System and apparatus for providing localized turbulence for delivering medical embolizing agents

Abstract

A system or device for injecting a therapeutic agent into a patient's blood vessel, comprising a catheter structure and a turbulence-inducing structure. The catheter structure extends from a distal end to a proximal end, having an outer surface and an inner surface. The catheter structure includes an opening at its distal end, which forms a continuous flow path with a lumen extending through the catheter structure, defined by the inner surface. The turbulence-inducing structure is formed from or attached to the outer surface or distal end of the catheter structure. The turbulence-inducing structure is configured to induce turbulence in the blood flowing through a local region of the blood vessel. The turbulence-inducing structure is of a suitable size and shape so as not to completely occlude the blood vessel, allowing blood to flow through the turbulence-inducing structure.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 457,730, filed Apr. 6, 2023, which is hereby incorporated by reference in its entirety.

[0002] The present invention generally relates to an infusion catheter for delivering therapeutic agents, particularly embolization agents, into the bloodstream of a patient.

Background Art

[0003] The systemic infusion of therapeutic agents has been used to treat various diseases in patients. The effectiveness of such systemic delivery can vary depending on various different factors such as the concentration required to achieve a therapeutic effect, the toxicity of the therapeutic agent, and / or undesirable effects. However, for some therapeutic agents such as radiological embolization agents, chemotherapeutic agents, or biological agents with systemic toxicity, systemic delivery is not desirable as it can have harmful effects on the patient. For example, the systemic delivery of embolization agents can lead to non-target embolism, which can lead to adverse events and morbidity.

[0004] The non-target delivery of embolization agents can have significant undesirable effects on the human body. For example, in liver treatment, the non-target delivery of embolization agents can have undesirable effects on other organs including the stomach and small intestine. In uterine fibroid treatment, the non-target delivery of embolization agents can embolize one or both ovaries, leading to loss of the menstrual cycle, subtle ovarian damage that can reduce fertility, premature menopause, and in some cases substantial damage to the ovaries. Other unintended adverse events include unilateral deep buttock pain, buttock necrosis, and uterine necrosis. As another example, it may be desirable to locally deliver chemotherapeutic agents to increase the local concentration of the chemotherapeutic agent near the tumor being treated to improve effectiveness while reducing the dose-limiting toxicity of the whole body.

[0005] Local delivery of therapeutic drugs is achieved by cannulating a catheter (e.g., a conventional terminal-hole microcatheter) into a blood vessel in the vascular system near the target area (e.g., the tumor to be treated) and delivering a flow of a fluid pharmaceutical composition (e.g., a solution or suspension) containing the therapeutic drug through the catheter into the patient's bloodstream. For example, in the treatment of a liver tumor, the catheter is placed in the hepatic artery vascular system and the flow of the fluid pharmaceutical composition (e.g., a solution or suspension) containing the therapeutic drug is delivered into the bloodstream through the catheter. In another example, for the treatment of a pancreatic tumor, the catheter is placed in the pancreatic artery arising from the splenic artery or the gastroduodenal artery and the flow of the fluid pharmaceutical composition (e.g., a solution or suspension) containing the therapeutic drug is delivered into the bloodstream through the catheter.

[0006] During localized intravascular injection, the therapeutic agent is delivered into the patient's blood vessels through a catheter. The distal tip of the catheter is positioned within the lumen of the blood vessel, and a fluid pharmaceutical composition stream (e.g., a solution or suspension) containing the therapeutic agent is delivered into the lumen of the blood vessel through the catheter. When the catheter is operational and inserted into the blood vessel, blood flow passes through the distal tip of the catheter. Once the fluid pharmaceutical composition stream is injected into the blood vessel, the injected composition travels forward with the blood flow.

[0007] Blood flowing through blood vessels tends to flow in layers. Generally, when injecting therapeutic drugs using conventional catheters, the layered blood flow is maintained without disturbance, and the therapeutic drug tends to travel downstream along a path defined by the local region of that laminar flow. The region of laminar flow within a blood vessel tends to follow a path defined downstream to a specific branch of the vascular system. Therefore, the position of the catheter at the injection point can affect the effectiveness of therapeutic drug delivery to the target region via the blood vessel supplied by the local flow of fluid within its laminar flow path.

[0008] Therapeutic agents are delivered as a solution or as particles, suspended in a pharmaceutical formulation, such as a liquid, foam, or gel, which is injected into the patient's vascular structure. Therapeutic agent particles may be undissolved solid embolic agents (e.g., embolic beads) or beads or microsphere carriers containing the therapeutic agent (e.g., embolic agent). The beads or microspheres may contain the therapeutic agent (e.g., embolic agent) internally or be coated with the therapeutic agent. The delivery of such therapeutic agent particles via a catheter (e.g., a conventional open-tip microcatheter) is often dependent on particle-fluid dynamics and catheter placement, which do not yield consistent results. For example, when a catheter is placed in a layered blood flow, the position of the device within that layered blood flow can cause variability in particle distribution. Even slight displacement of the distal tip of the catheter in this laminar flow can dramatically alter the downstream path taken by the particles.

[0009] The fluid-particle dynamics for injecting particle formulations into the bloodstream using conventional open-tip microcatheters are not well-characterized and can contribute to the unpredictability of the therapeutic dose actually delivered to the target area. For example, as a result of the complex interaction between angiogenesis in the target tissue, particle-fluid dynamics, and the placement of conventional open-tip microcatheters, the target tissue may receive a dose of particles below or above the therapeutic level. In addition, particles may accumulate in non-target areas and damage tissue in those areas (e.g., the lungs), especially if the particles contain embolizing or chemotherapeutic agents.

[0010] In particular, during radioembolization therapy, mapping procedures are typically performed to identify the areas where radioactive particles from subsequent infusions are most likely to flow. Mapping is usually performed using low-radioactivity tracer elements attached to quasi-embolic protein complexes (e.g., Tc-99m macroagglutinated albumin (MAA)). This tracer allows for a method of measuring particle distribution without embolizing blood vessels. This mapping also provides an indicator of infusion safety and helps determine whether there is blood shunting to sensitive organs such as the lungs (pulmonary shunt rate). When conventional open-tip microcatheters are placed in laminar blood flow, the distribution of radioembolic particles can vary depending on the device's position within that laminar flow. Even slight misalignment of the tip of a conventional open-tip microcatheter in this flow can dramatically alter the downstream path of the particles, potentially resulting in drug delivery not coinciding with the mapping procedure. Without guidance from the mapping procedure, undertreatment or overtreatment of tissues within the infusion zone is possible, potentially resulting in dangerous amounts of drug being shunted to non-target organs such as the lungs.

[0011] Therefore, there is still a need for more predictable and safer methods for locally injecting therapeutic drugs into blood vessels and delivering them to nearby target areas via the vascular system. [Overview of the Initiative]

[0012] This application relates to an intravascular infusion catheter for injecting therapeutic drugs into a patient's blood vessels. In some examples, the therapeutic drug is contained within particles or coated on their surface. For example, the therapeutic drug may be a radioembolizer, and the therapeutic drug is contained within or coated on microspheres. The intravascular infusion catheter comprises a catheter structure extending from a distal end to a proximal end, having an outer surface and an inner surface. The inner surface defines a lumen that penetrates the catheter structure. In another example, the catheter structure is a single catheter. Alternatively, the catheter structure comprises an outer catheter and an inner catheter, configured to deploy a turbulence-inducing structure by longitudinally displacing the outer catheter from the inner catheter. The catheter structure includes an opening at the distal end of the catheter structure that forms a continuous flow path with the lumen. The turbulence-inducing structure is formed from or attached to the outer surface or distal end of the catheter structure. In certain examples, the turbulence-inducing structure is attached to the distal end of the catheter structure. A turbulence-inducing structure is configured to induce turbulence in the blood flowing through a local region of a blood vessel. In some examples, the induced turbulence provides a shear force that does not exceed the shear force for hemolysis of red blood cells. The turbulence-inducing structure is also configured not to completely occlude the blood vessel, so that blood can always flow through the turbulence-inducing structure. In some examples, the turbulence-inducing structure does not completely occlude the blood vessel, so that blood can flow through the turbulence-inducing structure in a downstream or upstream direction. In some examples, the turbulence-inducing structure includes a leading edge at the distal or proximal end of the catheter structure that is substantially perpendicular to or obtuse to the longitudinal axis of the catheter structure. The turbulence-inducing structure may be spherical, cylindrical, conical, oval, ellipsoidal, or toroidal. In some examples, the turbulence-inducing structure partially occludes the blood vessel, so that blood can flow through the turbulence-inducing structure in a downstream or upstream direction. In some examples, the turbulence-inducing structure includes a plurality of arranged ridges. The arrangement may include a pattern, which may include a counterclockwise spiral from proximal to distal or a clockwise spiral from proximal to distal.

[0013] These and other aspects of the present invention will become apparent to those skilled in the art after reading the following detailed description of the invention, including the drawings and the appended claims. [Brief explanation of the drawing]

[0014] Further objectives, features, and advantages of this disclosure will become apparent from the following detailed description, in conjunction with the accompanying drawings illustrating exemplary embodiments of this disclosure.

[0015] [Figure 1] Figure 1 shows an exemplary delivery system for intravascular injection of a therapeutic drug according to one embodiment of the present application.

[0016] [Figure 2A] Figure 2A is a front view from the distal end of an exemplary turbulence-inducing structure according to one embodiment of the present application.

[0017] [Figure 2B] Figure 2B is a side view of an exemplary turbulence-inducing structure having a spherical shape according to one embodiment of the present application.

[0018] [Figure 2C] Figure 2C is a side view of an exemplary turbulence-inducing structure according to one embodiment of the present application, having a leading edge at its distal end that is substantially perpendicular or obtuse with respect to the longitudinal axis of the catheter structure.

[0019] [Figure 2D] Figure 2D is a side view of an exemplary turbulence-inducing structure according to one embodiment of the present application, having a leading edge at its proximal end that is substantially perpendicular or obtuse with respect to the longitudinal axis of the catheter structure.

[0020] [Figure 2E] Figure 2E is a side view of an exemplary turbulence-inducing structure according to one embodiment of the present application, having a sharper curve at the distal end than at the proximal end.

[0021] [Figure 2F] Figure 2F is a side view of an exemplary turbulence-inducing structure having a distal portion of a catheter assembly and a cylindrical shape, according to one embodiment of the present application.

[0022] [Figure 2G] Figure 2G is a side view of an exemplary turbulence-inducing structure having a distal portion of a catheter assembly and an inner surface including a first portion parallel to the outer surface of the catheter assembly and a second portion extending away from the outer surface of the catheter assembly, according to one embodiment of the present application.

[0023] [Figure 2H] Figure 2H is a side view of an exemplary turbulence-inducing structure having a distal portion of a catheter assembly and a toroidal shape, according to one embodiment of the present application.

[0024] [Figure 2I] Figure 2I is a side view of an exemplary turbulence-inducing structure having a distal portion of a catheter assembly and attached to the distal tip of the catheter assembly, according to one embodiment of the present application.

[0025] [Figure 2J] Figure 2J is a side view of an exemplary turbulence-inducing structure formed at the distal portion of a catheter assembly and at the distal tip of the catheter assembly, according to one embodiment of the present application.

[0026] [Figure 2K] Figure 2K is a side view of an exemplary turbulence-inducing structure formed at the distal portion of a catheter assembly and at the distal tip of the catheter assembly, according to one embodiment of the present application.

[0027] [Figure 2L] Figure 2L is a side view of another example of a turbulence-inducing structure formed at the distal end of a catheter assembly.

[0028] [Figure 2M]Figure 2M is a side view of yet another example of a turbulence-inducing structure attached to the distal end of a catheter component.

[0029] [Figure 2N] Figure 2N is a side view of yet another example of a turbulence-inducing structure attached to the distal end of a catheter component.

[0030] [Figure 3] Figure 3 shows the chemical structure of the sodium salt of SD-101. [Modes for carrying out the invention]

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in which the present invention pertains. Otherwise, certain terms used herein have the meanings set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if they were fully contained herein. Note that where used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise.

[0032] Throughout this specification and the subsequent claims, unless the context otherwise requires, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to mean the inclusion of any integer or step or group of integers or steps described, but not the exclusion of any other integer or step or group of integers or steps. Where used herein, the term “comprising” may be replaced by the terms “containing” or “including,” and where used herein, by the term “having.”

[0033] As used herein, the conjunction "and / or" between multiple enumerated elements is understood to encompass both individual options and combined options. For example, when two elements are joined by "and / or," the first option refers to the applicability of the first element without the second element. The second option refers to the applicability of the second element without the first element. The third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning of the term "and / or" as used herein and thus satisfies its requirements. The simultaneous applicability of multiple options is also understood to fall within its meaning and thus satisfies the requirements of the term "and / or."

[0034] As used herein, the terms “subject” or “patient” refer to an animal, preferably a mammal. According to certain embodiments, the subject or patient is a mammal, including non-primates (e.g., camels, donkeys, zebras, cattle, pigs, horses, goats, sheep, cats, dogs, rats, rabbits, guinea pigs, marmosets, or mice) or primates (e.g., monkeys, chimpanzees, or humans). In certain embodiments, the subject or patient is a human.

[0035] As used herein, the terms “proximal” and “distal” are defined with reference to the user’s hand of the devices and systems described herein. “Proximal” means close to the user’s hand, and “distal” means farther from the user’s hand and often located further inside the patient’s body during use.

[0036] This application provides a device comprising a catheter for injecting a therapeutic agent into a patient's blood vessel, and a structure provided at or near the distal end of the catheter to induce turbulence within the blood vessel as the flow of the therapeutic agent is injected into the bloodstream. The bloodstream flows in layers before passing through the distal end of the catheter. As the bloodstream passes through the structure provided at or near the distal end of the catheter, the structure induces local turbulence in the bloodstream. When the flow of the therapeutic agent is injected into the bloodstream from the distal tip of the catheter, the local turbulence contains vortices, thereby mixing the therapeutic agent with the bloodstream passing through the distal end of the catheter. This local turbulence improves the distribution of the therapeutic agent in the bloodstream (compared to when the blood passes through the distal end of the catheter as laminar flow), and the blood returns to laminar flow downstream from the catheter's position and enters the vascular pathway for delivery to the tissue of the target area for treatment (e.g., the tumor to be treated). This localized turbulence is thought to allow for more consistent delivery of therapeutic drugs to the target area (compared to when blood passes through the distal end of the catheter as laminar flow).

[0037] Figure 1 shows an exemplary delivery system 10 for intravascular injection of a therapeutic drug. The delivery system 10 comprises a catheter component 12, a turbulence-inducing structure 14, and a pump system 16. The system 10 is sized and shaped for use in injecting a therapeutic drug into a target area via an arterial or venous vessel. In particular, the catheter component 12 and the turbulence-inducing structure 14 are sized and shaped for sliding into and inserting into a vessel when the turbulence-inducing structure 14 is deployed and operating within the vessel. The vessel contains a lumen defined by the inner wall of vascular cells with a diameter of approximately 2 μm to approximately 10,000 μm. The vessel is located in any organ where treatment with the therapeutic drug is desired. For example, organs include the pancreas, liver, kidneys, lungs, uterus, ovaries, cervix, prostate, head and neck tissues (jaw, gums), brain, adrenal glands, intestines or colon, breasts, thyroid gland, spleen, stomach, gallbladder, thymus, skin, bladder, lymphatic system, and various other organs or tissues suffering from tumors or other disease conditions that can be treated by local delivery of therapeutic drugs. The diameter of blood vessels is larger than the size of a red blood cell and is less than approximately 5 cm, less than approximately 4 cm, less than approximately 3 cm, less than approximately 2 cm, less than approximately 1 cm, less than approximately 10 mm, less than approximately 9 mm, less than approximately 8 mm, less than approximately 7 mm, less than approximately 6 mm, or less than approximately 5 mm. The diameter of blood vessels is approximately 8 μm to approximately 5 cm, or approximately 10 μm to approximately 3 cm. In particular, the blood vessels may be hepatic arteries. The diameter of these blood vessels is approximately 8 μm to approximately 10 mm, approximately 10 μm to approximately 9 mm, or approximately 1 mm to approximately 6 mm. In another example, the blood vessel may be a pancreatic artery arising from the splenic artery or the gastroduodenal artery. The diameter of the blood vessel is approximately 8 μm to 1 cm, approximately 10 μm to 6 mm, or approximately 1 mm to 5 mm. In one example, the catheter component 12 and the turbulence-inducing structure 14 are preferably sized and shaped to have a diameter smaller than the diameter of the lumen defined by the inner wall of the cells of the blood vessel into which it is deployed. The system 10 and its use prevent, reduce, or minimize the systemic circulation of the therapeutic agent.

[0038] The catheter structure 12 has a proximal end 20, a distal end 22, and a lumen 18 extending between the proximal and distal ends 20, 22. The lumen 18 is defined by the inner surface of the catheter structure. The turbulence-inducing structure 14 is part of or attached to the catheter structure 12 at or near the distal end 22. The proximal end 22 of the catheter structure 12 is operably connected to a handle 24, and the catheter structure 12 is operated by operating the handle 24. The handle 24 is configured to allow manual operation from the outside when the catheter structure 12 is in the patient's vascular structure. The handle 24 also includes a flow path 26 extending between the pump system 16 and the lumen 18 of the catheter structure. The pump system 16 is fluidly connected to the proximal end 20 via the flow path 26 of the handle 24, and a continuous flow path extends from the pump system 16 through the flow path 26 and the lumen 18 to the opening 30 at the distal end 22 of the catheter structure 12. The opening 30 at the distal tip 23 of the catheter component 12 is configured to dispense a flow of therapeutic drug from the pump system 16 into the patient's bloodstream when the catheter component 12 is deployed into the patient's blood vessel.

[0039] The turbulence-inducing structure 14 is configured to induce turbulence in the blood vessel at or near the distal end 22 of the catheter component 12 when the drug flow is injected into the bloodstream. When the delivery system 10 is deployed into the patient's vascular system and the catheter component 12 is positioned within the blood vessel, the turbulence-inducing structure 14 does not completely occlude the blood vessel so that blood can always flow through the turbulence-inducing structure 14 when the turbulence-inducing structure 14 is in its deployed configuration (i.e., when the turbulence-inducing structure is not folded or compressed to advance the distal end 22 of the catheter component 12 into place, and when the turbulence-inducing structure 14 is deployed to the desired position within the blood vessel to induce turbulence in the blood flow). In another example, once the delivery system 10 is deployed into the patient's vascular system and the catheter 12 is positioned within the blood vessel, the turbulence-inducing structure 14 does not completely occlude the blood vessel, allowing blood to flow through the turbulence-inducing structure 14 in both the downstream (i.e., proximal to distal) and / or upstream (i.e., distal to proximal) directions.

[0040] As blood flows through the turbulence-inducing structure 14, the turbulence of the blood flow increases in the local region near the turbulence-inducing structure 14. After the blood flow moves further downstream from the turbulence-inducing structure 14, the turbulence of the blood flow decreases, and the blood flow returns to laminar flow. The turbulence-inducing structure 14 or the local region near it where the increase in turbulence occurs may extend downstream from the turbulence-inducing structure 14 for a certain length, which is approximately 0.1 to 5 times the diameter of the blood vessel through which the system 10 is deployed. For example, this length may be approximately 0.1 mm to 30 mm.

[0041] As blood flow enters the local region, the turbulence-inducing structure 14 induces local turbulence or vortices in the blood flow. When the fluid pharmaceutical composition containing the therapeutic agent exits the opening 30 at the distal end 22 of the catheter structure and is injected into the blood flow, the increase in turbulence in the local region mixes the fluid pharmaceutical composition with the blood flow passing through the local region, improving the distribution of the therapeutic agent in the blood flow (compared to when blood passes through the distal end of the catheter as laminar flow). The blood returns to laminar flow downstream from the local region and continues to flow into the vascular pathway for delivery to the tissue of the target region for treatment (e.g., the tumor to be treated).

[0042] The turbulence-inducing structure 14 has any suitable size and shape to increase turbulence within a local region. For example, the turbulence-inducing structure 14 increases the Reynolds number of intravascular blood flow within a local region from less than 2300 to more than 2900. The blood flow upstream of the distal end of the catheter is laminar. For example, the blood flow upstream of the distal end of the catheter has a Reynolds number of less than 2300, and the turbulence-inducing structure 14 increases the Reynolds number of blood flow within a local region by at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 1500, at least about 2000, at least about 2500, at least about 5000, at least about 7500, or at least about 10,000.

[0043] It is understood that the turbulence-inducing structure 14 increases turbulence within a local region, while this increase in turbulence also increases the shear force of blood flow. For the turbulence-inducing structure 14 to be suitable for use in blood vessels, the level of turbulence induced by the turbulence-inducing structure 14 must be limited to turbulence that generates a shear force less than the shear force required for hemolysis of cells, particularly red blood cells. Specifically, the level of turbulence induced by the turbulence-inducing structure 14 must be limited to turbulence that generates a shear force less than the level required to damage or kill cells, particularly red blood cells. For example, the maximum shear force generated by turbulence is approximately 60 dyn / cm 2 Or it is approximately 400 N / m². The level of turbulence induced by the turbulence induction structure 14 is approximately 20 dyn / cm² to approximately 60 dyn / cm². 2 It generates shear force.

[0044] In some examples, the turbulence-inducing structure 14 includes one or more radially arranged structures that displace the lumen 18 of the catheter structure 12 from the vessel wall of the blood vessel into which the catheter structure 12 is inserted. When deployed, the turbulence-inducing structure 14 pushes the outer surface 15 of the catheter structure 12 away from the vessel wall, thereby causing the opening 30 of the catheter structure to be located more centrally within the blood vessel (e.g., closer to the longitudinal axis of the vessel). Even under laminar flow conditions, the path through the central part of the lumen of the vessel tends to distribute the flow of the fluid pharmaceutical composition in the most uniform manner compared to injection from a position further away from the longitudinal axis of the vessel. The closer to the vessel wall, the more likely particles are to be preferentially and non-uniformly carried along the laminar flow path.

[0045] In one example, the turbulence-inducing structure 14 may be a structure attached to the outer surface 15 at the distal end 22 of the catheter structure 12. In particular, the turbulence-inducing structure 14 may extend radially away from the longitudinal axis of the catheter structure and / or surround part or all of the distal end 22 of the catheter structure 12. As shown in Figure 2A, the turbulence-inducing structure 202 includes an inner surface 102 defining an opening 103 for receiving the catheter structure 12 through which it penetrates, and an outer surface 104. The inner surface 102 of the turbulence-inducing structure 14 may be attached to the outer surface of the catheter structure 12. In some examples, the turbulence-inducing structure is integrally formed (e.g., molded) on the outer surface 15 of the catheter structure 12. In another example, the turbulence-inducing structure 12 may include multiple components attached to the outer surface 15 of the catheter structure 15, such as grooved elements, fins, etc. The turbulence-inducing structure 14 may be a rigid structure, a foldable structure, or a compressible structure attached to the outer surface 15 of the catheter structure 12.

[0046] The collapsible structure may be formed from any elastic material suitable for medical applications, such as a shape memory material, such as a shape memory metal (e.g., Nitinol), or a shape memory medical-grade elastomer. In another example, the collapsible structure is an inflatable structure such as a balloon (e.g., a balloon that can be inflated with fluid or air), a self-expanding or manually expandable filter, or a mechanically expandable Malecot wing structure. For example, the collapsible structure may be a balloon that can be inflated with fluid or air. The collapsible structure is fluidly connected to a second lumen for filling the collapsible structure with fluid or air to inflate it. The second lumen for filling the collapsible structure may be part of the catheter structure 12, or part of a separate catheter.

[0047] The foldable structure is folded when the catheter component 12 is advanced to the operating position within the blood vessel, and unfolded when the distal end 22 of the catheter component 12 is at the desired position for injecting a fluid pharmaceutical composition containing the therapeutic agent. In the folded state, it has a reduced diameter for intravascular advancement to the desired operating position within the blood vessel. In the unfolded configuration, it has a larger diameter than the folded configuration, where the foldable structure is expanded to induce turbulence in the blood flow.

[0048] A compressible structure is any elastic structure that can be compressed to reduce the size of the structure to a compressed configuration and then released to an expanded configuration. A compressible structure is formed, for example, from an elastomer foam, and when pressure is applied to the foam, the structure is compressed, and when the pressure is removed from the structure, it returns to its original shape. A compressible structure is in a compressed state when the catheter structure 12 is advanced to the operating position in the blood vessel, and is in an expanded state (for example, when pressure is removed from the structure) when the distal end 22 of the catheter structure 12 is at the desired position for injecting a fluid pharmaceutical composition containing the therapeutic agent. In the compressed state, it has a reduced diameter for advancement in the blood vessel to the desired operating position. In the expanded state, it has a larger diameter than the compressed configuration, and here the compressed structure expands to the expanded state to induce turbulence in the blood flow.

[0049] For example, the turbulence-inducing structure 14 includes a plurality of projections (not shown) extending from the outer surface 15 of the catheter structure. The projections increase the drag in the blood flow and induce the formation of vortices. The projections may be rigid structures, or they may be foldable or compressible, being folded or compressed when the catheter structure 12 is advanced to the operating position in the blood vessel, and unfolded when the distal end 22 of the catheter structure 12 is at the desired position for injecting a fluid pharmaceutical composition containing a therapeutic agent.

[0050] In some examples, the outer surface 104 of the turbulence-inducing structure 202 has a curved shape. The turbulence-inducing structure 202 has a distal end 203 and a proximal end 204. When in use, the turbulence-inducing structure 202 is positioned so that the flow moves through the turbulence-inducing structure in the direction from the proximal end 204 to the distal end 203. Therefore, the turbulence-inducing structure 202 may have a spherical, cylindrical, conical, oval, ellipsoidal, or other curved shape. For example, as shown in Figures 2B to 2E, the outer surface 104 of the turbulence-inducing structures shown in these figures all have a curved shape.

[0051] Figure 2B shows a side view of a turbulence-inducing structure 202b having a spherical shape as an example, and the turbulence-increasing effect of the structure on a flow moving through the structure from the proximal end 204 to the distal end 203.

[0052] Figure 2C shows a side view of an exemplary turbulence-inducing structure having a leading edge that is substantially perpendicular or obtuse to the longitudinal axis of the catheter structure at the distal end 203, and the turbulence-increasing effect of the structure on flow moving past the structure from the proximal end 204 to the distal end 203.

[0053] Figure 2D shows a side view of an exemplary turbulence-inducing structure having a leading edge that is substantially perpendicular or obtuse to the longitudinal axis of the catheter structure at the proximal end 204, and the turbulence-increasing effect of the structure on flow moving past the structure in the direction from the proximal end 204 to the distal end 203.

[0054] Figure 2E shows a side view of another example of a turbulence-inducing structure 202e, which has a sharper curve at the distal end 203 than at the proximal end 204, and the turbulence-increasing effect of the structure on flows moving through the structure from the proximal end 204 to the distal end 203.

[0055] Figure 2F is a side view of another example of a turbulence-inducing structure 202f attached to the distal end 22 of the catheter component 12. In this example, the turbulence-inducing structure 202f is cylindrical and surrounds the distal end 22 of the catheter component.

[0056] Figure 2G is a side view of yet another example of a turbulence-inducing structure 202g attached to the distal end 22 of a catheter structure 12. The turbulence-inducing structure 202g includes a curved outer surface 104g and an inner surface 102g which includes a first portion parallel to the outer surface 15 of the catheter structure 12 for receiving the catheter structure 12 through its interior, and a second portion extending away from the outer surface 15 of the catheter structure 12. The distal end 203 of the turbulence-inducing structure 202g may have an irregular cross-sectional edge 205g or a linear (not shown) cross-sectional edge.

[0057] Figure 2H is a side view of yet another example of a turbulence-inducing structure 202h attached to the distal end 22 of a catheter structure 12. In this example, the turbulence-inducing structure 202h is toroidal (e.g., donut-shaped, also called toroidal) and defines an opening for receiving the catheter structure 12 through its interior. In certain examples, the turbulence-inducing structure 202h is an inflatable or compressible structure. For example, the turbulence-inducing structure 202h is a balloon. In another example, the turbulence-inducing structure 202h is formed from a compressible foam.

[0058] In some other examples, the turbulence-inducing structure 14 includes one or more projections extending from the distal tip 23 of the catheter structure 12. When the drug flow is dispensed from the opening 30 at the distal tip 23 of the catheter structure 12, the drug flow is disturbed by the one or more projections, thus inducing vortices in the blood flow. The one or more projections have any suitable shape for inducing turbulence in a local area within the blood flow. For example, the one or more projections may have a planar shape with a flat surface extending parallel to the longitudinal axis of the catheter structure, or a cylindrical, conical, irregular shape, etc. For example, Figure 2I is a side view of an example of a turbulence-inducing structure 202i attached to the distal tip 23 of a catheter structure 12. In this example, the turbulence-inducing structure 202i is a flare attached to the distal tip 23 of the catheter structure 12 and has a flat surface extending parallel to the longitudinal axis of the catheter structure 12.

[0059] In some other examples, the turbulence-inducing structure 14 is molded or formed on the distal end 22 of the catheter structure 12. For example, the outer surface 15 of the distal end 22 of the catheter structure 12 may be modified to include features that induce turbulence in the blood flow when the device is in an operating position within the patient's blood vessel. Figure 2J is a side view of a turbulence-inducing structure 202j formed on the distal end 22 of the catheter structure 12, yet another example. The turbulence-inducing structure 202j includes one or more grooves 203j engraved on the outer surface 15 of the distal tip 23 of the catheter structure 12. The grooves 203j induce turbulence within a local area of ​​the distal end 22 of the catheter structure 12. As shown in Figure 2J, the grooves may extend spirally around the distal end 22 of the catheter structure 12. Alternatively, the groove 203j may be parallel, perpendicular, or acute with respect to the longitudinal axis of the catheter component 12 extending from the proximal end 20 to the distal end 22, or it may be obtuse with respect to the longitudinal axis of the catheter component 12 extending from the proximal end 20 to the distal end 22.

[0060] In another example, the distal tip 23 of the catheter component 12 may be modified to include features that induce turbulence in the blood flow when the device is in an operating position within the patient's blood vessel. Figure 2K is a side view of another example of a turbulence-inducing structure 202k formed on the distal tip 23 of the catheter component 12. The turbulence-inducing structure 202k includes one or more slits cut into the distal tip 23 of the catheter component 12, forming a feature portion 203k that extends away from the longitudinal axis of the catheter component 12. The branched feature portion 203k induces turbulence within a local area of ​​the distal end 33 of the catheter component 12. The slits cut into the distal tip 23 and the branched feature portion 203k may have any preferred shape for inducing turbulence. As shown in Figure 2K, the distal tip 23 of the catheter structure 12 may be modified with four slits forming four different branching features 203k, but any number of slits (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) may be used to form a number of branching features 203k corresponding to the distal tip 23 of the catheter structure 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0061] Figure 2L is a side view of another example of a turbulence-inducing structure 202l formed at the distal tip 23 of a catheter structure 12. The turbulence-inducing structure 202l includes a distal structure 203l around the opening 30 at the distal tip 23 of the catheter structure 12, and a plurality of support portions 204l connecting the distal structure 203l to the rest of the catheter structure 12. The turbulence-inducing structure 202l may be formed by removing a portion from the wall of the catheter structure 12 at the distal end 22 of the catheter structure 12 to form a gap 205l. As shown in Figure 2L, the turbulence-inducing structure 202l may have two support portions, but any number of support portions (e.g., 3, 4, 5, 6, 7, 8, 8, 10) may be formed from the distal end 22 of the catheter structure. The gap 205l disrupts the blood flow and further disperses the fluid pharmaceutical composition injected into the blood vessel by the catheter structure 12. The distal structure 203l allows the guidewire to extend through the opening 30. This distal structure 203l may be cone-shaped, hemispherical, ring-shaped, or other in shape. The distal structure 203l may be coaxial with the catheter structure 12. In one example, the distal structure 203 may be expandable in the same manner as a foldable or compressible structure, as will be further described below. In the example shown in Figure 2L, the distal structure 203l includes a distal plane substantially perpendicular to the longitudinal axis of the catheter structure 12 and a proximal plane substantially perpendicular to the longitudinal axis. The proximal plane initiates turbulence in the blood flow, and the distal plane amplifies the turbulence.

[0062] Figure 2M is a side view of another example of a turbulence-inducing structure 202m attached to the distal end 22 of a catheter structure 12. The turbulence-inducing structure 202m includes a plurality of grooved fins 203m arranged longitudinally along the distal end 22 (not shown) of the catheter structure 12, or spirally along the length of the distal end 22 of the catheter structure 12. As blood flows downstream through the turbulence-inducing structure 202m, the grooved fins 203m disrupt the laminar flow of the blood. Blood passing through the turbulence-inducing structure 202m is induced to swirl as it passes through the distal end 22 of the catheter structure. This swirling action disrupts the laminar flow and generates turbulence for mixing the fluid pharmaceutical composition in the patient's blood.

[0063] In one example, the catheter structure 12 is a single microcatheter containing a lumen 18 that extends through its interior from a proximal end 20 to a distal end 22.

[0064] In another example, the catheter configuration 12 is a multi-catheter configuration that can be used to deploy and fold or compress a foldable or compressible turbulence-inducing structure 14. For example, the catheter configuration 12 includes an outer catheter and an inner catheter. The inner catheter is of a suitable size and shape to slide within the lumen of the outer catheter. The foldable or compressible turbulence-inducing structure 14 is held in a folded or compressed state by the outer catheter and the inner catheter (for example, between the outer surface of the inner catheter and the lumen of the outer catheter). The foldable or compressible turbulence-inducing structure 14 is deployed and / or reconfigured by sliding the outer catheter and the inner catheter relative to each other to provide longitudinal displacement for deployment of the foldable or compressible turbulence-inducing structure 14. In this example, the handle 24 also comprises a stationary portion and a movable portion for manipulating the catheter configuration. In particular, the proximal end of the outer catheter is coupled to a stationary part to prevent longitudinal movement, and the proximal end of the inner catheter is coupled to a movable part. The movable part can be manually operated relative to the stationary part to slide the inner and outer catheters relative to each other, providing longitudinal displacement for deploying a foldable or compressible turbulence-inducing structure 14.

[0065] Figure 2N is a side view of another example of a turbulence-inducing structure 202n attached to the distal end of a catheter structure 12. The turbulence-inducing structure 202n includes a plurality of ridges 203n. The plurality of ridges 203n may be arranged along the distal end 22 of the catheter structure 12. The turbulence-inducing structure includes, for example, ridges along the distal end of the catheter structure. A ridge may include, for example, one or more facets. Each of the one or more facets is oriented in a certain direction, such that an axis extending perpendicularly from the surface of the facet points in that direction. A ridge may include, for example, one or more facets oriented proximal. A ridge may include, for example, one or more facets oriented distal. A ridge may include, for example, one or more facets oriented perpendicular to the outer surface of the catheter structure. A ridge may include, for example, one or more facets oriented perpendicular to the longitudinal axis of the catheter structure. The ridge may include, for example, one or more facets oriented proximal, distal, perpendicular to the outer surface of the catheter structure, and / or perpendicular to the longitudinal axis of the catheter structure.

[0066] The ridge may include, for example, one or more facets oriented at an angle between the proximal and distal directions. The ridge may include, for example, one or more facets oriented at an angle between the proximal direction and a direction perpendicular to the outer surface of the catheter structure. The ridge may include, for example, one or more facets oriented at an angle between the proximal direction and a direction perpendicular to the longitudinal axis of the catheter structure. The ridge may include, for example, one or more facets oriented at an angle between the distal direction and a direction perpendicular to the outer surface of the catheter structure. The ridge may include, for example, one or more facets oriented at an angle between the distal direction and a direction perpendicular to the longitudinal axis of the catheter structure. The ridge may include, for example, one or more facets oriented at an angle between a direction perpendicular to the outer surface of the catheter structure and a direction perpendicular to the longitudinal axis of the catheter structure.

[0067] A ridge may include, for example, a curved facet. A ridge may include, for example, one or more curved facets. One or more curved facets may include concave facets, convex facets, and / or combinations thereof. A curved facet may include one or more curves. A curved facet may include concave curves, convex curves, and / or combinations thereof. A ridge may include, for example, a planar facet. A ridge may include, for example, one or more planar facets. A ridge may include, for example, one or more curved facets and / or one or more planar facets. A ridge may include, for example, two facets, three facets, four facets, five facets, or six facets.

[0068] The ridge includes, for example, ridge width, ridge length, and / or ridge height. The ridge width may be in the range of 0.01 mm to 0.10 mm. The ridge width may be in the range of 0.01 mm to 0.20 mm. The ridge width may be in the range of 0.01 mm to 0.30 mm. The ridge width may be in the range of 0.02 mm to 0.30 mm. The ridge width may be in the range of 0.01 mm to 0.50 mm. The ridge width may be in the range of 0.01 mm to 0.75 mm. The ridge width may be in the range of 0.01 mm to 1.00 mm. The ridge width may be in the range of 0.10 mm to 1.00 mm. The ridge width may be in the range of 0.20 mm to 1.00 mm. The ridge width may be in the range of 0.30 mm to 1.00 mm. The ridge width may be in the range of 0.50 mm to 1.00 mm. The ridge width may be in the range of 0.75 mm to 1.00 mm. The ridge width may be shorter than the circumference of the catheter structure, equal to the circumference, and / or longer than the circumference. The ridge width may be a percentage of the circumference of the catheter structure. The ridge width may be 10% to 100% of the circumference of the catheter structure, 100% of the circumference of the catheter structure, and / or 100% to 300% of the circumference of the catheter structure.

[0069] The ridge length may be in the range of 0.10 mm to 0.25 mm. The ridge length may be in the range of 0.10 mm to 0.50 mm. The ridge length may be in the range of 0.10 mm to 0.75 mm. The ridge length may be in the range of 0.10 mm to 1.00 mm. The ridge length may be in the range of 0.10 mm to 1.25 mm. The ridge length may be in the range of 0.1 mm to 1.5 mm. The ridge length may be in the range of 0.10 mm to 2.00 mm. The ridge length may be in the range of 0.25 mm to 2.00 mm. The ridge length may be in the range of 0.75 mm to 2.00 mm. The ridge length may be in the range of 1.00 mm to 2.00 mm. The ridge length may be in the range of 1.25 mm to 2.00 mm. The ridge length may be in the range of 1.50 mm to 2.00 mm. The ridge length may be shorter than the distal portion of the catheter structure, equal to the distal portion, and / or longer than the distal portion. The ridge length may also be a percentage of the length of the distal portion of the catheter structure. The ridge length may be 10% to 100% of the length of the distal portion of the catheter structure, 100% of the length of the distal portion of the catheter structure, and / or 100% to 300% of the length of the distal portion of the catheter structure. The ridge length may be shorter than the length of the array, and / or equal to the length of the array. The ridge length may also be a percentage of the length of the array. The ridge length may be 10% to 100% of the length of the array, and / or 100% of the length of the array.

[0070] The ridge height may be in the range of 0.01 mm to 0.10 mm. The ridge height may be in the range of 0.01 mm to 0.20 mm. The ridge height may be in the range of 0.01 mm to 0.30 mm. The ridge height may be in the range of 0.01 mm to 0.50 mm. The ridge height may be in the range of 0.01 mm to 1.00 mm. The ridge height may be in the range of 0.01 mm to 1.50 mm. The ridge height may be in the range of 0.01 mm to 2.00 mm. The ridge height may be in the range of 0.01 mm to 3.00 mm. The ridge height may be in the range of 0.02 mm to 3.00 mm. The ridge height may be in the range of 0.01 mm to 5.00 mm. The ridge height may be in the range of 0.10 mm to 5.00 mm. The ridge height may be in the range of 0.20 mm to 5.00 mm. The ridge height may be in the range of 0.30 mm to 5.00 mm. The ridge height may be in the range of 0.50 mm to 5.00 mm. The ridge height may be in the range of 1.00 mm to 5.00 mm. The ridge height may be in the range of 1.50 mm to 5.00 mm. The ridge height may be in the range of 2.00 mm to 5.00 mm. The ridge height may be in the range of 3.00 mm to 5.00 mm. The ridge height may be shorter than the radius of the catheter component, equal to the radius of the catheter component, and / or longer than the radius of the catheter component. The ridge height may be a percentage of the radius of the catheter component. The ridge height may be 10% to 100% of the radius of the catheter component, 100% of the radius of the catheter component, and / or 100% to 300% of the radius of the catheter component.

[0071] The arrangement of multiple ridge203n in the catheter structure may include length and / or pattern. The arrangement length may be in the range of 1 mm to 5 mm. The arrangement length may be in the range of 1 mm to 10 mm. The arrangement length may be in the range of 1 mm to 15 mm. The arrangement length may be in the range of 1 mm to 20 mm. The arrangement length may be in the range of 1 mm to 25 mm. The arrangement length may be in the range of 1 mm to 50 mm. The arrangement length may be in the range of 1 mm to 75 mm. The arrangement length may be in the range of 1 mm to 100 mm. The arrangement length may be in the range of 5 mm to 100 mm. The arrangement length may be in the range of 10 mm to 100 mm. The arrangement length may be in the range of 15 mm to 100 mm. The arrangement length may be in the range of 20 mm to 100 mm. The row length may be in the range of 25 mm to 100 mm. The arrangement length may be in the range of 50 mm to 100 mm. The arrangement length may be in the range of 75 mm to 100 mm. The length of the array may be shorter than the distal portion of the catheter structure, equal to the distal portion, and / or longer than the distal portion. The length of the array may also be a percentage of the length of the distal portion of the catheter structure. The length of the array may be 10% to 100% of the length of the distal portion of the catheter structure, 100% of the length of the distal portion of the catheter structure, and / or 100% to 300% of the length of the distal portion of the catheter structure. The length of the array may be equal to the ridge length and / or longer than the ridge length. The length of the array may also be a percentage of the ridge length. The length of the array may be 100% of the ridge length, 100% to 500% of the ridge length, and / or 100% to 1000% of the ridge length.

[0072] The array pattern may include a clockwise spiral from proximal to distal, a counterclockwise spiral from proximal to distal, a ring, multiple rings, columns, and / or multiple columns. This pattern may include one or more circumferential lengths between circumferentially adjacent ridges. One or more circumferential lengths between circumferentially adjacent ridges may include lengths of 1 mm to 10 mm, 0 mm, and / or negative lengths of 1 mm to 10 mm, where negative lengths include overlaps of circumferential lengths between circumferentially adjacent ridges. One or more circumferential lengths between circumferentially adjacent ridges may include lengths of negative sizes equal to, longer than, shorter than, and / or opposite to the ridge height, ridge length, ridge width, and / or ridge height of one or more ridges in the array pattern. This pattern may include one or more circumferential lengths between circumferentially adjacent ridges where no ridges exist between them. This pattern may include one or more circumferential lengths between circumferentially adjacent ridges where there is an overlap of circumferential lengths between circumferentially adjacent ridges. One or more circumferential lengths between adjacent ridges in the circumferential direction may include the same circumferential length between each adjacent ridge, differ between adjacent ridges, and / or differ between adjacent ridges.

[0073] This pattern may include one or more circumferential lengths between longitudinally adjacent ridges. This pattern may include one or more circumferential lengths between longitudinally adjacent ridges where no ridges exist between them. This pattern may include one or more circumferential lengths between longitudinally adjacent ridges where there is an overlap in circumferential lengths between them. One or more circumferential lengths between longitudinally adjacent ridges may include the same circumferential length between each longitudinally adjacent ridge, differ between longitudinally adjacent ridges, and / or different circumferential lengths between each longitudinally adjacent ridge.

[0074] Ridges in a multi-ridge array may have the same ridge width, ridge length, ridge height, and / or one or more facets as each other ridge in the multi-ridge array. Ridges in a multi-ridge array may have different ridge width, ridge length, ridge height, and / or one or more facets as each other ridge in the multi-ridge array. Each ridge in a multi-ridge array may have different ridge width, ridge length, ridge height, and / or one or more facets as each other ridge in the multi-ridge array.

[0075] Figure 2N is a side view of another example of a turbulence-inducing structure 202n attached to the distal end of a catheter structure 12. The turbulence-inducing structure 202n includes a plurality of ridges 203n. The plurality of ridges 203n may be arranged along the distal end 22 of the catheter structure 12, and the arrangement may include a pattern. In this example, the arrangement includes a plurality of ridges 203n arranged in a pattern, where the pattern includes a counterclockwise spiral from proximal to distal. One of the plurality of ridges 203n includes a proximal-oriented facet, where the proximal-oriented facet is planar. Another of the plurality of ridges 203n includes a distal-oriented facet, where the distal-oriented facet is planar. Ridge 203n, one of a group of ridges 203n, contains multiple facets oriented perpendicular to the outer surface of the catheter structure, where these facets are convex facets. Ridge 203n, one of a group of ridges 203n, contains facets oriented perpendicular to the longitudinal axis of the catheter structure. Ridge 203n in an array of multiple ridges 203n contains the same ridge width, ridge length, ridge height, and one or more facets as each other ridge in the array. The multiple circumferential lengths between each ridge 203n in an array of multiple ridges 203n are positive values. The multiple longitudinal lengths between each ridge 203n in an array of multiple ridges 203n are positive values. The multiple circumferential lengths between adjacent ridges 203n in each circumferential direction are the same. The multiple circumferential lengths between adjacent ridges 203n in each longitudinal direction are the same. The lengths of multiple longitudinal sections between adjacent ridges 203n in each circumferential direction are the same.

[0076] The pump system 16 includes an infusion pump or injector (hereinafter collectively referred to as "pump") configured to take a fluid pharmaceutical composition containing a therapeutic agent from a storage container, supply a flow of the fluid pharmaceutical composition through the lumen 18 of the catheter structure 12, and dispense it into the patient's bloodstream through the opening 30 at the distal tip 23 of the catheter structure 12. The pump system 16 supplies a flow of the fluid pharmaceutical composition at any desired flow rate, for example, from about 0.01 mL / sec to about 10 mL / sec, or from about 0.1 mL / sec to about 5 mL / sec, or from about 1 mL / sec to about 3 mL / sec.

[0077] System 10 described herein can be used to inject any fluid pharmaceutical composition containing a therapeutic agent. System 10 is particularly useful for injecting fluid pharmaceutical compositions containing particles, such as particles suspended in a liquid, foam, or gel to be injected into a patient's vascular system. The particles may be of a size suitable for injection into a patient's blood vessels, for example, with a diameter of about 20 μm to about 1000 μm, 40 μm to about 1000 μm, 20 μm to about 40 μm, or about 10 μm to about 90 μm. The therapeutic agent particles may consist of an undissolved solid form of the therapeutic agent, or they may be beads or microsphere carriers containing the therapeutic agent. The beads or microspheres may contain the therapeutic agent internally or their external surface may be coated with the therapeutic agent. In some examples, the beads or microspheres have a diameter of about 20 μm to about 1000 μm, or about 40 μm to about 1000 μm, and the therapeutic agent is an embolizer. In another example, the beads or microspheres have a diameter of approximately 1 μm to 100 μm, and the therapeutic agent is a pharmacologically active drug. In yet another example, the beads or microspheres have a diameter of approximately 10 μm to 90 μm, and the therapeutic agent is a low-radioactive tracer, e.g., MAA. In yet another example, the beads or microspheres have a diameter of approximately 20 μm to 40 μm, and the therapeutic agent is a radioembolic agent, e.g., Y-90.

[0078] The therapeutic agent delivered using the system 10 described herein may be any pharmaceutically active agent suitable for local delivery to a target area of ​​the patient's body (e.g., any organ to which treatment with the therapeutic agent is desired). For example, such organs may include the pancreas, liver, kidneys, lungs, uterus, ovaries, cervix, prostate, head and neck tissues (jaw, gums), brain, adrenal glands, intestines or colon, breasts, thyroid gland, spleen, stomach, gallbladder, thymus, skin, bladder, lymphatic system, and various other organs or tissues suffering from tumors or other disease conditions that can be treated by local delivery of the therapeutic agent.

[0079] The therapeutic agents may be formulated into embolic agents (e.g., radioembolic agents or chemoembolic agents), contrast agents, Lipiodol, chemotherapeutic agents, immunotherapeutic agents, oncolytic viruses, gene therapies, cisplatin (or other alkylating agents), antibodies, checkpoint inhibitors, cytokines, oncolytic viruses, cancer vaccines, cytotoxic agents, branded embolic agents, combination therapies, growth factor inhibitors, nanoparticle encapsulation therapy, live cell therapy, and fluid pharmaceutical compositions, and may include any other therapeutic agents suitable for local injection.

[0080] In one example, the therapeutic agent is an embolizing agent (e.g., a radioembolic agent or a chemoembolic agent) contained within or coated on the outer surface of a bead or microsphere carrier. An example of a radioembolic agent is any activator that emits ionizing radiation to kill cells in a target area (e.g., a tumor to be treated), such as yttrium-90 (Y-90). An example of a chemoembolic agent is any chemotherapeutic agent that kills actively dividing cells, such as cancer cells, by disrupting their DNA, such as mitomycin, cisplatin, and doxorubicin. Embolizing agents are usually formulated into gel pharmaceutical compositions containing hydrogel-based polymers (e.g., gelatin, PVA, etc.) that can absorb the drug into their hydrated polymer network and then slowly release it into the tissue.

[0081] In another example, therapeutic agents include Toll-like receptor (TLR) agonists, particularly TLR9 agonists, and more specifically, type C TLR9 agonists.

[0082] Therapeutic agents may include synthetic CpG-oligonucleotides (CPG-ONDs) that mimic the immunostimulatory properties of microbial CpG-DNA. For example, oligonucleotides are oligodeoxynucleotides (ODNs). CpG-ODNs exist in several different classes, including Class A, Class B, Class C, Class P, and Class S, which share specific structural and functional characteristics. In this regard, Class A CPG-ODNs (or CPG-A ODNs) are associated with pDC maturation, have little effect on B cells, and induce the highest degree of IFNα production. Class B CPG-ODNs (or CPG-B ODNs) potently induce B cell proliferation and activate pDC and monocyte maturation, NK cell activation, and inflammatory cytokine production. Class C CPG-ODNs (or CPG-C ODNs) can induce B cell proliferation and IFN-α production. CPG-C ODN may be associated with the following attributes: (i) a non-methylated dinucleotide CpG motif, (ii) a juxtaposed CpG motif with adjacent nucleotides (e.g., AACGTTCGAA), (iii) a complete phosphorothioate (PS) backbone linking nucleotides (in contrast to the native phosphodiester (PO) backbone found in bacterial DNA), and (iv) a self-complementary palindromic sequence (e.g., AACGTT). In this regard, CPG-C ODN may bind to itself due to its palindromic nature, thereby forming double-stranded dimers (e.g., dimers) or hairpin structures.

[0083] In one example, the TLR9 agonist is CPG-OND. For example, the therapeutic agent comprises SD-101 or a pharmaceutically acceptable salt thereof (e.g., the sodium salt shown in Figure 3), as described in WO2022 / 066670 incorporated herein by reference. In particular, the therapeutic agent is SD-101 or a pharmaceutically acceptable salt thereof, or a derivative of SD-101 or a pharmaceutically acceptable salt thereof. Furthermore, in one example, the CPG-C ODN sequence may correspond to SEQ ID NO: 172, as described in whole in U.S. Patent No. 9,422,564, which is incorporated herein by reference.

[0084] In one example, the therapeutic agent includes a checkpoint inhibitor (CPI). The CPI may include a programmed cell death 1 receptor (PD-1) antagonist. The PD-1 antagonist may be a monoclonal antibody (mAb) or its antigen-binding fragment that specifically binds to PD-1 or PD-L1, preferably specifically to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In some examples, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred examples, the human constant region is IgG1 or IgG4 constant region. In some examples, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments. Furthermore, the PD-1 antagonist may be an immunoadhesive that specifically binds to PD-1 or PD-L1, preferably specifically to human PD-1 or human PD-L1, for example, a fusion protein in which the extracellular or PD-1 binding portion of PD-L1 or PD-L2 is fused to a constant region such as the Fc region of an immunoglobulin molecule. For example, the PD-1 antagonist may be nivolumab, pembrolizumab, semiprimab, relatrimab, or a combination thereof.

[0085] In one specific case, the therapeutic agent includes a TLR9 agonist or a combination of CPG-OND and CPI, as described above.

[0086] The invention described and claimed herein is not limited in scope by the specific embodiments disclosed herein, for these embodiments are intended to illustrate some aspects of the invention. Any equivalent embodiments are intended to fall within the scope of the invention. Indeed, in addition to those shown and described herein, various modifications of the invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All publications cited herein are incorporated in their entirety by reference.

Claims

1. An intravascular injection catheter for injecting therapeutic drugs into a patient's blood vessels, a) A catheter structure that extends from the distal end to the proximal end, has an outer surface and an inner surface, the inner surface defining a lumen through which the interior is penetrated, and includes an opening at the distal end that forms a continuous flow path with the lumen, b) A turbulence-inducing structure formed from or attached to the outer surface or distal tip of the catheter structure and configured to induce turbulence in the blood flowing through a local region of a blood vessel, A vascular injection catheter wherein the turbulence-inducing structure is configured not to completely occlude the blood vessel, so that blood can always flow through the turbulence-inducing structure.

2. The intravascular injection catheter according to claim 1, wherein the therapeutic agent is located inside the particles or coated on their surface.

3. The vascular injection catheter according to claim 1, wherein the catheter component is a single catheter.

4. The vascular injection catheter according to claim 1, wherein the catheter structure includes an outer catheter and an inner catheter, and is configured to deploy the turbulence-inducing structure by longitudinal displacement of the outer catheter relative to the inner catheter.

5. The intravascular injection catheter according to claim 1, wherein the therapeutic agent is a TLR9 agonist.

6. The intravascular injection catheter according to claim 5, wherein the TLR9 agonist is SD-101 or a pharmaceutically acceptable salt thereof.

7. The vascular injection catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure is attached to the distal tip of the catheter component.

8. The vascular injection catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure does not completely occlude the blood vessel so that blood can flow through the turbulence-inducing structure in a downstream or upstream direction.

9. The intravascular injection catheter according to any one of claims 1 to 6, wherein the induced turbulence provides a shear force that does not exceed the shear force for hemolysis of red blood cells.

10. The vascular infusion catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure includes a leading edge at the distal or proximal end of the catheter component that is substantially perpendicular to or obtuse with respect to the longitudinal axis of the catheter component.

11. The vascular injection catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure is spherical, cylindrical, conical, oval, ellipsoidal, or toroidal.

12. The intravascular injection catheter according to any one of claims 1 to 6, wherein the therapeutic agent is a radioembolic agent, and the therapeutic agent is contained within or coated on the particles.

13. The vascular injection catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure partially occludes the blood vessel so that blood can flow through the turbulence-inducing structure in a downstream or upstream direction.

14. The vascular injection catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure includes a plurality of arranged ridges.

15. The vascular injection catheter according to claim 14, wherein the arrangement includes a pattern, and the pattern includes a counterclockwise spiral from proximal to distal or a clockwise spiral from proximal to distal.

16. A system for intravenously injecting therapeutic drugs into a patient's blood vessels, A catheter structure extending from the distal end to the proximal end, having an outer surface and an inner surface, wherein the inner surface defines a lumen through which the interior is penetrated, and the catheter structure includes an opening at the distal end that forms a continuous flow path with the lumen, A turbulence-inducing structure is formed from or attached to the outer surface or distal tip of the catheter structure and is configured to induce turbulence in the blood flowing through a local region of a blood vessel. A handle is operably connected to the proximal end of the catheter component, which is made operable for manipulating the catheter component. A pump system fluidly connected to the proximal end of the catheter structure such that it forms a continuous flow path with the distal tip opening and the lumen, the pump system configured to dispense a fluid pharmaceutical composition containing the therapeutic agent from the pump system through the opening and the continuous flow path into the blood vessel, The turbulence-inducing structure is configured not to completely occlude the blood vessel so that blood can always flow through the turbulence-inducing structure.

17. The system according to claim 16, wherein the therapeutic agent is located inside the particles or coated on their surface.

18. The system according to claim 16, wherein the catheter component is a single catheter.

19. The system according to claim 16, wherein the catheter structure includes an outer catheter and an inner catheter, and is configured to deploy the turbulence-inducing structure by longitudinal displacement of the outer catheter from the inner catheter.

20. The system according to claim 16, wherein the therapeutic agent is a TLR9 agonist.

21. The system according to claim 16, wherein the TLR9 agonist is SD-101 or a pharmaceutically acceptable salt thereof.

22. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure is attached to the distal tip of the catheter component.

23. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure does not completely occlude the blood vessel so that blood can flow through the turbulence-inducing structure in a downstream or upstream direction.

24. The system according to any one of claims 16 to 21, wherein the induced turbulence provides a shear force that does not exceed the shear force for hemolysis of red blood cells.

25. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure includes a leading edge at the distal or proximal end of the catheter component that is substantially perpendicular to or obtuse with respect to the longitudinal axis of the catheter component.

26. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure is spherical, cylindrical, conical, oval, ellipsoidal, or toroidal.

27. The system according to any one of claims 16 to 21, wherein the therapeutic agent is a radioembolizer, and the therapeutic agent is contained within particles or coated on particles.

28. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure partially occludes the blood vessel so that blood can flow through the turbulence-inducing structure in a downstream or upstream direction.

29. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure includes a plurality of arranged ridges.

30. The system according to claim 29, wherein the arrangement includes a pattern, and the pattern includes a counterclockwise spiral from proximal to distal or a clockwise spiral from proximal to distal.

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