System and device for providing localized turbulence for delivering a medical embolizing agent

Abstract

A system or device for infusing a therapeutic agent to a blood vessel of a patient includes a catheter arrangement and a turbulence inducing structure. The catheter arrangement extends from a distal end to a proximal end, having an outer surface and an inner surface. The catheter arrangement includes an opening at a distal tip of the catheter arrangement in a continuous fluid passage having a lumen extending through the catheter arrangement defined by the inner surface. The turbulence inducing structure is formed by or attached to the outer surface of the catheter arrangement or the distal tip of the catheter arrangement. The turbulence inducing structure is configured to induce turbulence on blood flowing through a localized region of the blood vessel. The turbulence inducing structure is dimensioned and shaped appropriately to incompletely occlude the blood vessel such that the blood can flow through the turbulence inducing structure.

Description

W O 2 0 2 4 / 4 / 2 1 1 7 9 2 A 2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 10 October 2024 (10.10.2024) (10) International Publication Number WO 2024 / 211792 A2 WIPO PCT (51) International Patent Classification: A61M 25 / 00 (2006.01) (21) International Application Number: PCT / US2024 / 023382 (22) International Filing Date: 05 April 2024 (05.04.2024) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 63 / 457.730 06 April 2023 (06.04.2023) US (71) Applicant: TRISALUS LIFE SCIENCES, INC. [US / US]; 6272 West 91st Avenue, Westminster, CO 80031 (US). (72) Inventors: JAROCH, David; 7630 Barbara Ann Drive, Arvada, CO 80004 (US). COX, Bryan, F.; 3472 Big Sky Dr., Muscatine, IA 52761 (US). WEIGEL, Melody; 3783 N Franklin St, Denver, CO 80205 (US). (74) Agent: HATHERILL, Trenton; Haug Partners LLP, 745 Fifth Avenue, 10th Floor,New York, NY 10151 (US). (81) (84) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CV. CZ, DE, DJ. DK, DM. DO, DZ. EC. EE, EG. ES. FI., GB. GD. GE. GH. GM. GT. HN, HR, HU, ID, IL, IN. IO, IR, IS, IT, JM. JO, JP. KE, KG. KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS. ZA, ZM, ZW. Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, CV, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO,RS, SE. SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: without international search report and to be republished upon receipt of that report (Rule 48.2(g)) (54) Title: SYSTEM AND DEVICE FOR PROVIDING LOCALIZED TURBULENCE FOR DELIVERING A MEDICAL EM- BOLIZING AGENT (57) Abstract: A system or device for infusing a therapeutic agent to a blood vessel of a patient, comprising a catheter arrangement and a turbulence inducing structure. The catheter arrangement extends from a distal end to a proximal end having an outer surface and an interior surface. The catheter arrangement comprising an opening at a distal tip of the catheter arrangement in a continuous fluid pathway with a lumen extending through the catheter arrangement defined by the interior surface. The turbulence inducing structure is formed from or attached to the outer surface or the distal tip of the catheter arrangement. The turbulence inducing structure is configured toinduce turbulence to blood flowing through a localized region of the blood vessel. The turbulence inducing structure is suitably sized and shaped to not fully occlude the blood vessel such that the blood can flow past the turbulence inducing structure. 5 WO 2024 / 211792 PCT / US2024 / 023382 SYSTEM AND DEVICE FOR PROVIDING LOCALIZED TURBULENCE FOR DELIVERING A MEDICAL EMBOLIZING AGENT Inventors: David Jaroch, Bryan F. Cox, and Melody Weigel CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 457,730, filed April 6, 2023, which is hereby incorporated by reference in its entirety. 10 FIELD OF INVENTION

[0002] The present invention relates generally to an infusion catheter for delivering therapeutic agent, particularly an embolizing agent, to the blood stream of a patient. a 15 20 BACKGROUND OF INVENTION

[0003] Systemic infusion of therapeutic agents have been used to treat various diseases in patients. Theeffectiveness of such systemic delivery can vary based on a variety of different factors, such as, for example, concentrations needed to reach a therapeutic effect, toxicity of the therapeutic agent, and / or undesired effects. However, for some therapeutic agents, such as a radio- embolization agent, a chemotherapy agent, or a biologic agent having systemic toxicity, systemic delivery may have a detrimental effect to the patient and is therefore, not desirable. For example, systemic delivery of an embolizing agent can lead to non-targeted embolization, which can lead to adverse events and morbidity.

[0004] Non-targeted delivery of the embolic agent may have significant unwanted effects on the human body. For example, in liver treatment, non-targeted delivery of the embolic agent may 25 have undesirable impacts on other organs including the stomach and small intestine. In uterine fibroid treatment, the non-targeted delivery of the embolic agent may embolize one or both ovaries leading toloss of menstrual cycle, subtle ovarian damage that may reduce fertility, early onset of menopause, and in some cases, substantial damage to the ovaries. Other unintended adverse events include unilateral deep buttock pain, buttock necrosis, and uterine necrosis. In another example, 30 it may be desirable to deliver a chemotherapy agent locally to reduce systemic dose-limiting toxicity, while increasing localized concentration of the chemotherapy agent near the tumor treated to improve efficacy. 1 WO 2024 / 211792 PCT / US2024 / 023382 5 10

[0005] Localized delivery of the therapeutic agent may be accomplished by cannulizing a blood vessel in the vasculature near the target area (e.g., the tumor to be treated) with a catheter (e.g., a conventional end-hole microcatheter) and delivering a flow of a fluid pharmaceutical composition (e.g., a solution or a suspension) comprising the therapeutic agent through the catheter to the blood stream of the patient. For example, in the treatment of livertumors, the catheter is placed in the hepatic arterial vasculature and a flow of a fluid pharmaceutical composition (e.g., a solution or a suspension) comprising the therapeutic agent is delivered into the blood stream through the catheter. In another example, for the treatment of pancreatic tumors, the catheter is placed in the pancreatic arteries arising from the splenic artery or gastroduodenal artery for delivering a flow of a fluid pharmaceutical composition (e.g., a solution or a suspension) comprising the therapeutic agent into the blood stream through the catheter.

[0006] During localized vascular infusion, the therapeutic agent is delivered into a blood vessel of a patient through the catheter. A distal tip of the catheter is positioned within a lumen of the blood vessel and a flow of a fluid pharmaceutical composition (e.g., a solution or a suspension) 15 comprising the therapeutic agent is delivered through the catheter and into the lumen of the blood vessel. The bloodstream flows past the distal tip of the catheter when the catheter is in an operating configuration and inserted into the blood vessel. As the flow of the fluid pharmaceutical composition is infused into the blood vessel, the infused composition flows forward with the flow of the blood stream. 20

[0007] Blood flowing through blood vessels tend to flow in a laminar manner. Typically, when a therapeutic agent is infused using a conventional catheter, the laminar flow of the bloop stream remains undisrupted and the therapeutic will tend to travel down the path defined by the local regions of laminar flow. Regions of laminar flow within the blood vessel tend to follow defined paths downstream to specific sets of branches of the vasculature. Therefore, the position 25 of the catheter at the point of infusion can bias effectiveness of delivery of the therapeutic agent to a target area via blood vessels fed by the local stream of fluid in that laminar pathway.

[0008] A therapeutic agent maybe delivered in solution or as particles in suspension in a pharmaceutical formulation, such as, for example, a liquid, foam or gel that is infused into the vasculature of the patient. Particles of the therapeutic agent may be undissolved solid forms of an 30 embolizing agent (e.g., embolizing beads), or may be beads or microsphere carriers comprising a therapeutic agent (e.g., embolizing agent). The beads or microspheres may contain the therapeutic 2 WO 2024 / 211792 PCT / US2024 / 023382 5 agent (e.g., embolizing agent) within or may be coated with the therapeutic agent. Delivery of such particles of a therapeutic agent via a catheter (e.g., a conventional end-hole microcatheter) often depend on particle-fluid dynamics and catheter placement that do not provide consistent results. For example, when the catheter is placed within the laminar flow of the blood stream, there may be variable distribution of particles dependent upon the position of the device within that laminal flow stream. Asmall displacement of a distal tip of the catheter within this laminar flow can dramatically alter the downstream pathway the particles will take.

[0009] The fluid-particle dynamics for infusing a particulate formulation into the blood stream using a conventional end-hole microcatheter are not well characterized and can contribute to 10 unpredictability in the therapeutic dose actually delivered to the target area. For example, the target tissue may receive sub-therapeutic amounts or above therapeutic amounts of the particles as a result of the complex interplay between vascularization of the target tissue, particle-fluid dynamics and placement of the conventional end-hole microcatheter. Additionally, the particles may accumulate in non-targeted areas and damage tissue in the non-targeted areas (e.g., lungs), 15 particularly when the particles comprise an embolizing agent or a chemotherapy agent.

[0010] In particular, during radioembolization, a mapping procedure is typically performedto determine where a subsequent infusion of radioactive particles will most likely flow. Mapping is typically performed using a lightly radioactive tracer element attached to a sub-embolic protein complex (e.g., Tc-99m macro-aggregated albumin (MAA)). This tracer allows for a way to 20 measure distribution of particles without embolizing the blood vessel. This mapping also provides a safety indicator for the infusion, helping to determine if there is blood shunting to sensitive organs such as the lungs (lung shunt fraction). When a conventional end-hole microcatheter is placed within the laminar flow of the blood stream, there can be variable distribution of the radio- embolizing particles depending upon the position of the device within that laminal flow stream. A 25 small displacement of the tip of the conventional end-hole microcatheter within this flow can dramatically alter the downstream pathway the particles will take such that the therapy delivery may not match the mappingprocedure. Without guidance from the mapping procedure, there can be under or over treatment of tissue in the infusion zone and may result in unsafe amounts of therapeutics being shunted to non-target organs, such as the lungs. 3 W O 2 2 0 2 4 / 2 1 1 7 9 2 A З (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2024 / 211792 AЗ 10 October 2024 (10.10.2024) WIPO PCT (51) International Patent Classification: A61M 25 / 00 (2006.01) A61K 51 / 12 (2006.01) Dr., Muscatine, IA 52761 (US). WEIGEL, Melody; 3783 N Franklin St, Denver, CO 80205 (US). (21) International Application Number: PCT / US2024 / 023382 (74) Agent: HATHERILL, Trenton; Haug Partners LLP, 745 Fifth Avenue, 10th Floor, New York, NY 10151 (US). (22) International Filing Date: 05 April 2024 (05.04.2024) (25) Filing Language: English (26) Publication Language:English (30) Priority Data: 63 / 457,730 06 April 2023 (06.04.2023) US (71) Applicant: TRISALUS LIFE SCIENCES, INC. [US / US]; 6272 West 91st Avenue, Westminster, CO 80031 (US). (72) Inventors: JAROCH, David; 7630 Barbara Ann Drive. Arvada, CO 80004 (US). COX, Bryan, F.; 3472 Big Sky Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DМ, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO. RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV. SY, TH. TJ, TM, TN, TR, TT, TZ, UA, UG, US. UZ, VC, VN, WS. ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, CV, GH.GM, KE, LR, LS. MW. MZ, NA, RW. SC. SD. SL, ST. (81) (54) Title: SYSTEM AND DEVICE FOR PROVIDING LOCALIZED TURBULENCE FOR DELIVERING A MEDICAL EM- BOLIZING AGENT 10 22 14 15 12 S 30 18 23 Fig. 1 20 26 16 24 (57) Abstract: A system or device for infusing a therapeutic agent to a blood vessel of a patient, comprising a catheter arrangement and a turbulence inducing structure. The catheter arrangement extends from a distal end to a proximal end having an outer surface and an interior surface. The catheter arrangement comprising an opening at a distal tip of the catheter arrangement in a continuous fluid pathway with a lumen extending through the catheter arrangement defined by the interior surface. The turbulence inducing structure is formed from or attached to the outer surface or the distal tip of the catheter arrangement. The turbulence inducing structure is configured to induce turbulence to blood flowing through a localized region of the blood vessel. The turbulence inducingstructure is suitably sized and shaped to not fully occlude the blood vessel such that the blood can flow past the turbulence inducing structure. [Continued on next page] WO 2024 / 211792 A3 SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: - with international search report (Art. 21(3)) (88) Date of publication of the international search report: 26 December 2024 (26.12.2024) INTERNATIONAL SEARCH REPORT International application No. PCT / US2024 / 023382 A. CLASSIFICATION OF SUBJECT MATTER IPC - INV. A61M 25 / 00; A61K 51 / 12 (2024.01) ADD. CPC INV. A61M 25 / 0068; A61K 51 / 1282; A61M 25 / 0082 ADD. A61M 25 / 003; A61M 2025 / 0073; A61M 2206 / 20 According to International Patent Classification (IPC) or to both national classification and IPC B.FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) See Search History document Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched See Search History document Electronic database consulted during the international search (name of database and, where practicable, search terms used) See Search History document C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* ☑ Y Y Y Citation of document, with indication, where appropriate, of the relevant passages US 2011 / 0238039 A1 (LEONARD, ET AL) 29 September 2011; figures 3, 4, 8, 9, 11; paras

[0057] ,

[0059] ,

[0068] -

[0070] ,

[0072] ,

[0108] ,

[0122] ,

[0181] WO 2022 / 212690 A1 (TRISALUS LIFE SCIENCES, INC.) 06 October 2022; paras

[0086] ,

[0097] ,

[0098] US 2017 / 0095643 A1 (BOSTON SCIENTIFIC SCIMED, INC.) 06 April 2017; figure 2D; paras Relevant to claim No. 1-4, 7 / 1-4, 8 / 1-4, 10 / 1-4. 11 / 1-4, 13 / 1-4, 14 / 1-4, 16-19, 22 / 16-19,23 / 16-19, 25 / 16-19, 26 / 16-19, 28 / 16-19. 29 / 16-19 5, 6, 7 / 5-6, 8 / 5-6, 9,10 / 5-6, 11 / 5-6, 12. 13 / 5-6, 14 / 5-6, 15, 20. 21, 22 / 20-21, 23 / 20-21. 24, 25 / 20-21. 26 / 20-21. 27, 28 / 20-21, 29 / 20-21, 30 5, 6, 7 / 5-6, 8 / 5-6, 9 / 5-6, 10 / 5-6, 11 / 5-6, 12, 13 / 5-6, 14 / 5-6, 15 / 14 / 5-6, 20, 21. 22 / 20-21, 23 / 20-21, 24 / 20-21. 25 / 20-21. 26 / 20-21, 27, 28 / 20-2, 29 / 20-21, 30 / 29 / 20-21 9, 15, 24, 30 ☑ + Further documents are listed in the continuation of Box C. Special categories of cited documents: "A" document n defining the general state of the art which is not considered to be of particular relevance "D" document cited by the applicant in the international application "E" earlier application or patent but published on or after the international filing date "L" document which may throw doubts on priority claim(s) or whịch is cited to establish the publication date of another citation or other special reason (as specified) "O" document referring to an oral disclosure, use, exhibition or other means "P" documentpublished prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search 10 July 2024 (10.07.2024) Name and mailing address of the ISA / Mail Stop PCT, Attn: ISA / US, Commissioner for Patents P.O. Box 1450, Alexandria, Virginia 22313-1450 Facsimile No. 571-273-8300 Form PCT / ISA / 210 (second sheet) (July 2022) لم "י y" ☐☐ See patent family annex. later document published after the international filing date or priority date and not in conflict with the application but cited to understanddate and not in conflict with the application but the principle or theory underlying the invention document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is combined with one or more other suchdocuments, such combination combined with one or more documents suen docun being obvious to a person skilled in the art "&" document member of the same patent family Date of mailing of the international search report AUG 20 2024 Authorized officer Shane Thomas Telephone No. PCT Helpdesk: 571-272-4300 + INTERNATIONAL SEARCH REPORT International application No. PCT / US2024 / 023382 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

[0053] ,

[0068] Form PCT / ISA / 210 (continuation of second sheet) (July 2022) (19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480034393.X (22) Application Date 2024.04.05 (30) Priority Data 63 / 457,730 2023.04.06 US (85) PCT International Application Entering National Phase Date 2025.11.21 (86) PCT International Application Application Data PCT / US2024 / 023382 2024.04.05 (87) PCT International Application Publication Data WO2024 / 211792 EN 2024.10.10 (71) Applicant Teresa Life Sciences, Inc. Address Colorado, USA (72) Inventors D. Arlok B.F. Cox M. Wiegand (74) Patent Agency Zhong Lun Law Firm, Beijing 11410 Patent Attorney Wang Yixun (51) Int.Cl. A61M 25 / 00 (2006.01) A61K51 / 12 (2006.01) (54) Title of Invention System and Apparatus for Providing Local Turbulence to Deliver Medical Embolizing Agents (57) Abstract A system or apparatus for infusing a therapeutic agent into a patient's blood vessel, comprising a catheter arrangement and a turbulence-inducing structure. The catheter arrangement extends from a distal end to a proximal end and has an outer surface and an inner surface. The catheter arrangement includes an opening at a distal tip of the catheter arrangement in a continuous fluid passage having a lumen extending through the catheter arrangement and defined by the inner surface. The turbulence-inducing structure is formed by or attached to the outer surface or the distal tip of the catheter arrangement. The turbulence-inducing structure is configured to induce turbulence in blood flowing through a local area of ​​the blood vessel. The size and shape of the turbulence-inducing structure are suitably designed to not completely obstruct the blood vessel, allowing blood to flow through the turbulence-inducing structure. Claims 2 pages, Description 14 pages, Drawings 7 pages, CN 121568740 A 2026.02.24 CN 1 21 56 87 40 A 1. A vascular infusion catheter for infusing a therapeutic agent into a patient's blood vessel, the vascular infusion catheter comprising: a catheter arrangement extending from a distal end to a proximal end, having an outer surface and an inner surface, the inner surface defining a lumen through the inner surface, the catheter arrangement including an opening at a distal tip of the catheter arrangement in a continuous fluid passage having the lumen; and a turbulence-inducing structure formed by or attached to the outer surface or the distal tip of the catheter arrangement, the turbulence-inducing structure being configured to induce turbulence in blood flowing through a local region of the blood vessel, wherein the turbulence-inducing structure is configured not to completely obstruct the blood vessel, such that the blood can always flow through the turbulence-inducing structure. 2. The vascular infusion catheter of claim 1, wherein the therapeutic agent is within the particle or coated on the surface of the particle. 3. The vascular infusion catheter of claim 1, wherein the catheter arrangement is a single catheter. 4. The vascular infusion catheter of claim 1, wherein the catheter arrangement comprises an outer catheter and an inner catheter configured to deploy the turbulence-inducing structure by longitudinal displacement of the outer catheter relative to the inner catheter. 5. The vascular infusion catheter of claim 1, wherein the therapeutic agent is a TLR9 agonist. 6. The vascular infusion catheter of claim 5, wherein the TLR9 agonist is SD-101 or a pharmaceutically acceptable salt thereof. 7. The vascular infusion catheter of any one of claims 1 to 6, wherein the turbulence-inducing feature is attached to the distal tip of the catheter arrangement.8. The vascular infusion catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure does not completely obstruct the blood vessel, allowing blood to flow through the turbulence-inducing structure in a downstream or upstream direction. 9. The vascular infusion catheter according to any one of claims 1 to 6, wherein the induced turbulence provides shear force, the shear force not exceeding the shear force used for lysing 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 that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the catheter arrangement at the distal or proximal end of the catheter arrangement. 11. The vascular infusion catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure is spherical, cylindrical, conical, oval, ellipsoidal, or annular in shape. 12. The vascular infusion catheter according to any one of claims 1 to 6, wherein the therapeutic agent is a radioembolic agent, the therapeutic agent being contained within or coated onto a particle. 13. The vascular infusion catheter of any one of claims 1 to 6, wherein the turbulence-inducing structure partially obstructs the blood vessel, allowing blood to flow through the turbulence-inducing structure in a downstream or upstream direction. 14. The vascular infusion catheter of any one of claims 1 to 6, wherein the turbulence-inducing structure comprises a plurality of ridges arranged in an array. 15. The vascular infusion catheter of claim 14, wherein the array comprises a pattern, and wherein the pattern comprises a proximal-to-distal counterclockwise spiral or a proximal-to-distal clockwise spiral. 16. A system for vascular infusion of a therapeutic agent into a patient's blood vessel, the system comprising: a catheter arrangement extending from a distal end to a proximal end, having an outer surface and an inner surface, the inner surface defining a lumen through the inner surface, the catheter arrangement including an opening at a distal tip of the catheter arrangement in a continuous fluid pathway having the lumen; and a turbulence-inducing structure formed by or attached to the outer surface or the distal tip of the catheter arrangement, the turbulence-inducing structure being configured to induce turbulence in blood flowing downstream through a local region of the blood vessel; A handle operably connected to the proximal end of the catheter arrangement, enabling manipulation of the handle to manipulate the catheter arrangement; and a pump system fluidly connected to the proximal end of the catheter arrangement in a continuous fluid passage having the opening and the lumen at the distal tip, the pump system being configured to dispense a flow of a fluid pharmaceutical composition containing the therapeutic agent from the pump system through the continuous fluid passage via the opening to the blood vessel.17. The system of claim 16, wherein the therapeutic agent is within the particle or coated on the surface of the particle. 18. The system of claim 16, wherein the catheter arrangement is a single catheter. 19. The system of claim 16, wherein the catheter arrangement comprises an outer catheter and an inner catheter, configured to deploy the turbulence-inducing structure by longitudinal displacement of the outer catheter relative to the inner catheter. 20. The system of claim 16, wherein the therapeutic agent is a TLR9 agonist. 21. The system of claim 16, wherein the TLR9 agonist is SD-101 or a pharmaceutically acceptable salt thereof. 22. The system of any one of claims 16 to 21, wherein the turbulence-inducing feature is attached to the distal tip of the catheter arrangement. 23. The system of any one of claims 16 to 21, wherein the turbulence-inducing structure does not completely obstruct the blood vessel, allowing blood to flow through the turbulence-inducing structure in a downstream or upstream direction. 24. The system of any one of claims 16 to 21, wherein the induced turbulence provides shear force that does not exceed the shear force used for lysing red blood cells. 25. The system of any one of claims 16 to 21, wherein the turbulence-inducing structure includes a leading edge that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the catheter arrangement at the distal or proximal end of the catheter arrangement. 26. The system of any one of claims 16 to 21, wherein the turbulence-inducing structure is spherical, cylindrical, conical, oval, ellipsoidal, or annular in shape. 27. The system of any one of claims 16 to 21, wherein the therapeutic agent is a radioembolic agent contained within or coated onto a particle. 28. The system of any one of claims 16 to 21, wherein the turbulence-inducing structure partially obstructs the blood vessel, allowing blood to flow through the turbulence-inducing structure in a downstream or upstream direction. 29. The system of any one of claims 16 to 21, wherein the turbulence-inducing structure includes a plurality of ridges arranged in an array. 30. The system of claim 29, wherein the array comprises a pattern, and wherein the pattern comprises a proximal-to-distal counterclockwise spiral or a proximal-to-distal clockwise spiral. Claims 2 / 2 pages 3 CN 121568740 A System and apparatus for providing localized turbulence to deliver medical embolic agents

[0001] Inventors: David Jaroch, Bryan F. Cox, and Melody Weigel Technical Field

[0002] This invention generally relates to an infusion catheter for delivering therapeutic agents, particularly embolic agents, into the bloodstream of a patient. Background Art

[0003] Systemic infusion of therapeutic agents has been used to treat a variety of diseases in patients. The effectiveness of such systemic delivery can vary based on a variety of different factors, such as, for example, 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 radioembolic agents, chemotherapeutic agents, or biological agents with systemic toxicity, systemic delivery may have adverse effects on the patient and is therefore undesirable. For example, systemic delivery of embolic agents may lead to off-target embolization, which may result in adverse events and morbidity.

[0004] Off-target delivery of embolic agents can have significant undesirable effects on the human body. For example, in liver treatment, off-target delivery of embolic agents may have undesirable effects on other organs, including the stomach and small intestine. In the treatment of uterine fibroids, off-target delivery of embolic agents may embolize one or both ovaries, leading to menstrual cycle disorders, minor ovarian damage that may reduce fertility, premature menopause, and in some cases, serious damage to the ovaries. Other unintended adverse events include unilateral deep hip pain, hip necrosis, and uterine necrosis. In another instance, local delivery of the chemotherapeutic agent may be desired to reduce systemic dose-limiting toxicity while increasing the local concentration of the chemotherapeutic agent near the treated tumor to improve efficacy.

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

[0006] During local vascular infusion, a therapeutic agent is delivered through a catheter into the patient's blood vessel. The distal tip of the catheter is positioned within the lumen of the blood vessel, and a fluid pharmaceutical composition (e.g., a solution or suspension) containing the therapeutic agent is delivered through the catheter and into the lumen of the blood vessel. When the catheter is in its working configuration and inserted into the blood vessel, blood flows through the distal tip of the catheter. As the fluid pharmaceutical composition is infused into the blood vessel, the infused composition flows forward with the flow of blood.

[0007] Blood flowing through a blood vessel tends to flow in a laminar manner. Typically, when using a conventional catheter for infusion of treatment, the instructions for use are as described on page 1 / 14 of CN 121568740 A.During administration, the laminar flow of blood remains undisturbed, and the therapeutic agent will tend to travel along a path defined by a localized region of laminar flow. Regions of laminar flow within a vessel tend to travel downstream along defined paths to specific branches of the vascular system. Therefore, the location of the catheter at the infusion point can deviate the effectiveness of therapeutic agent delivery via a vessel supplied by a localized fluid flow within that laminar flow pathway.

[0008] The therapeutic agent can be delivered as a solution or as suspended particles in a pharmaceutical formulation, such as, for example, a liquid, foam, or gel infused into a patient's vascular system. The particles of the therapeutic agent can be embolic agents in the form of insoluble solids (e.g., embolic beads), or can be bead or microsphere carriers containing a therapeutic agent (e.g., an embolic agent). Beads or microspheres may contain a therapeutic agent (e.g., an embolic agent) internally or may be coated with a therapeutic agent. Delivery of such particles of the therapeutic agent via a catheter (e.g., a conventional end-hole microcatheter) often depends on particle-hydrodynamics and catheter placement that do not provide consistent results. For example, when a catheter is placed within a laminar flow of blood, variable particle distribution may exist depending on the device's position within that laminar flow. Even minute displacement of the distal tip of the catheter within this laminar flow can significantly alter the downstream pathway the particles will take.

[0009] The fluid-particle dynamics of infusing particulate formulations into the bloodstream using conventional end-hole microcatheters are not well characterized and may contribute to unpredictability of the therapeutic dose actually delivered to the target area. For example, the target tissue may receive either a lower or higher dose of particles due to the complex interactions between the vascular distribution of the target tissue, particle-fluid dynamics, and the placement of conventional end-hole microcatheters. Additionally, particles may accumulate in non-target areas and damage tissue in non-target areas (e.g., the lungs), particularly when the particles contain embolic or chemotherapeutic agents.

[0010] In particular, during radioembolization, mapping procedures are typically performed to determine where subsequent infusions of radioactive particles are most likely to flow. Mapping is typically performed using weakly radioactive tracer elements attached to subembolic protein complexes (e.g., Tc-99m macroalbumin (MAA)). This tracer enables the measurement of particle distribution without embolizing blood vessels. The mapping also provides a safety indicator for infusion, helping to determine whether there is blood shunting to sensitive organs such as the lungs (pulmonary shunting fraction). When a conventional end-hole microcatheter is placed within a laminar flow of blood, there may be a variable distribution of radioembolic particles depending on the device's position within that laminar flow. Even minute displacement of the tip of a conventional end-hole microcatheter in this flow can significantly alter the downstream pathway the particles will take, potentially causing treatment delivery to be mismatched with the mapping procedure. Without guidance from the mapping procedure, there may be insufficient or excessive treatment of tissue in the infusion area, potentially leading to unsafe amounts of therapeutic agent being shunted to non-target organs, such as the lungs.

[0011] Therefore, there remains a need for more predictable and safer methods to locally infuse therapeutic agents into blood vessels and deliver them to nearby target areas via the vascular system. Summary of the Invention

[0012] This application relates to a vascular infusion catheter for infusing a therapeutic agent into a patient's blood vessels. In some instances, the therapeutic agent is contained within or coated on the surface of particles. For example, the therapeutic agent may be a radioembolic agent, contained within or coated on microspheres. The vascular infusion catheter includes a catheter arrangement having an outer surface and an inner surface extending from a distal end to a proximal end. The inner surface defines a lumen through the catheter arrangement. In another instance, the catheter arrangement is a single catheter. Alternatively, the catheter arrangement includes an outer catheter and an inner catheter configured to deploy a turbulence-inducing structure by longitudinal displacement of the outer catheter relative to the inner catheter. The catheter arrangement includes an opening at the distal tip of the catheter arrangement in a continuous fluid passage having the lumen. The turbulence-inducing structure is formed by or attached to the outer surface or distal tip of the catheter arrangement. In some instances, the turbulence-inducing feature is attached to the distal tip of the catheter arrangement. This turbulence-inducing structure is configured to induce turbulence in blood flowing through a localized area of ​​the vessel. In some instances, the induced turbulence provides shear forces that do not exceed the shear forces used to lyse red blood cells. The turbulence-inducing structure is also configured to not completely obstruct the vessel, allowing blood to always flow through it. In some instances, the turbulence-inducing structure does not completely obstruct the vessel, allowing blood to flow through it in a downstream or upstream direction. In some instances, the turbulence-inducing structure includes a leading edge that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the catheter arrangement at the distal or proximal end. The turbulence-inducing structure can be spherical, cylindrical, conical, oval, ellipsoidal, or annular in shape. In some instances, the turbulence-inducing structure partially obstructs the blood vessel, allowing blood to flow through the turbulence-inducing structure in a downstream or upstream direction. In some instances, the turbulence-inducing structure includes a plurality of ridges arranged in an array. The array may include a pattern, and wherein the pattern includes a proximal-to-distal counterclockwise spiral or a proximal-to-distal clockwise spiral.

[0013] These and other aspects of the invention will become clear to those skilled in the art after reading the following detailed description of the invention (including the accompanying drawings and appended claims). Brief Description of the Drawings

[0014] Other objects, features, and advantages of the present disclosure will become clear from the following detailed description, taken in conjunction with the accompanying drawings illustrating illustrative embodiments of the present disclosure.

[0015] FIG1 illustrates an exemplary delivery system for vascular infusion of a therapeutic agent in a blood vessel according to an embodiment of the present application.

[0016] FIG2A shows a front view of the distal end of an exemplary turbulence-inducing structure according to an embodiment of the present application.

[0017] FIG2B shows a side view of an exemplary turbulence-inducing structure having a spherical shape according to an embodiment of the present application.

[0018] FIG2C shows a side view of an exemplary turbulence-inducing structure having a leading edge that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the catheter arrangement at its distal end.

[0019] FIG2D shows a side view of an exemplary turbulence-inducing structure having a leading edge that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the catheter arrangement at its proximal end.

[0020] FIG2E shows a side view of an exemplary turbulence-inducing structure having a sharper bend at its distal end than at its proximal end.

[0021] FIG2F provides a side view of the distal portion of a catheter arrangement and an exemplary turbulence-inducing structure having a cylindrical shape according to an embodiment of the present application.

[0022] FIG2G provides a side view of the distal portion of a catheter arrangement according to an embodiment of the present application and an exemplary turbulence-inducing structure having an inner surface, the inner surface including a first portion parallel to the outer surface of the catheter arrangement and a second portion extending away from the outer surface of the catheter arrangement.

[0023] FIG2H provides a side view of the distal portion of a catheter arrangement according to an embodiment of the present application and an exemplary turbulence-inducing structure having a ring-shaped form.

[0024] FIG2I provides a side view of the distal portion of a catheter arrangement according to an embodiment of the present application and an exemplary turbulence-inducing structure attached to the distal tip of the catheter arrangement.

[0025] FIG2J provides a side view of the distal portion of a catheter arrangement according to an embodiment of the present application and an exemplary turbulence-inducing structure formed at the distal tip of the catheter arrangement.

[0026] FIG2K provides a side view of the distal portion of a catheter arrangement according to an embodiment of the present application and an exemplary turbulence-inducing structure formed at the distal tip of the catheter arrangement.

[0027] FIG2L provides a side view of another example of a turbulence-inducing structure formed at the distal end of a catheter arrangement. Specification 3 / 14 pages 6 CN 121568740 A

[0028] FIG2M provides a side view of yet another example of a turbulence-inducing structure attached to the distal end of a catheter arrangement.

[0029] FIG2N provides a side view of yet another example of a turbulence-inducing structure attached to the distal end of a catheter arrangement.

[0030] FIG3 shows the chemical structure of the sodium salt of SD-101. Detailed Description

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Additionally, some terms used herein have the meanings as described in the specification.The meaning set forth herein. All patents, published patent applications and publications cited herein are incorporated by reference as if fully set forth herein. It should be noted that, unless the context clearly requires otherwise, the singular forms “a,” “an,” and “the” as used herein and in the appended claims include plural references.

[0032] Throughout this specification and the appended claims, unless the context requires otherwise, the word “comprise” and its variations (such as “comprises” and “comprising”) should be understood to imply inclusion of the integer or step or a group of integers or steps, but not to exclude any other integer or step or a group of integers or steps. When used herein, the term “comprising” may be replaced by the terms “containing” or “including,” or sometimes by the term “having” as used herein.

[0033] As used herein, the connecting term “and / or” between a plurality of enumerated elements is understood to cover both individual options and combined options. For example, where two elements are linked by "and / or", the first option refers to the applicability of the first element in the absence of the second element. The second option refers to the applicability of the second element in the absence of the first element. The third option refers to the applicability of the first and second elements together. Any of these options is understood to fall within this meaning and therefore satisfies the requirement of the term "and / or" as used herein. The coexistence of more than one option is also understood to fall within this meaning and therefore satisfies the requirement of the term "and / or".

[0034] As used herein, the terms "subject" or "patient" refer to an animal, preferably a mammal. According to a particular embodiment, 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 a particular embodiment, 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 in relation to the device and system described herein. The term “proximal” is closer to the user’s hand, and the term “distal” is further away from the user’s hand, such as when it is often located deeper inside the patient’s body during use.

[0036] This application provides a device comprising a catheter for infusing a therapeutic agent into a patient’s blood vessel and a structure located at or near the distal end of the catheter for inducing turbulence within the blood vessel as the therapeutic agent flow is infused into the blood flow. The blood flow is laminar before flowing through the distal end of the catheter. As the blood flow passes through the structure located at or near the distal end of the catheter,This structure induces local turbulence in the blood flow. When a therapeutic agent is infused into the blood flow from the distal tip of the catheter, the local turbulence includes eddies that mix the therapeutic agent with the blood flow passing through the distal end of the catheter. This local turbulence improves the distribution of the therapeutic agent within the blood flow (compared to laminar blood flow passing through the distal end of the catheter) as the blood returns to laminar flow downstream of the catheter location and enters the vascular pathway for delivery to tissue in the target area for treatment (e.g., the tumor to be treated). It is believed that this local turbulence can provide more consistent delivery of the therapeutic agent to the target area (compared to laminar blood flow passing through the distal end of the catheter).

[0037] Figure 1 illustrates an exemplary delivery system 10 for vascular infusion of a therapeutic agent in a blood vessel. The delivery system 10 includes a catheter arrangement 12, a turbulence-inducing structure 14, and a pump system 16. The system 10 is sized and shaped appropriately to infuse the therapeutic agent to the target area via an artery or vein. Specifically, the dimensions and shapes of the catheter arrangement 12 and the turbulence-inducing structure 14 (see page 4 / 14 of the specification, CN 121568740 A) are suitably designed for slidable insertion into a blood vessel (when the turbulence-inducing structure 14 is in its deployed configuration and operating within the blood vessel). The blood vessel comprises a lumen with a diameter of about 2 µm to about 10,000 µm, defined by the cellular walls of the vessel. The blood vessel can be located in any organ desired to be treated with a therapeutic agent. For example, organs can be pancreas, liver, kidney, lung, uterus, ovary, cervix, prostate, head and neck tissues (jaw, gums), brain, adrenal glands, intestine or colon, breast, thyroid gland, spleen, stomach, gallbladder, thymus, skin, bladder, lymphatic system, and many other organs or tissues subject to local delivery of a therapeutic agent for treatment of tumors or other disease states. The blood vessel may have a diameter larger than the size of a red blood cell and less than about 5 cm, less than about 4 cm, less than about 3 cm, less than about 2 cm, less than about 1 cm, less than about 10 mm, less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, or less than about 5 mm. The blood vessel may have a diameter of about 8 µm to about 5 cm, or about 10 µm to about 3 cm. In particular, the blood vessel may be a hepatic artery. The blood vessel may have a diameter of about 8 µm to about 10 mm, about 10 µm to about 9 mm, or about 1 mm to about 6 mm. In another example, the blood vessel may be a pancreatic artery originating from the splenic artery or the gastroduodenal artery. The blood vessel may have a diameter of 8 µm to about 1 cm, about 10 µm to about 6 mm, or about 1 mm to about 5 mm. In one example, the size and shape of the catheter arrangement 12 and the turbulence-inducing structure 14 are suitably designed to have a diameter smaller than the diameter of the lumen defined by the cellular wall of the blood vessel (in which it unfolds). System 10 and its use therein to prevent, reduce, or minimize the systemic circulation of therapeutic agents.

[0038] The catheter arrangement 12 has a proximal end 20, a distal end 22, and a lumen 18 extending between its proximal and distal ends 20, 22. The lumen 18 is defined by an inner surface of the catheter arrangement. A turbulence-inducing structure 14 is attached to or part of the catheter arrangement 12 at or near the distal end 22. The proximal end 22 of the catheter arrangement 12 is operatively connected to a handle 24, such that manipulation of the handle 24 manipulates the catheter arrangement 12. The handle 24 is configured externally for manual manipulation while the catheter arrangement 12 is within the patient's vascular system. The handle 24 also includes a fluid passage 26 extending between a pump system 16 and the lumen 18 of the catheter arrangement. The pump system 16 is fluidly connected to the proximal end 20 via the fluid passage 26 of the handle 24, such that a continuous fluid passage extends from the pump system 16 through the fluid passage 26 and the lumen 18 to an opening 30 at the distal end 22 of the catheter arrangement 12. An opening 30 at the distal tip 23 of the catheter arrangement 12 is configured to distribute a flow of therapeutic agent from the pump system 16 into the patient's blood flow when the catheter arrangement 12 is deployed in the patient's blood vessel.

[0039] A turbulence-inducing structure 14 is configured to induce turbulence within the blood vessel located at or adjacent to the distal end 22 of the catheter arrangement 12 when the therapeutic agent flow is infused into the blood flow. When the delivery system 10 is deployed into the patient's vascular system and the catheter arrangement 12 is positioned within the blood vessel, the turbulence-inducing structure 14 does not completely obstruct the blood vessel, such that when the turbulence-inducing structure 14 is in the deployed configuration (i.e., when the turbulence-inducing structure is not retracted or compressed to advance the distal end 22 of the catheter arrangement 12 into place, and the turbulence-inducing structure 14 is deployed at the desired location in the blood vessel to induce turbulence in the blood flow), blood can always flow through the turbulence-inducing structure 14. In another example, when the delivery system 10 is deployed into the patient's vascular system and the catheter 12 is positioned within the vessel, the turbulence-inducing structure 14 does not completely obstruct the vessel, allowing blood to flow downstream (i.e., proximal to distal) and / or upstream (i.e., distal to proximal) of the turbulence-inducing structure 14.

[0040] As blood flows through the turbulence-inducing structure 14, the turbulence of the blood flow in a localized region near the turbulence-inducing structure 14 is enhanced. After the blood flow moves further downstream from the turbulence-inducing structure 14, the turbulence of the blood flow decreases and the flow returns to laminar flow. The localized region of enhanced turbulence located at or near the turbulence-inducing structure 14 may extend downstream from the turbulence-inducing structure 14 by a length approximately 0.1 to approximately 5 times the diameter of the vessel in which the system 10 is deployed. For example, the length may be approximately 0.1 mm to approximately 30 mm.

[0041] When blood flows into a localized area, the turbulence-inducing structure 14 induces localized turbulence or eddies in the blood flow. This occurs when the fluid drug composition containing the therapeutic agent exits from the opening 30 at the distal end 22 of the catheter arrangement and is infused into the bloodstream.At this time, the enhanced turbulence in the local area mixes the fluid drug composition with the blood flow passing through the local area to improve the distribution of the drug in the blood flow (compared to laminar blood flow through the distal end of the catheter). The blood returns to laminar flow downstream of the local area and continues to flow in the vascular pathway for delivery to the target area for treatment (e.g., the tumor to be treated).

[0042] The turbulence-inducing structure 14 can have any suitable size and shape to enhance turbulence in the local area. For example, the turbulence-inducing structure 14 can increase the Reynolds number of blood flow in the blood vessel from below 2300 to above 2900 in the local area. 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 the blood flow in the local area 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] While the turbulence-inducing structure 14 can enhance turbulence in the local area, it should be understood that the enhancement of turbulence also increases the shear force of the blood flow. In order to make the turbulence-inducing structure 14 suitable for use in blood vessels, the level of turbulence induced by the turbulence-inducing structure 14 is limited to producing turbulence with shear forces smaller than those used for lysing cells (especially red blood cells). Specifically, the turbulence level induced by the turbulence-inducing structure 14 is limited to turbulence that produces shear forces smaller than those that damage or kill cells (especially red blood cells). For example, the maximum shear force produced by the turbulence may be about 60 dyn / cm2 or about 400 N / m2. The turbulence level induced by the turbulence-inducing structure 14 produces shear forces of about 20 dyn / cm2 to about 60 dyn / cm2.

[0044] In some instances, the turbulence-inducing structure 14 includes one or more radially arranged structures that displace the lumen 18 of the catheter arrangement 12 away from the vessel wall of the blood vessel into which the catheter arrangement 12 is inserted. When deployed, the turbulence-inducing structure 14 can push the outer surface 15 of the catheter arrangement 12 away from the vessel wall, such that the opening 30 of the catheter arrangement 14 is positioned more centrally within the blood vessel (e.g., closer to the longitudinal axis of the blood vessel). Even under laminar flow conditions, the pathway in the central portion of the blood cavity tends to distribute the flow of the fluid drug composition most uniformly compared to infusion from a location further away from the longitudinal axis of the vessel. The closer to the vessel wall, the more likely particles are to be preferentially and unevenly carried along in the laminar flow path.

[0045] In one example, the turbulence-inducing structure 14 may be located at the distal end 22 and the outer surface 15 of the catheter arrangement 12.Attached Structure. Specifically, the turbulence-inducing structure 14 may extend radially away from the longitudinal axis of the catheter arrangement and / or surround a portion or all of the distal end 22 of the catheter arrangement 12. As shown in FIG2A, the turbulence-inducing structure 202 may include an inner surface 102 and an outer surface 104, the inner surface defining an opening 103 for receiving the catheter arrangement 12 passing through it. The inner surface 102 of the turbulence-inducing structure 14 may be attached to the outer surface of the catheter arrangement 12. In some instances, the turbulence-inducing structure is integrally formed (e.g., molded) on the outer surface 15 of the catheter arrangement 12. In another instance, the turbulence-inducing structure 12 may include multiple components, such as, for example, grooved elements, fins, etc., attached to the outer surface 15 of the catheter arrangement. The turbulence-inducing structure 14 may be a rigid, collapsible, or compressible structure attached to the outer surface 15 of the catheter arrangement 12.

[0046] The collapsible structure can be formed of any suitable elastic material for medical use, such as, for example, shape memory materials, such as shape memory metals (e.g., nitinol), or shape memory medical-grade elastomers. In another example, the collapsible structure is an inflatable structure, such as, for example, a balloon (e.g., a fluid or air-inflatable balloon), a self-expanding or manually inflatable filter, or a mechanically inflatable Marico wing structure. For example, the collapsible structure may be a fluid or air-inflatable balloon. The collapsible structure is fluidly connected to a secondary lumen for filling the collapsible structure with fluid or air to inflate it. The secondary lumen used to fill the collapsible structure may be part of the catheter arrangement 12 or may be part of a separate catheter.

[0047] The collapsible structure can be in a collapsible configuration when the catheter arrangement 12 is being advanced into the working position within the blood vessel, and in an expanded configuration when the distal end 22 of the catheter arrangement 12 is in the desired position for infusing a fluid pharmaceutical composition containing a therapeutic agent (see page 6 / 14 of the specification, CN 121568740 A). The collapsible configuration has a reduced diameter for advancement into the desired working position within the blood vessel. The expanded configuration has a larger diameter than the collapsible configuration, wherein the collapsible structure expands into the expanded configuration to induce turbulence within the blood flow.

[0048] The compressible structure can be any elastomeric structure that can be compressed to reduce the size of the structure in a compressed configuration and subsequently released into an expanded configuration. The compressible structure can be formed, for example, from an elastomeric foam, such that the structure can be compressed when pressure is applied to the foam and returns to the original shape of the structure when pressure is removed from the structure. The compressible structure can be in a compressed configuration when the catheter arrangement 12 is being advanced into the intravascular working position, and in an expanded configuration when the distal end 22 of the catheter arrangement 12 is in the desired position for infusing a fluid pharmaceutical composition containing a therapeutic agent (e.g., when pressure is removed from the structure). The compressed configuration has a reduced diameter for advancement into the desired intravascular working position.The expanded configuration has a larger diameter than the compressed configuration, wherein the compressed structure expands into the expanded configuration to induce turbulence within the blood flow.

[0049] For example, the turbulence-inducing structure 14 includes a plurality of protrusions (not shown) extending from the outer surface 15 of the catheter arrangement. The protrusions can increase resistance to blood flow and induce the formation of eddies. The protrusions can be rigid structures or can be collapsible or compressible, wherein the protrusions are in a collapsible or compressed configuration when the catheter arrangement 12 is being advanced to the working position within the blood vessel, and in an expanded configuration when the distal end 22 of the catheter arrangement 12 is in the desired position for infusing a fluid pharmaceutical composition containing a therapeutic agent.

[0050] In some instances, the outer surface 104 of the turbulence-inducing structure 202 may have a curved shape. The turbulence-inducing structure 202 has a distal end 203 and a proximal end 204. The turbulence-inducing structure 202, when in use, is positioned such that the flow moves through the turbulence-inducing structure in a direction from the proximal end 204 to the distal end 203. Therefore, the turbulence-inducing structure 202 can 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 provides a side view of an example of a turbulence-inducing structure 202b with a spherical shape and its effect on enhancing turbulence in a flow moving through it in a direction from the proximal end 204 to the distal end 203.

[0052] Figure 2C shows a side view of an exemplary turbulence-inducing structure and its effect on enhancing turbulence in a flow moving through it in a direction from the proximal end 204 to the distal end 203, the exemplary turbulence-inducing structure having a leading edge that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the duct arrangement at the distal end 203.

[0053] FIG2D shows a side view of an exemplary turbulence-inducing structure and its effect on enhancing turbulence of a flow moving in the direction from the proximal end 204 to the distal end 203. This exemplary turbulence-inducing structure has a leading edge that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the catheter arrangement at the proximal end 204.

[0054] FIG2E provides a side view of another example of a turbulence-inducing structure 202e having a sharper bend at the distal end 203 than at the proximal end 204 and its effect on enhancing turbulence of a flow moving in the direction from the proximal end 204 to the distal end 203.

[0055] FIG2F provides a side view of another example of a turbulence-inducing structure 202f attached to the distal end 22 of the catheter arrangement 12. In this example, the turbulence-inducing structure 202f has a cylindrical shape and surrounds the distal end 22 of the catheter arrangement.

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

[0057] FIG2H provides a side view of yet another example of a turbulence-inducing structure 202h attached to the distal end 22 of the catheter arrangement 12. In this example, the turbulence-inducing structure 202h is torus-shaped (e.g., donut-shaped, also called toroidal) which defines an opening for receiving the catheter arrangement 12 passing through it. In a particular instance, the turbulence-inducing structure 202h is an inflatable or compressible structure. For example, the turbulence-inducing structure 202h is a balloon. In another instance, the turbulence-inducing structure 202h is formed from compressible foam.

[0058] In some other instances, the turbulence-inducing structure 14 includes one or more protrusions extending from the distal tip 23 of the catheter arrangement 12. When a therapeutic flow is dispensed from the opening 30 at the distal tip 23 of the catheter arrangement 12, the therapeutic flow is disturbed by one or more protrusions, and thus eddies are induced in the flow of blood. The one or more protrusions may have any suitable shape for inducing turbulence in a localized area within the blood flow. For example, the one or more protrusions may have a planar shape (having a flat surface extending parallel to the longitudinal axis of the catheter arrangement), a cylindrical shape, a conical shape, an irregular shape, etc. For example, FIG2I shows a side view of an example of a turbulence-inducing structure 202i attached to the distal tip 23 of the catheter arrangement 12. In this example, the turbulence-inducing structure 202i is a flared portion attached to the distal tip 23 of the catheter arrangement 12, having a flat surface extending parallel to the longitudinal axis of the catheter arrangement 12.

[0059] In some other examples, the turbulence-inducing structure 14 is molded or formed into the distal end 22 of the catheter arrangement 12. For example, the outer surface 15 of the distal end 22 of the catheter arrangement 12 may be modified to include features that induce turbulence in the blood flow when the device is in the working position within a patient's blood vessel. FIG2J provides a side view of yet another example of a turbulence-inducing structure 202j formed into the distal end 22 of the catheter arrangement 12. The turbulence-inducing structure 202j includes one or more grooves 203j etched into the outer surface 15 of the distal tip 23 of the catheter arrangement 12. The grooves 203j induce turbulence in a localized region at the distal end 22 of the catheter arrangement 12. As shown in Figure 2J, the groove can be spirally wrapped around the distal end 22 times of the conduit arrangement 12.Alternatively, the groove 203j may be parallel, perpendicular, or at an acute angle to the longitudinal axis of the catheter arrangement 12 extending from the proximal end 20 to the distal end 22, or at an obtuse angle to the longitudinal axis of the catheter arrangement 12 extending from the proximal end 20 to the distal end 22.

[0060] In another embodiment, the distal tip 23 of the catheter arrangement 12 may be modified to include features that induce turbulence in the blood flow when the device is in the working position within a patient's blood vessel. Figure 2K provides a side view of another example of a turbulence-inducing structure 202k formed at the distal tip 23 of the catheter arrangement 12. The turbulence-inducing structure 202k includes one or more slits cut into the distal tip 23 of the catheter arrangement 12, forming branching features 203k extending away from the longitudinal axis of the catheter arrangement 12. The branching features 203k induce turbulence in a localized region at the distal end 33 of the catheter arrangement 12. The slits and branching features 203k cut into the distal tip 23 can have any suitable shape for inducing turbulence. As shown in FIG2K, the distal tip 23 of the catheter arrangement 12 can be modified to have 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) can be used at the distal tip 23 of the catheter arrangement 12 to form a corresponding number of branching features 203k (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0061] FIG2L provides a side view of another example of a turbulence-inducing structure 202l formed at the distal tip 23 of the catheter arrangement 12. The turbulence-inducing structure 202l includes a distal structure 203l surrounding the opening 30 of the distal tip 23 of the catheter arrangement 12 and a plurality of support portions 204l connecting the distal structure 203l to the rest of the catheter arrangement 12. The turbulence-inducing structure 2021 can be formed by removing a portion of the wall of the catheter arrangement 12 at the distal end 22 to form a gap 205l. As shown in FIG2L, 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 arrangement. The gap 205l disperses blood flow and further disperses the fluid drug composition infused into the blood vessel through the catheter arrangement 12. The distal structure 203l allows the guidewire to extend through the opening 30. The distal structure 203l may be in the form of a cone, hemisphere, ring, or other shape. The distal structure 203l may be coaxial with the catheter arrangement 12. In one example, the distal structure 203 may be expandable in the same manner as a collapsible or compressible structure, as further described below. In the example shown in Figure 2L, the distal structure 203l includes...The catheter arrangement 12 has a distal plane substantially perpendicular to its longitudinal axis and a proximal plane substantially perpendicular to its longitudinal axis. The proximal plane induces turbulence within the blown flow, and the distal plane amplifies the turbulence.

[0062] FIG2M provides a side view of another example of a turbulence-inducing structure 202m attached to the distal end 22 of the catheter arrangement 12. The turbulence-inducing structure 202m includes a plurality of grooved fins 203m arranged longitudinally (not shown) along the distal end 22 of the catheter arrangement 12 or spirally arranged around a length of the distal end 22 of the catheter arrangement 12. As blood flows downstream through the turbulence-inducing structure 202m, the grooved fins 203m interfere with the laminar flow of the blood. Blood passing through the turbulence-inducing structure 202m can be induced to swirl as it passes the distal end 22 of the catheter arrangement. This swirling effect interferes with laminar flow and creates turbulence to mix the fluid drug composition in the patient's blood.

[0063] In one example, the catheter arrangement 12 is a single microcatheter including a lumen 18 extending from its proximal end 20 to its distal end 22.

[0064] In another example, the catheter arrangement 12 is a multi-catheter configuration that can be deployed and retracted or compressed into a retractable or compressible turbulence-inducing structure 14. For example, the catheter arrangement 12 includes an outer catheter and an inner catheter. The inner catheter is sized and shaped to be slidable within the lumen of the outer catheter. The retractable or compressible turbulence-inducing structure 14 can be retracted or compressed by the outer and inner catheters and held in a retracted or compressed configuration (e.g., between the outer surface of the inner catheter and the inner lumen of the outer catheter). The retractable or compressible turbulence-inducing structure 14 can be deployed and / or reconfigured by sliding the outer and inner catheters relative to each other to provide longitudinal displacement for deploying the retractable or compressible turbulence-inducing structure 14. In this example, the handle 24 may also include a fixed portion and a movable portion for manipulating the catheter arrangement. Specifically, the proximal end of the external catheter is longitudinally fixedly coupled to the fixed portion, and the proximal end of the internal catheter is coupled to the movable portion. The movable portion can be manually manipulated relative to the fixed portion to allow the internal and external catheters to slide relative to each other to provide longitudinal displacement for deploying the retractable or compressible turbulence-inducing structure 14.

[0065] FIG2N provides a side view of another example of a turbulence-inducing structure 202n attached to the distal end of the catheter arrangement 12. The turbulence-inducing structure 202n may include a plurality of ridges 203n. The plurality of ridges 203n may be arranged in an array along the distal end 22 of the catheter arrangement 12. The turbulence-inducing structure may, for example, include ridges along the distal end of the catheter arrangement. The ridges may, for example, include one or more facets. Each of the one or more facets may be oriented in a direction such that an axis extending perpendicularly from the surface of the facet points in that direction. The ridges may, for example, include facets along the proximal end.One or more facets oriented in a directional direction. A ridge may, for example, include one or more facets oriented in a distal direction. A ridge may, for example, include one or more facets oriented in a direction perpendicular to the outer surface of the catheter arrangement. A ridge may, for example, include one or more facets oriented in a direction perpendicular to the longitudinal axis of the catheter arrangement. A ridge may, for example, include one or more facets oriented in a proximal direction, a distal direction, a direction perpendicular to the outer surface of the catheter arrangement, and / or a direction perpendicular to the longitudinal axis of the catheter arrangement.

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

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

[0068] The ridge may include, for example, a ridge width, a ridge length, and / or a 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 can be in the range of mm. The ridge width can be in the range of 0.10 mm to 1.00 mm. The ridge width can be in the range of 0.20 mm to 1.00 mm. The ridge width can be in the range of 0.30 mm to 1.00 mm. The ridge width can be in the range of 0.50 mm to 1.00 mm. The ridge width can be in the range of 0.75 mm to 1.00 mm. The ridge width can be less than, equal to and / or greater than the circumference of the catheter arrangement. The ridge width can be a percentage of the circumference of the catheter arrangement. The ridge width can be between 10% and 100% of the circumference of the catheter arrangement, is 100% of the circumference of the catheter arrangement, and / or is between 100% and 300% of the circumference of the catheter arrangement.

[0069] The ridge length can be in the range of 0.10 mm to 0.25 mm. The ridge length can be in the range of 0.10 mm to 0.50 mm. The length of the ridge can range from 0.10 mm to 0.75 mm. The length of the ridge can range from 0.10 mm to 1.00 mm. The length of the ridge can range from 0.10 mm to 1.25 mm. The length of the ridge can range from 0.1 mm to 1.5 mm. The length of the ridge can range from 0.10 mm to 2.00 mm. The length of the ridge can range from 0.25 mm to 2.00 mm. The length of the ridge can range from 0.75 mm to 2.00 mm. The length of the ridge can range from 1.00 mm to 2.00 mm. The length of the ridge can range from 1.25 mm to 2.00 mm. The length of the ridge can range from 1.50 mm to 2.00 mm. The length of the ridge can be less than, equal to, and / or greater than the length of the distal portion of the catheter arrangement. The length of the ridge can be a percentage of the length of the distal portion of the catheter arrangement. The ridge length can be between 10% and 100% of the length of the distal portion of the catheter arrangement, 100% of the length of the distal portion of the catheter arrangement, and / or between 100% and 300% of the length of the distal portion of the catheter arrangement. The ridge length can be less than and / or equal to the length of the array. The ridge length can be a percentage of the length of the array. The ridge length can be between 10% and 100% of the length of the array and / or 100% of the length of the array.

[0070] The ridge height can be in the range of 0.01 mm to 0.10 mm. The ridge height can be in the range of 0.01 mm to 0.20 mm. The ridge height can be in the range of 0.01 mm to 0.30 mm. The ridge height can be in the range of 0.01 mm to 0.50 mm. The ridge height can be in the range of 0.01 mm to 1.00 mm. The ridge height can beThe ridge height can be in the range of 0.01 mm to 1.50 mm. The ridge height can be in the range of 0.01 mm to 2.00 mm. The ridge height can be in the range of 0.01 mm to 3.00 mm. The ridge height can be in the range of 0.02 mm to 3.00 mm. The ridge height can be in the range of 0.01 mm to 5.00 mm. The ridge height can be in the range of 0.10 mm to 5.00 mm. The ridge height can be in the range of 0.20 mm to 5.00 mm. The ridge height can be in the range of 0.30 mm to 5.00 mm. The ridge height can be in the range of 0.50 mm to 5.00 mm. The ridge height can be in the range of 1.00 mm to 5.00 mm. The ridge height can be in the range of 1.50 mm to 5.00 mm. The ridge height can be in the range of 2.00 mm to 5.00 mm. The height of the ridge can be in the range of 3.00 mm to 5.00 mm. The height of the ridge can be less than, equal to, and / or greater than the radius of the catheter arrangement. The height of the ridge can be a percentage of the radius of the catheter arrangement. The height of the ridge can be between 10% and 100% of the radius of the catheter arrangement, is 100% of the radius of the catheter arrangement, and / or is between 100% and 300% of the radius of the catheter arrangement.

[0071] An array of multiple ridges 203n of the catheter arrangement can include length and / or pattern. The length of the array can be in the range of 1 mm to 5 mm. The length of the array can be in the range of 1 mm to 10 mm. The length of the array can be in the range of 1 mm to 15 mm. The length of the array can be in the range of 1 mm to 20 mm. The length of the array can be in the range of 1 mm to 25 mm. The length of the array can be in the range of 1 mm to 50 mm. The length of the array can range from 1 mm to 75 mm. The length of the array can range from 1 mm to 100 mm. The length of the array can range from 5 mm to 100 mm. The length of the array can range from 10 mm to 100 mm. The length of the array can range from 15 mm to 100 mm. The length of the array can range from 20 mm to 100 mm. The length of the array can range from 25 mm to 100 mm. The length of the array can range from 50 mm to 100 mm. The length of the array can range from 75 mm to 100 mm. The length of the array can be less than, equal to, and / or greater than the length of the distal portion of the catheter arrangement. The length of the array can be a percentage of the length of the distal portion of the catheter arrangement.Between 10% and 100% of the length, 100% of the length of the distal portion of the catheter arrangement, and / or between 100% and 300% of the length of the distal portion of the catheter arrangement. The length of the array can be equal to and / or greater than the length of the ridge. The length of the array can be a percentage of the length of the ridge. The length of the array can be 100% of the length of the ridge, between 100% and 500% of the length of the ridge, and / or between 100% and 1000% of the length of the ridge.

[0072] The pattern of the array can include a proximal-to-distal clockwise spiral, a proximal-to-distal counterclockwise spiral, a loop, multiple loops, pillars, and / or multiple pillars. The pattern can include one or more circumferential lengths between circumferentially adjacent ridges. One or more circumferential lengths between circumferentially adjacent ridges can include lengths between 1 mm and 10 mm, 0 mm, and / or negative lengths between 1 mm and 10 mm, wherein the negative length includes circumferential length overlap between circumferentially adjacent ridges. One or more circumferential lengths between circumferentially adjacent ridges may include lengths that are equal to, greater than, smaller 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. The pattern may include one or more circumferential lengths between circumferentially adjacent ridges, wherein there are no ridges between circumferentially adjacent ridges. The pattern may include one or more circumferential lengths between circumferentially adjacent ridges, wherein there is an overlap in circumferential lengths between circumferentially adjacent ridges. One or more circumferential lengths between circumferentially adjacent ridges may include the same circumferential length between each circumferentially adjacent ridge, may be different between circumferentially adjacent ridges, and / or may include different circumferential lengths between each circumferentially adjacent ridge.

[0073] The pattern may include one or more circumferential lengths between longitudinally adjacent ridges. The pattern may include one or more circumferential lengths between longitudinally adjacent ridges, wherein there are no ridges between longitudinally adjacent ridges. The pattern may include one or more circumferential lengths between longitudinally adjacent ridges, wherein there is an overlap of circumferential lengths between longitudinally adjacent ridges. One or more circumferential lengths between longitudinally adjacent ridges may include the same circumferential length between each longitudinally adjacent ridge, may be different between longitudinally adjacent ridges, and / or may include different circumferential lengths between each longitudinally adjacent ridge.

[0074] The ridges in an array of multiple ridges may include the same ridge width, ridge length, ridge height, and / or one or more facets as each ridge in the array of multiple ridges. The ridges in the array of multiple ridges may be associated with the multiple ridges in terms of ridge width, ridge length, ridge height, and / or one or more facets.The different ridges in the array of ridges are different. Each ridge in the array of multiple ridges may include a ridge width, ridge length, ridge height and / or one or more facets that are different from each other ridge in the array of multiple ridges.

[0075] FIG2N provides a side view of another example of a turbulence-inducing structure 202n attached to the distal end of the catheter arrangement 12. The turbulence-inducing structure 202n includes multiple ridges 203n. The multiple ridges 203n may be arranged in an array along the distal end 22 of the catheter arrangement 12, wherein the array may include a pattern. In this example, the array includes multiple ridges 203n arranged in a pattern, wherein the pattern includes a counterclockwise spiral from proximal to distal. The ridges 203n in the multiple ridges 203n include facets oriented in a proximal direction, wherein the facets oriented in a proximal direction are planar. A ridge 203n among a plurality of ridges 203n includes facets oriented distally, wherein the facets oriented distally are planar. A ridge 203n among a plurality of ridges 203n includes a plurality of facets oriented in a direction perpendicular to the outer surface of the catheter arrangement, wherein the plurality of facets oriented in a direction perpendicular to the outer surface of the catheter arrangement are convex facets. A ridge 203n among a plurality of ridges 203n includes facets oriented in a direction perpendicular to the longitudinal axis of the catheter arrangement. A ridge 203n in an array of a plurality of ridges 203n includes the same ridge width, ridge length, ridge height, and one or more facets as each other ridge in the array of a plurality of ridges. A plurality of circumferential lengths between each ridge 203n in the array of a plurality of ridges 203n are positive values. A plurality of longitudinal lengths between each ridge 203n in the array of a plurality of ridges 203n are positive values. Multiple circumferential lengths between each circumferentially adjacent ridge 203n are the same. Multiple circumferential lengths between each longitudinally adjacent ridge 203n are the same. Multiple longitudinal lengths between each circumferentially adjacent ridge 203n are the same. Multiple longitudinal lengths between each longitudinally adjacent ridge 203n are the same.

[0076] The pump system 16 includes an infusion pump or syringe (hereinafter collectively referred to as the "pump") configured to draw a fluid pharmaceutical composition containing a therapeutic agent from a reservoir and provide a flow of the fluid pharmaceutical composition through a lumen 18 of the catheter arrangement 12 and dispensed into the patient's bloodstream from an opening 30 at the distal tip 23 of the catheter arrangement 12. The pump system 16 can provide a flow of the fluid pharmaceutical composition at any desired flow rate, such as about 0.01 mL / s to about 10 mL / s, or about 0.1 mL / s to about 5 mL / s, or about 1 mL / s to about 3 mL / s.

[0077] The system 10 described herein can be used for the infusion of any fluid pharmaceutical composition containing a therapeutic agent. System 10 is particularly suitable for the infusion of fluid pharmaceutical compositions containing particles (e.g., suspended particles in a liquid, foam, or gel, for example, infused into a patient's vascular system). The particle size can be suitably designed for infusion into a patient's blood vessels, such as having a diameter of, for example, 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 can contain the therapeutic agent in an insoluble solid form, or can be bead or microsphere carriers containing the therapeutic agent. The beads or microspheres can contain the therapeutic agent internally, or can be coated with the therapeutic agent on their outer surface. In some instances, 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 embolic agent. In another example, the beads or microspheres have a diameter of about 1 µm to about 100 µm and the therapeutic agent is a pharmacologically active agent. In yet another example, the beads or microspheres have a diameter of about 10 µm to about 90 µm and the therapeutic agent is a weak radiotracer, such as MAA. In yet another example, the beads or microspheres have a diameter of about 20 µm to about 40 µm and the therapeutic agent is a radioembolizing agent, such as Y-90.

[0078] The therapeutic agent delivered using the system 10 described herein can be any pharmaceutically active agent suitable for local delivery to a target area of ​​a patient's body (e.g., in any organ that is desired to be treated with the therapeutic agent). For example, organs can be pancreas, liver, kidney, lung, uterus, ovary, cervix, prostate, head and neck tissues (jaw, gums), brain, adrenal gland, intestine or colon, breast, thyroid, spleen, stomach, gallbladder, thymus, skin, bladder, lymphatic system, and a variety of other organs or tissues that are subject to local delivery of the available therapeutic agent for treatment.

[0079] Therapeutic agents may include embolic agents (e.g., radioembolic agents or chemoembolic agents), contrast agents, iodized oil, chemotherapy drugs, immunotherapeutic agents, oncolytic viruses, gene therapy, cisplatin (or other alkylating agents), antibodies, checkpoint inhibitors, cytokines, oncolytic viruses, cancer vaccines, cytotoxic agents, embolic agents alone, combination therapies, growth factor inhibitors, nanoparticle encapsulation therapies, live cell therapies, and any other therapies that can be formulated into fluid pharmaceutical compositions and are suitable for local infusion.

[0080] In one example, the therapeutic agent is an embolic agent (e.g., a radioembolic agent or chemoembolic agent) contained within or coated onto the outer surface of a bead or microsphere carrier. Examples of radioembolic agents include any active agent that emits ionizing radiation to kill cells in a target area (e.g., a tumor to be treated), such as yttrium-90 (Y-90).Examples of embolic agents include any chemotherapeutic agent that kills actively dividing cells, such as cancer cells, by destroying DNA, such as mitomycin, cisplatin, and doxorubicin. Embolic agents are typically formulated in gel pharmaceutical compositions comprising a hydrogel-based polymer (e.g., gelatin, PVA, etc.) that allows the drug to be absorbed into its hydrated polymer network and then slowly released into the tissue.

[0081] In another example, the therapeutic agent comprises a Toll-like receptor (TLR) agonist, particularly a TLR9 agonist, and more particularly a C-type TLR9 agonist.

[0082] The therapeutic agent may comprise a synthetic CpG-oligonucleotide (CPG-OND) that mimics the immunostimulatory properties of microbial CpG-DNA. According to one example, the oligonucleotide is an oligodeoxynucleotide (ODN). There are many different CpG-ODN class types, such as class A, class B, class C, class P, and class S, which share certain structural and functional characteristics. In this regard, type A CPG-ODN (or CPG-A ODN) is associated with pDC maturation, has little effect on B cells, and induces the highest level of IFNα; type B CPG-ODN (or CPG-B ODN) strongly induces B cell proliferation, activates pDC and monocyte maturation, NK cell activation, and inflammatory cytokine production; and type C C CPG-ODN (or CPG-C ODN) can induce B cell proliferation and IFN-α production. CPG-C ODN can be associated with the following properties: (i) unmethylated dinucleotide CpG motifs, (ii) juxtaposed CpG motifs with flanking nucleotides (e.g., AACGTTCGAA), (iii) a fully phosphate-thioester (PS) backbone linking nucleotides (as opposed to the native phosphate-diester (PO) backbone found in bacterial DNA), and (iv) self-complementary palindromic sequences (e.g., AACGTT). In this respect, CPG-C ODN can bind itself due to its palindromic nature, thereby producing a double-stranded duplex (e.g., a dimer) or a hairpin structure.

[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., a sodium salt as shown in Figure 3), as described in WO2022 / 066670, which is 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, according to one example, the CPG-C ODN sequence may correspond to SEQ ID NO: 172 as described in U.S. Patent No. 9,422,564, which is incorporated herein by reference in its entirety.

[0084] In one example, the therapeutic agent comprises a checkpoint inhibitor (CPI). The CPI may comprise a programmed death 1 receptor (PD-1 receptor).1) Antagonists. PD-1 antagonists may include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, and preferably specifically bind to human PD-1 or human PD-L1. mAbs may be human antibodies, humanized antibodies, or chimeric antibodies, and may include a human constant region. In some instances, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred instances, the human constant region is an IgG1 or IgG4 constant region. In some instances, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments. Alternatively, PD-1 antagonists may be immunoadhesives that specifically bind to PD-1 or PD-L1, and preferably immunoadhesives that specifically bind to human PD-1 or human PD-L1, such as fusion proteins containing an extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region (such as the Fc region of an immunoglobulin molecule). For example, a PD-1 antagonist may be nivolumab, pembrolizumab, cimiprimab, relatimab, or a combination thereof.

[0085] In one specific example, the therapeutic agent comprises a combination of a TLR9 agonist or CPG-OND in combination with a CPI, as described above. Specification 13 / 14 pages 16 CN 121568740 A

[0086] The scope of the invention described and claimed herein is not limited to the specific embodiments disclosed herein, as these embodiments are intended to illustrate several aspects of the invention. Any equivalent embodiments are intended to be within the scope of the invention. In fact, various modifications to the invention will become apparent to those skilled in the art from the foregoing description, in addition to those shown and described herein. Such modifications are also intended to fall within the scope of the appended claims. All publications cited herein are incorporated herein by reference in their entirety. Instruction Manual Page 14 / 14 17 CN 121568740 A Figure 1 Instruction Manual Figure 1 / 7 Page 18 CN 121568740 A Figure 2A Figure 2B Figure 2C Instruction Manual Figure 2 / 7 Page 19 CN 121568740 A Figure 2D Figure 2E Figure 2F Figure 2G Instruction Manual Figure 3 / 7 Page 20 CN 121568740 A Figure 2H Figure 2I Figure 2J Instruction Manual Figure 4 / 7 Page 21 CN 121568740 A Figure 2K Figure 2L Figure 2M Instruction Manual Figure 5 / 7 Page 22 CN 121568740 A Figure 2N Instruction Manual Figure 6 / 7 Page 23CN 121568740 A Figure 3 Instruction Manual Drawing 7 / 7 Page 24 CN 121568740 A

Claims

1. A vascular infusion catheter for infusing a therapeutic agent into a patient's blood vessel, the vascular infusion catheter comprising: A catheter arrangement extending from a distal end to a proximal end has an outer surface and an inner surface, the inner surface defining a lumen through the inner surface, the catheter arrangement including an opening at the distal tip of the catheter arrangement in a continuous fluid passage having the lumen; as well as A turbulence-inducing structure, formed by or attached to the outer surface or distal tip of the catheter arrangement, is configured to induce turbulence in blood flowing through a localized region of the blood vessel. The turbulence-inducing structure is configured to not completely block the blood vessel, allowing the blood to flow through the turbulence-inducing structure at all times.

2. The vascular infusion catheter according to claim 1, wherein the therapeutic agent is within the particles or coated on the surface of the particles.

3. The vascular infusion catheter according to claim 1, wherein the catheter arrangement is a single catheter.

4. The vascular infusion catheter of claim 1, wherein the catheter arrangement comprises an outer catheter and an inner catheter, configured to deploy the turbulence-inducing structure by longitudinal displacement of the outer catheter relative to the inner catheter.

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

6. The vascular infusion catheter of claim 5, wherein the TLR9 agonist is SD-101 or a pharmaceutically acceptable salt thereof.

7. The vascular infusion catheter according to any one of claims 1 to 6, wherein the turbulence-inducing feature is attached to the distal tip of the catheter arrangement.

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

9. The vascular infusion catheter according to any one of claims 1 to 6, wherein the induced turbulence provides shear force, the shear force not exceeding the shear force used for lysing 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 that is substantially perpendicular to or at an obtuse angle to the longitudinal axis of the catheter arrangement at the distal or proximal end of the catheter arrangement.

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

12. The vascular infusion catheter according to any one of claims 1 to 6, wherein the therapeutic agent is a radioembolic agent, the therapeutic agent being contained within or coated onto particles.

13. The vascular infusion catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure partially obstructs the blood vessel, allowing blood to flow through the turbulence-inducing structure in a downstream or upstream direction.

14. The vascular infusion catheter according to any one of claims 1 to 6, wherein the turbulence-inducing structure comprises a plurality of ridges arranged in an array.

15. The vascular infusion catheter of claim 14, wherein the array comprises a pattern, and wherein the pattern comprises a proximal-to-distal counterclockwise spiral or a proximal-to-distal clockwise spiral.

16. A system for vascularizing a therapeutic agent into a patient's blood vessel, the system comprising: A catheter arrangement extending from a distal end to a proximal end has an outer surface and an inner surface, the inner surface defining a lumen through the inner surface, the catheter arrangement including an opening at the distal tip of the catheter arrangement in a continuous fluid passage having the lumen; A turbulence-inducing structure, which is formed by or attached to the outer surface or distal tip of the catheter arrangement, is configured to induce turbulence in blood flowing downstream through a local area of ​​the blood vessel. A handle, which is operably connected to the proximal end of the catheter arrangement, allows the handle to be manipulated to manipulate the catheter arrangement; as well as A pump system, which is fluidly connected to the proximal end of the catheter arrangement in a continuous fluid passage having the opening and the cavity at the distal tip. ， The pump system is configured to dispense a flow of a fluid drug composition containing the therapeutic agent from the pump system through the continuous fluid passage and via the opening into the blood vessel. The turbulence-inducing structure is configured to not completely block the blood vessel, allowing the blood to flow through the turbulence-inducing structure at all times.

17. The system of claim 16, wherein the therapeutic agent is within the particle or coated on the surface of the particle.

18. The system of claim 16, wherein the catheter arrangement is a single catheter.

19. The system of claim 16, wherein the conduit arrangement comprises an outer conduit and an inner conduit, configured to deploy the turbulence-inducing structure by longitudinal displacement of the outer conduit relative to the inner conduit.

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

21. The system of 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 feature is attached to the distal tip of the conduit arrangement.

23. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure does not completely block the blood vessel, allowing blood to 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 used to lyse red blood cells.

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

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

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

28. The system according to any one of claims 16 to 21, wherein the turbulence-inducing structure partially obstructs the blood vessel, allowing blood to 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 comprises a plurality of ridges arranged in an array.

30. The system of claim 29, wherein the array comprises a pattern, and wherein the pattern comprises a proximal-to-distal counterclockwise spiral or a proximal-to-distal clockwise spiral.

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