutic agent338.

In one embodiment, the container330comprises an inlet tube340having a first end341and a second end342, which is disposed adjacent to one circumferential side of the container (in the example ofFIGS.6A-6B, the right side in the figures). The inlet tube340may protrude into the container340by a distance di, as referenced inFIG.6A. The container330may optionally include a blank space345, i.e., where fluid and therapeutic agent do not flow, at a location opposing the inlet tube340(in this example, the blank space345is at the left side of the figures).

The plate360may be disposed in the container330at a circumferential location between the inlet tube340and the blank space345, as shown inFIGS.6A-6B. In one embodiment, the plate360comprises an outer diameter that is substantially the same, or slightly less, than the distance between interior regions of the inlet tube340and the blank space345, as depicted inFIGS.6A-6B. In this manner, an outer perimeter361of the plate360is substantially flush with the interior of the container330, and the plate360has an ability to move vertically within the container330.

In one embodiment, the plate360comprises an upper region362, a central region364, and a lower region366. The upper region362comprises a vertically upraised segment363that is similar to a cylindrical tube, and which comprises the outer perimeter361that is substantially flush with the interior of the container330, as shown inFIGS.6A-6B.

The central region364of the plate360may comprise an inward taper364aand a lower ledge364b, as shown inFIGS.6A-6B. The lower ledge364bof the plate360may be positioned above an upper ledge335bof the platform335, as depicted inFIGS.6A-6B.

A resiliently compressible member328is disposed vertically between the lower ledge364bof the plate360and the upper ledge335bof the platform335, as shown inFIGS.6A-6B. In one embodiment, the resiliently compressible member328may comprise a compression spring, as generally depicted; however, in other embodiments, the resiliently compressible member328may comprise other biasing elements, such as compressible foam or other mechanical members which tend to bias the plate360upward, as explained below.

The inward taper364aof the plate360transitions into the lower region366of the plate360. The lower region366may comprise an upraised segment that is both radially inward of the resiliently compressible member328, and radially inward of a wall portion335cof the platform335, as depicted inFIGS.6A-6B. In this manner, the plate360forms a generally “funnel shape” having the upraised upper region362, the central tapered region364, and the upraised lower region366. The funnel-shaped nature of the plate360surrounds the therapeutic agent338, and provides a tendency to funnel the therapeutic agent338towards a tapered section335aof the platform335.

During use, pressurized fluid flows in a manner generally described above, i.e., from the pressure source68ofFIGS.1-2, then from a first end341towards a second end342of the inlet tube340. The pressurized fluid flows beneath the platform335, in a first direction to a second direction, and then is re-directed through an opening336in the platform335, where it then flows from a second end352towards a first end351of an outlet tube350. As described above with respect toFIGS.1-3, a combination of the pressurized fluid and the therapeutic agent338then flows out of the outlet tube350, and towards the catheter90for delivery to the target site.

As therapeutic agent338is being delivered to the target site, the plate360is free to move in a vertical direction within the container330, particularly if a user shakes the delivery handle. The provision of the plate360improves therapeutic agent flow because the “shaking” movement of the plate360helps to continue compaction of the powder adjacent to the platform335, and may provide a more predictable dose of powder delivery with each actuation of the button28by a user. Further, the plate360reduces the ability of the powder to haphazardly compile within the reservoir333, which can lead to an inconsistent delivery.

In one example, the resiliently compressible member328provides a desirable vibration effect that helps expedite the settling of powder, while dislodging buildup of stagnant material in the container330. In short, the ability of the plate360to move freely within the container330, using vibration-assisted action from the resiliently compressible member328, provides a desirable agitation of the therapeutic agent338and may avoid undesirable powder compaction over time.

In the embodiment ofFIGS.6A-6B, it should be noted that, if the resiliently compressible member328comprises a spring, then the spring constant may be selected to be a relatively moderate amount. If the sprint constant is too high (rigid), then a desirable vibration may not be imparted to the plate360. If the spring constant is too low (loose), then too much agitation may occur and it may be difficult to settle down the powder, particularly in-between user-actuated button presses. Thus, a moderate spring constant can be selected to provide a balanced level of movement for the plate360.

Referring now toFIGS.7A-7B, a further alternative system420comprises a container430, with a plate460disposed within a reservoir433that holds a therapeutic agent438.

In this embodiment, the plate460may comprise a circular shape and may be dimensioned such that an outer perimeter461of the plate460is substantially flush with the interior of the container430, with the plate460having an ability to move vertically within the container430.

In this example, the therapeutic agent438is retained above the plate460at all times, and further, a resiliently compressible member428is disposed vertically beneath the plate460, as shown inFIGS.7A-7B. In one embodiment, the resiliently compressible member428may comprise a single compression spring that is centered within the container430, as generally depicted; however, in other embodiments, the resiliently compressible member428may comprise multiple compression springs positioned at spaced-apart locations beneath the plate460, or alternatively may comprise other biasing elements, such as compressible foam or other mechanical members which tend to bias the plate460upward, as explained below.

The system ofFIGS.7A-7Bfurther comprises a catheter490having an upstream region490a, a downstream region490b, and a constriction492disposed therebetween. The constriction492aligns axially with the container430, as shown inFIGS.7A-7B. In one embodiment, a connecting tube496is disposed between an upper end431of the container430and a lower side492bof the catheter490, as shown inFIG.7A, thereby enabling passage of the therapeutic agent438from within the container430into the catheter490via the connecting tube496.

The constriction492may comprises an indented segment492cformed in the upper side492aof the catheter490. The indented segment492cmay extend between about 5% and about 70% into the otherwise unobstructed lumen491of the catheter490. In other words, the constriction492cmay extend between about 5% and about 70% from the upper side492atowards the lower side492bof the catheter490. The constriction492cmay comprise a generally arcuate shape, where the apex of the arc is centered relative to the connecting tube496and the container430, as shown inFIGS.7A-7B.

During use, pressurized fluid flows from the pressure source68ofFIGS.1-2, then from the upstream region490atowards the downstream region490bof the catheter490. The pressurized fluid flows across the constriction492, at which time a combination of the pressurized fluid and the therapeutic agent438then flows out of the container430via the connecting tube496, and towards the downstream region90bfor delivery to the target site. The action of withdrawing the therapeutic agent438in this manner may also be referred to as a “Venturi effect.”

As therapeutic agent438is being delivered to the target site, then a reduced weight of therapeutic agent438is placed upon the plate460, allowing the plate460to move in a vertical direction within the container430, particularly due to the bias of the resiliently compressible member428, as shown among the state ofFIG.7AtoFIG.7B.

Advantageously, the resiliently compressible member428helps to raise the height of the therapeutic agent438within the container430, which facilitates a consistent powder supply to be exposed in the upper region of the container430and near the connecting tube496. The constriction492of the catheter490at a location vertically aligned with the connecting tube496and the container430creates the Venturi effect with an increased velocity of the pressurized fluid near the constriction492, thus drawing the therapeutic agent438out of the container430and propelling it forward towards the downstream region490bof the catheter490. In short, the Venturi-style constriction of the catheter490works in synergy with the resiliently compressible member428in the container430, to provide an improved stream of therapeutic agent into the catheter490.

While various embodiments of the invention have been described, the invention is not to be restricted except in light of the attached claims and their equivalents. Moreover, the advantages described herein are not necessarily the only advantages of the invention and it is not necessarily expected that every embodiment of the invention will achieve all of the advantages described.