Local drug administration methods

Abstract

The present invention aims to treat only specific organs with a high concentration of a drug, thereby increasing the efficacy of the drug in those organs and eliminating side effects on other organs, while reducing the amount of drug used compared to systemic administration, thereby reducing drug costs. The present invention provides a pharmaceutical agent for administration to an organ in a subject's body that is independent of the bloodstream.

Description

[Technical Field]

[0001] The present invention relates to a method for topical administration of drugs. [Background technology]

[0002] The toxicity of pharmaceuticals to humans is primarily due to the active ingredients acting not only on diseased tissues and target cells, but also on healthy tissues and cells. Furthermore, individual differences in metabolic capacity, as well as factors such as the route of administration and formulation, can make the same drug more likely to cause serious side effects. If such toxicity becomes apparent, it not only makes it difficult to continue treatment, but also risks significantly impairing the patient's quality of life (QOL). Therefore, ensuring efficacy while reducing toxicity is a crucial issue in pharmaceutical development and clinical practice.

[0003] Measures to reduce toxicity include, for example, improving formulation design and dosage form. The use of sustained-release or controlled-release formulations can prevent a sudden rise in blood concentration and mitigate side effects. Alternatives to systemic toxicity can also be effective by devising the administration route itself, such as inhalation, eye drops, or even local injection. Furthermore, by utilizing drug delivery systems (DDS) and prodrug design, mechanisms that activate drugs only at the target site can be introduced to reduce drug exposure to unwanted areas. In particular, DDSs using nanoparticles or liposomes can be used to deliver drugs exclusively to cancer tissues and minimize side effects. However, each of these technologies is unique and requires optimization for each drug and treatment, making them uncommon.

[0004] Non-Patent Document 1 describes a study of machine perfusion techniques and drug administration to reduce ischemia-reperfusion injury during kidney transplantation. Non-Patent Document 1 also describes a study comparing hypothermia, hypothermic oxygen supply, and normothermic perfusion methods, and examining the effects of antioxidants (NAC, quercetin), complement inhibitors (C1-INH, siRNA), and hydrogen sulfide (HS), which are promising agents for reducing ischemia-reperfusion injury.

[0005] Non-Patent Document 2 examines the possibility of applying gene therapy during extracorporeal cardiac perfusion during heart transplantation. Non-Patent Document 2 describes that while conventional static preservation methods pose problems such as myocardial damage and ischemia-reperfusion injury, the use of machine perfusion may enable the direct application of gene therapy to improve the condition of the heart, and in particular, gene transfer using adenovirus, adeno-associated virus, and liposomes has been investigated, and describes that these methods can be used to alleviate ischemia-reperfusion injury, regulate immune responses, correct pathological gene mutations, and so on.

[0006] Non-Patent Document 3 describes the verification that normothermic extracorporeal kidney perfusion reduces ischemia-reperfusion injury in kidney transplantation. Using a porcine kidney transplant model, a comparison of normothermic extracorporeal kidney perfusion with conventional static cold preservation revealed that the normothermic extracorporeal kidney perfusion group maintained mitochondrial function, had higher ATP levels, and suppressed post-transplant oxidative stress and inflammation. Furthermore, administration of the hydrogen sulfide donor AP39 during normothermic extracorporeal kidney perfusion further improved mitochondrial function and renal function after transplantation. Non-Patent Document 3 suggests that the combination of normothermic extracorporeal kidney perfusion and AP39 may be a new strategy for kidney preservation and transplantation. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Front Immunol. 2021 Jul 6:12:673562. [Non-patent document 2] Front Cardiovasc Med. 2023 Oct 16:10:1264449. [Non-patent document 3] Nat Commun. 2024 Sep 15;15(1):8086. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to treat only specific organs with a high concentration of a drug, thereby increasing the efficacy of the drug in those organs and eliminating side effects on other organs, while reducing the amount of drug used compared to systemic administration, thereby reducing drug costs. [Means for solving the problem]

[0009] After extensive research, the inventors have found that by temporarily isolating a specific organ from the bloodstream in the body, treating the organ with a drug, and then reconnecting it to the bloodstream, it is possible to treat a drug at a high concentration only in the specific organ, thereby not only increasing the drug's efficacy in that organ but also eliminating side effects on other organs, and further reducing the amount of drugs with high manufacturing costs, such as ASO, used compared to systemic administration, thereby suppressing drug costs.The inventors have also developed a device that can be used to temporarily isolate a specific organ from the bloodstream in the body, treat the organ with a drug, and then reconnect it to the bloodstream.

[0010] Since methods such as pulmonary perfusion (EVLP) have already been established in transplantation, it is possible to temporarily isolate specific organs from the body's blood flow and administer drugs to them.

[0011] That is, the present invention provides the following. [Aspect 1] A drug for administration to an organ in a subject's body that is separate from the bloodstream. [Aspect 2] The agent according to embodiment 1, wherein the subject is a mammal. [Aspect 3] The agent according to embodiment 1, wherein the subject is a human. [Aspect 4] The agent according to aspect 1, wherein the organ is the liver, heart, lung, pancreas, kidney, brain, spinal cord, or small intestine. [Aspect 5] The drug according to aspect 1, wherein the drug is a low molecular weight drug or a high molecular weight drug. [Aspect 6] The agent according to aspect 5, wherein the macromolecular pharmaceutical is an antibody pharmaceutical, a protein pharmaceutical, a peptide pharmaceutical, or a nucleic acid pharmaceutical. [Aspect 7] The agent according to aspect 6, wherein the nucleic acid drug is an antisense oligonucleotide, siRNA, miRNA, aptamer, decoy, CpG oligo, or mRNA. [Aspect 8] The agent according to aspect 7, wherein the antisense oligonucleotide is an antisense oligonucleotide of p53. [Aspect 9] The agent of aspect 5, wherein the small molecule pharmaceutical agent is an anti-cancer drug, an anti-infective drug, an immunosuppressant, an anti-inflammatory drug, or a steroid. [Aspect 10] The method of embodiment 1, wherein the subject is suffering from a disease. [Aspect 11] The agent according to aspect 10, wherein the disease is lung cancer, autoimmune hepatitis, neuroendocrine tumors, glioma, bacterial and viral hepatitis, or pulmonary fibrosis. [Aspect 12] 2. The agent according to embodiment 1 for use in combination with a transfection reagent. [Aspect 13] The agent according to aspect 1, which is intended to reconnect an organ that has been isolated from the bloodstream in the subject's body to the bloodstream. [Aspect 14] An apparatus for circulating a first liquid, which is different from the second liquid, in a part of a system in which a second liquid circulates, and for circulating the second liquid in a part of the system in which the second liquid circulates excluding the part of the system in which the second liquid circulates, comprising: a shielding portion for shielding the part; a first pipe for distributing a first liquid; a second pipe for passing a second liquid; An apparatus comprising: [Aspect 15] the first pipe has an opening for the inflow of the first liquid and an opening for the outflow of the first liquid; the second pipe has an opening for the second liquid to flow in and an opening for the second liquid to flow out; the shielding portion is located downstream of an opening in the first pipe for allowing the first liquid to flow in, based on a direction in which the first liquid flows in the first pipe; an opening in the second pipe for allowing the second liquid to flow out is located downstream of the shielding portion with respect to the flow direction of the first liquid in the first pipe; 15. The apparatus of embodiment 14. [Aspect 16] the first pipe has an opening for the inflow of the first liquid and an opening for the outflow of the first liquid; the second pipe has an opening for the second liquid to flow in and an opening for the second liquid to flow out; the shielding portion is located upstream of an opening in the first pipe for allowing the first liquid to flow out, based on a direction in which the first liquid flows in the first pipe; an opening in the second pipe for allowing the second liquid to flow in is located upstream of the shielding portion with respect to the flow direction of the first liquid in the first pipe; 15. The apparatus of embodiment 14. [Aspect 17] An apparatus as described in aspect 14, wherein the direction in which the second liquid is passed through the second pipe is opposite to the direction in which the first liquid is passed through the first pipe. [Aspect 18] a first pipe for distributing a first liquid is connected to a first pump for circulating the first liquid; a second pipe for distributing a second liquid therethrough, the second pipe being for connection to a second pump for circulating the second liquid; 15. The apparatus of embodiment 14. [Aspect 19] An apparatus comprising: the apparatus of embodiment 15; the apparatus of embodiment 16; a first pump for circulating the first liquid; and a second pump for circulating the second liquid. [Aspect 20] The device of embodiment 14, wherein the device is a catheter. [Aspect 21] A method for circulating a first liquid in a part of a system in which the first liquid circulates, by circulating a second liquid different from the first liquid in a part of the system in which the first liquid circulates, and circulating the first liquid in a part of the system in which the first liquid circulates excluding the part of the system, comprising: A method using the device according to embodiment 14. [Aspect 22] 15. The device of claim 14, wherein an end of a second pipe for circulating a second liquid compresses and stores the shielding portion. [Aspect 23] The device of embodiment 14, wherein an end of a second pipe for passing a second liquid covers the shielding portion, and sliding the end toward the other end of the second pipe exposes the shielding portion. [Effects of the Invention]

[0012] According to the present invention, a drug can be administered at a high concentration only to a specific organ, thereby not only enhancing the efficacy of the drug in that organ but also eliminating side effects on other organs. According to the present invention, the amount of drugs with high production costs, such as ASO, used can be reduced compared to systemic administration, thereby reducing drug costs. In the present invention, which uses nucleic acid drugs such as ASO, it is possible to use transfection reagents, which can be expected to achieve higher efficacy. According to the device of the present invention, by being configured with a shielding section, it is possible to prevent the drug from flowing into non-target organs and avoid side effects. In addition, this method is less invasive than surgical procedures on the target organ, and reduces the physical and mental burden on the patient. For example, by using this method without open-chest surgery on the lungs, treatment can be provided to patients with weaker physical conditions. Furthermore, unlike the individual drug delivery methods that have been studied for each drug and treatment up until now, this method is general and has a wide range of applications, including the use of already approved drugs. While these individual drug delivery methods may use chemical ligands that have affinity for the target organ or polymers such as micelles to safely deliver drugs to the target organ, these chemical ligands and polymers such as micelles may themselves be toxic. Therefore, physically delivering drugs directly to the organ using this method avoids the risk of such toxicity. According to the present invention, firstly, it is possible to use a small amount of drug, and even if expensive drugs or drugs that are difficult to manufacture are used for treatment, more patients can be saved at low cost. Second, the present invention allows for less invasive surgery, for example, lung surgery can be performed by simply passing a few catheters rather than opening the chest and removing ribs. Furthermore, this invention prevents the drug from circulating throughout the body, so by washing the drug out after surgery, the amount of drug circulating throughout the body can be minimized. This means that clinical trials can be conducted only with microdose toxicity tests, which is expected to drastically reduce the cost and time of clinical development and enable faster access to medical care for patients. Furthermore, the present invention avoids the use of unknown chemical delivery techniques, thereby reducing toxicity associated with delivery. According to the present invention, drugs can be administered only to specific organs, allowing for administration at high concentrations while minimizing concerns about systemic toxicity, and therefore high efficacy can be expected. In addition, while the conventional techniques are all individual techniques that require optimization for each drug or treatment and are not general in nature, the method of the present invention can be used generally. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a cross-sectional view showing one end of a catheter according to an embodiment of the present invention. [Figure 2] FIG. 2 is a cross-sectional view showing the other end of the catheter according to the embodiment of the present invention. [Figure 3] FIG. 3 is a cross-sectional view showing one end of a catheter according to an embodiment of the present invention. [Figure 4] FIG. 4 is a cross-sectional view showing the other end of the catheter according to the embodiment of the present invention. [Figure 5] 5 is a cross-sectional view showing one end of a catheter according to an embodiment of the present invention, in which the balloon support compresses the balloon. [Figure 6] 6 is a cross-sectional view of one end of a catheter according to an embodiment of the present invention, in which the balloon support releases the balloon. [Figure 7] FIG. 7 is a cross-sectional view showing the other end of the catheter according to the embodiment of the present invention. [Figure 8] FIG. 8 is a diagram showing a configuration when a catheter according to an embodiment of the present invention is applied to a human body. [Figure 9] FIG. 9 is an enlarged view of one end of the first catheter in FIG. [Figure 10] FIG. 10 is an enlarged view of one end of the second catheter in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0014] Glossary: Ischemia-reperfusion injury: Damage to tissue that occurs when blood flows again to tissue that has been in a state of ischemia or hypoxia for a period of time.

[0015] ASO: Antisense Oligonucleotide. A single-stranded nucleic acid designed to hybridize (complement) to a target mRNA.

[0016] EVLP: ex vivo lung perfusion, a method of preserving excised organs while maintaining ventilation and perfusion.

[0017] siRNA: Double-stranded RNA consisting of 21-23 base pairs. It suppresses the expression of target mRNA by degrading it through RNA interference.

[0018] mRNA: A molecule made of ribonucleic acid corresponding to a gene sequence. When this sequence is read by ribosomes, the corresponding protein is synthesized.

[0019] Transfection: The introduction of nucleic acids, such as DNA or RNA, into cultured cells.

[0020] S100 protein: A group of proteins that contain an EF-hand type calcium-binding domain (loop-helix-loop).

[0021] Bleomycin: A type of drug used in cancer treatment that causes cancer cell death by cutting DNA or inhibiting its synthesis.

[0022] Bronchoalveolar lavage: A method in which saline is injected into the bronchi through a bronchoscope to wash the alveoli and peripheral airways, and the cellular and liquid components of the recovered fluid are analyzed.

[0023] Surfactant protein D: A glycoprotein produced by type II alveolar epithelial cells, it is a lung-specific marker used for the diagnosis, follow-up observation, and prognosis prediction of lung diseases.

[0024] ECMO: Extracorporeal membrane oxygenation, an extracorporeal membrane oxygenator.

[0025] SpO2: Oxygen saturation in the blood (the percentage of oxygen bound to hemoglobin in arterial blood). It can be measured with a pulse oximeter, and the normal value is 96-98%.

[0026] Sweep gas volume: The flow rate of oxygen sent to the oxygenator. Used when introducing extracorporeal membrane oxygenation (ECMO, etc.).

[0027] PT-INR (prothrombin time-international normalized ratio): Indicates blood clotting ability and is primarily used to manage the dosage of warfarin, an anticoagulant.

[0028] Drugs: The present invention provides pharmaceutical agents for administration to organs within a subject's body that are independent of the bloodstream.

[0029] The subject may be, for example, a vertebrate. The vertebrate may be, for example, a mammal, such as a mouse, a rat, a rabbit, a pig, a cow, a monkey, or a human. The mammal is preferably a human. The subject may be of any age, including a fetus, an infant, a juvenile, an adolescent, an adult, or an elderly person. The subject may also be a deceased subject.

[0030] Examples of organs include the liver, heart, lungs, pancreas, kidneys, brain, spinal cord, and small intestine. Devices that perfuse drugs into organs already exist (e.g., OrganOx for the liver; OrganOx-OrganOx).

[0031] The drug may be, for example, a low molecular weight drug, a high molecular weight drug, etc. The drug may be contained in a pharmaceutical composition.

[0032] Examples of polymeric pharmaceuticals include antibody drugs, proteins, peptide drugs, nucleic acid drugs, etc. Nucleic acid drugs are generally highly toxic, so local administration according to the present invention is effective.

[0033] Examples of nucleic acid drugs include antisense oligonucleotides, siRNA, miRNA, aptamers, decoys, CpG oligos, and mRNA.

[0034] Examples of antisense oligonucleotides include p53 antisense oligonucleotides, EWS / FLI1 (Ewing's sarcoma) antisense oligonucleotides, VPS4A / 4B (VPS4B function-deficient cancer) antisense oligonucleotides, miR-21 (Alport syndrome) antisense oligonucleotides, lncRNA H19 (triple-negative breast cancer) antisense oligonucleotides, NOTHC2NLC (neuronal intranuclear inclusion disease) antisense oligonucleotides, SAA1 / 2 (AA amyloidosis) antisense oligonucleotides, IL36RN (pustular psoriasis) antisense oligonucleotides, GATA3 (asthma) antisense oligonucleotides, and TDP-43-related (ALS) antisense oligonucleotides.

[0035] Examples of drugs include anticancer drugs, anti-infective drugs, immunosuppressants, anti-inflammatory drugs, steroids, immunosuppressants such as tacrolimus and cyclosporine, anticancer drugs such as kinase inhibitors and platinum preparations, anti-obesity drugs, antiviral drugs, enzymes, peptide drugs, and antibody drugs.

[0036] The subject may be, for example, a subject suffering from a disease.

[0037] Diseases include lung cancer, autoimmune hepatitis, neuroendocrine tumors, gliomas, bacterial and viral hepatitis, pulmonary fibrosis, various cancers including liver cancer and triple-negative breast cancer, Alport syndrome, neuronal intranuclear inclusion disease, amyloidosis, pustular psoriasis, asthma, ALS, obesity, infectious diseases, and enzyme deficiencies such as mucopolysaccharidoses. Diseases include cancers of the nervous system and hepatitis caused by infectious diseases. Anticancer drugs are likely to have side effects on proliferating cells in nervous system cancers, so their effectiveness may be even greater in non-proliferating nervous system cancers. Meanwhile, in infectious diseases, anti-infective drugs are effective within a short time in cell experiments. However, administration to animals and humans requires administration for more than a week, which poses challenges such as balancing side effects and ensuring the drug reaches the necessary areas.

[0038] The agents of the present invention are intended for use in combination with, for example, transfection reagents. Examples of transfection reagents include cationic lipid-based Lipofectamine and i-Fect, cationic polymer (e.g., polyethyleneimine)-based jetPEI and PEI MAX, non-liposomal reagents composed of lipids and proteins, TransIT, a non-viral transfection reagent, GenomeONE, calcium phosphate-based CalFectin, and methods using DEAE-dextran. Transfection reagents are generally considered unsuitable for use in living organisms, and are generally used in vitro. The present invention can solve these problems.

[0039] In the present invention, an organ that has been isolated from the blood flow in the body of a subject is preferably intended to be reconnected to the blood flow.

[0040] The present invention provides a method for treating a subject, comprising the step of administering a drug to an organ isolated from the bloodstream within the subject's body. The present invention also provides a method for treating a disease in a subject, comprising the step of administering a drug to an organ isolated from the bloodstream within the subject's body. These methods may include the step of isolating the organ from the bloodstream within the subject's body. These methods may also include the step of reconnecting the organ, which has been isolated from the bloodstream within the subject's body and to which a drug has been administered, to the bloodstream. Furthermore, the step prior to reconnection to the bloodstream may include one or more of a step of washing with a secondary fluid that does not contain the drug used, or a step of detoxifying or neutralizing the drug. Disease treatments include not only disease therapy, but also pre-transplant treatment and disease prevention. Disease treatments include complete cure of disease, amelioration of disease symptoms, and alleviation of disease symptoms.

[0041] The present invention provides pharmaceutical compositions for administration to an organ in a subject's body that is independent of the bloodstream. The present invention also provides pharmaceutical compositions for administration to an organ in a subject's body that is independent of the bloodstream for treating a subject. The present invention also provides pharmaceutical compositions for administration to an organ in a subject's body that is independent of the bloodstream for treating a disease in a subject.

[0042] The present invention provides the use of a drug in the manufacture of a pharmaceutical composition for administration to an organ in the body of a subject that is independent of the bloodstream.The present invention provides the use of a drug in the manufacture of a pharmaceutical composition for administration to an organ in the body of a subject that is independent of the bloodstream, for treating a subject.Further, the present invention provides the use of a drug in the manufacture of a pharmaceutical composition for administration to an organ in the body of a subject that is independent of the bloodstream, for treating a disease in a subject.

[0043] Equipment: Hereinafter, embodiments of the present invention relating to a device such as a catheter will be described with reference to Figures 1 to 10. However, the present invention is not limited to the embodiments shown in Figures 1 to 10.

[0044] The catheter shown in Figures 1 and 2 includes a first tube 10, a second tube 11, a balloon 14, and a balloon 15. Figure 1 shows only one end of the catheter shown in Figures 1 and 2, and Figure 2 shows only the other end of the catheter shown in Figures 1 and 2. The left side of Figure 1 is omitted, and the right side of Figure 2 is omitted, but the left side of Figure 1 and the right side of Figure 2 are continuous.

[0045] The catheter shown in FIGS. 1 and 2 includes balloons 14 and 15 in FIG. 1, which allows for well-balanced shielding. However, the number of balloons included is not limited to two and may be one or more. In FIG. 1, balloon 14 is filled with gas 16. In FIG. 1, balloon 15 is filled with gas 17. Although not shown in FIG. 1, the catheter shown in FIGS. 1 and 2 may include a third tube for filling balloon 14 with gas 16. Although not shown in FIG. 1, the catheter shown in FIGS. 1 and 2 may include a fourth tube for filling balloon 15 with gas 17. The third tube and the fourth tube may be the same. That is, the third tube may be used to fill balloon 15 with gas 17.

[0046] 1 and 2, a first tube 10 has a first tube first opening 12 and a first tube second opening 22. A first liquid flows in from the first tube first opening 12 in the direction of the solid arrow in FIGS. 1 and 2, and flows out from the first tube second opening 22 in the direction of the solid arrow in FIGS.

[0047] 1 and 2, the second tube 11 has a second tube first opening 23, a second tube second opening 13, and an end 24. A second liquid flows in from the second tube first opening 23 in the direction of the dotted arrow in FIGS. 1 and 2, and flows out from the second tube second opening 13 in the corresponding direction.

[0048] The first liquid preferably contains a drug.

[0049] The second liquid preferably does not contain any of the drugs contained in the first liquid. However, when ECMO or the like is used, drugs that improve blood fluidity, such as antiplatelet drugs and anticoagulants, may be included.

[0050] The catheter shown in Figures 3 and 4 includes a first tube 30, a second tube 31, a balloon 34, and a balloon 35. Figure 3 shows only one end of the catheter shown in Figures 3 and 4, and Figure 4 shows only the other end of the catheter shown in Figures 3 and 4. The left side of Figure 3 is omitted from the configuration, and the right side of Figure 4 is omitted from the configuration, but the left side of Figure 3 and the right side of Figure 4 are continuous.

[0051] The catheter shown in Figures 3 and 4 includes balloons 34 and 35 in Figure 3, which allows for well-balanced shielding. However, the number of balloons included is not limited to two and may be one or more. In Figure 3, balloon 34 is filled with gas 36. In Figure 3, balloon 35 is filled with gas 37. Although not shown in Figure 3, the catheter shown in Figures 3 and 4 may include a third tube for filling balloon 34 with gas 36. Although not shown in Figure 3, the catheter shown in Figures 3 and 4 may include a fourth tube for filling balloon 35 with gas 37. The third tube and the fourth tube may be the same. That is, the third tube may be used to fill balloon 35 with gas 37.

[0052] 3 and 4, the first tube 30 has a first tube first opening 32 and a first tube second opening 42. A first liquid flows in from the first tube first opening 32 in the direction of the solid arrows in FIGS. 3 and 4, and flows out from the first tube second opening 42 in the direction of the solid arrows in FIGS. 3 and 4.

[0053] In the catheter shown in Figures 3 and 4, the second tube 31 has a second tube first opening 43, a second tube second opening 33, and an end 44. A second liquid flows in from the second tube first opening 43 in the direction of the dotted arrow in Figures 3 and 4, and flows out from the second tube second opening 33 in the direction of the dotted arrow in Figures 3 and 4. The second tube 31 surrounds the first tube 30. That is, the second liquid contacts not only the inner wall of the second tube 31 but also the outer wall of the first tube 30.

[0054] The first liquid preferably contains a drug.

[0055] The second liquid preferably does not contain any of the drugs contained in the first liquid. However, when ECMO or the like is used, drugs that improve blood fluidity, such as antiplatelet drugs and anticoagulants, may be included.

[0056] In FIG. 4, the end 44 of the second tube 41 surrounds the first tube 40, but the portion of the second tube 41 that contacts the first tube 40 is flexible, seamless, and tightly sealed, but allows the first tube 40 to move slightly.

[0057] The catheter shown in Figures 5 to 7 includes a first tube 50, a second tube 51, a third tube 52, a balloon 58, and a balloon 59. Figures 5 and 6 show only one end of the catheter shown in Figures 5 to 7, and Figure 7 shows only the other end of the catheter shown in Figures 5 to 7. The left side of Figures 5 and 6 omits some components, and the right side of Figure 7 omits some components, but the left side of Figures 5 and 6 and the right side of Figure 7 are continuous. In Figure 5, the balloon support part 53 of the second tube compresses the balloon 58, and the balloon support part 54 of the third tube compresses the balloon 59. In Figure 6, the balloon support part 53 of the second tube releases the balloon 58, and the balloon support part 54 of the third tube releases the balloon 59.

[0058] The catheters shown in FIGS. 5 to 7 include balloons 58 and 59 in FIG. 5, which allows for well-balanced shielding. However, the number of balloons included is not limited to two and may be one or more. In FIG. 5, balloon 58 is filled with gas 501. In FIG. 5, balloon 59 is filled with gas 502. Although not shown in FIG. 5, the catheters shown in FIGS. 5 to 7 may include a third tube for filling balloon 58 with gas 501. Although not shown in FIG. 5, the catheters shown in FIGS. 5 to 7 may include a fourth tube for filling balloon 59 with gas 502. The third tube and the fourth tube may be the same. That is, the third tube may be used to fill balloon 59 with gas 502. However, with the catheter shown in Figures 5 to 7, as will be described later, balloon 58 is compressed and released using balloon support portion 53 of the second tube, and balloon 59 is compressed and released using balloon support portion 54 of the third tube, so there is no need to provide a third tube and a fourth tube.

[0059] 5 to 7, the first tube 50 has first tube first openings 55, 65 and a first tube second opening 72. A first liquid flows in from the first tube first openings 55, 65 in the direction of the solid arrows in FIGS. 5 to 7, and flows out from the first tube second opening 65 in the direction of the solid arrow in FIGS.

[0060] In the catheter shown in Figures 5 to 7, the second tube 71 branches into second tubes 51, 61 and third tubes 52, 62 at the end shown in Figures 5 and 6. The second tube 71 has a second tube first opening 73. The second tubes 51, 61 have a second tube balloon support portion 53 and a second tube second opening 56. The second tubes 51, 61 are fixed to the first tube 50 at at least the fixing portion 503. The third tubes 52, 62 have a third tube balloon support portion 54 and a third tube second opening 57. The third tubes 52, 62 are fixed to the first tube 50 at at least the fixing portion 504. The second tube balloon support portion 53 shown in Figure 5 is made of a hard material. The second tube balloon support portion 53 shown in Figure 5 slides when the end shown in Figure 7 is pulled, and transitions to the second tube balloon support portion 63 shown in Figure 6. This allows the balloon support portion 53 of the second tube to release the balloon 58. The balloon support portion 54 of the second tube shown in FIG. 5 is made of a hard material. The balloon support portion 54 of the second tube shown in FIG. 5 slides by pulling the end shown in FIG. 7 and transitions to the balloon support portion 64 of the second tube shown in FIG. 6. This allows the balloon support portion 54 of the second tube to release the balloon 59. The second liquid flows in from the first opening 73 of the second tube in the direction of the dotted arrows in FIGS. 5 to 7, flows out from the second openings 56 and 66 of the second tube in the direction of the dotted arrows in FIGS. 5 to 7, and flows out from the second openings 57 and 67 of the third tube in the direction of the dotted arrows in FIGS. 5 to 7. The second tubes 51, 61, and 71 and the third tubes 52 and 62 surround the first tube 50.

[0061] The second opening 56 of the second tube is preferably not at the end of the second tube 51. The second opening 57 of the third tube is preferably not at the end of the third tube 52.

[0062] The first liquid preferably contains a drug.

[0063] The second liquid preferably does not contain any of the drugs contained in the first liquid. However, when ECMO or the like is used, drugs that improve blood fluidity, such as antiplatelet drugs and anticoagulants, may be included.

[0064] 1 to 7, a mechanical umbrella-shaped blood flow stopper may be used instead of a balloon to avoid risks associated with the balloon, such as balloon rupture. That is, in the device of the present invention, the shielding part is not limited to a balloon.

[0065] The catheters shown in Figures 1 to 7 may include a pin for rupturing the balloon. The pin is preferably a flexible pin disposed within the sheath, and the pin is bent outward. The pin does not interfere with the operation during insertion. In order to manipulate the balloon, the sleeve can be pulled or pushed as a means of avoiding damage due to friction between the sheath and the blood vessel. To rupture the balloon, the sheath can be pushed toward the balloon.

[0066] 8 to 10 are diagrams showing the configuration when a catheter according to an embodiment of the present invention is applied to a human body. When a catheter according to an embodiment of the present invention is applied to a human body, two catheters according to an embodiment of the present invention are used. Here, the two catheters used are referred to as a first catheter and a second catheter. The first catheter refers to the upper catheter of the two catheters shown in FIG. 8. The second catheter refers to the lower catheter of the two catheters shown in FIG. 8. The catheter shown in FIG. 9 is the first catheter. The catheter shown in FIG. 10 is the second catheter.

[0067] As shown in FIGS. 8 to 10 , a first liquid is supplied to an organ through a first opening of a first tube of a first catheter. The first liquid is collected from the organ through a first opening of a first tube of a second catheter. The first liquid collected through the first opening of the first tube of the second catheter is sent to the first opening of the first tube of the first catheter via a first pump 82. This allows the first liquid to circulate only in the organ. The organ is shielded by a balloon on the first catheter and a balloon on the second catheter. The first liquid preferably contains a drug. The first pump may be connected to a device such as an ECMO that introduces oxygen or the like into the blood to keep the isolated organ alive. The first pump may also include a sensor that monitors the drug concentration. The first pump may also include an injection system that administers the drug. The first pump preferably has these configurations.

[0068] As shown in FIGS. 8 to 10, the second liquid is collected from the second opening of the second tube of the first catheter. The second liquid collected from the second opening of the second tube of the first catheter is discharged from the second opening of the second tube of the second catheter via the second pump 81. This enables the circulation of the second liquid that was blocked to circulate the first liquid only in the organ. The second pump may include a device that replaces the function that the isolated organ provided to the whole body (ECMO, etc., in the case of an isolated lung). The second pump may include a sensor that monitors the health of blood throughout the body. The second pump may include a syringe that administers a drug or the like that improves blood fluidity. The second pump preferably has these configurations.

[0069] The method of the present invention allows for the return of a secondary fluid to a single organ within the body by placing a specific organ between the arterial and venous sections, assuming that the pipe is a blood vessel in the human body. In this case, the organ is separated from the body, and the organ's previous role must be replaced by a specific treatment. For example, if the lungs are separated, oxygen is introduced into the blood by connecting to ECMO. The method of the present invention can be applied to a method for treating a specific organ using a secondary fluid containing a drug. Furthermore, the method of the present invention can be applied to more effective treatment by monitoring the secondary fluid with a sensor and maintaining the drug concentration at its maximum. In treatments where drugs approved for human use are always used at their maximum concentration, the amount of drug introduced into the body can be minimized by using a sufficient secondary fluid.

[0070] 1 to 10 show examples of catheters, but the device of the present invention is not limited to catheters and may be used, for example, for cleaning pipes or painting. Accordingly, in the present invention, methods for circulating a second liquid different from the first liquid in a part of a system through which a first liquid circulates, and circulating the first liquid in parts of the system through which the first liquid circulates excluding the part of the system through which the first liquid circulates, include not only actions performed as therapeutic actions on humans but also actions that are not performed as therapeutic actions on humans. [Example]

[0071] Example 1 Autoimmune Hepatitis Model (Target Organ: Liver): The groups were composed of (1) a sham operation group, which only underwent perfusion surgery; (2) a positive control group, which underwent perfusion surgery and administered steroids systemically; and (3) a perfusion group, which underwent perfusion surgery and perfused steroids only to the liver. The protocol involves inducing autoimmune hepatitis with S100 protein, followed by perfusion surgery in mice (groups (1) and (2) undergo perfusion surgery alone, while group (3) undergoes perfusion with steroids). Group (2) also receives systemic administration of steroids. After drug administration, the therapeutic effect on the liver of autoimmune hepatitis is evaluated. After drug administration, renal function, a systemic side effect of steroids, will be evaluated.

[0072] Example 2 Normal mouse (target organ: heart): The groups will be (1) negative control (untreated), (2) a group in which p53 ASO is administered systemically, and (3) a group in which p53 ASO (antisense oligonucleotide) is perfused only in the heart. The protocol was as follows: (1) group received no treatment; (2) group received only systemic administration of p53 ASO; and (3) group received perfusion of p53 ASO only in the heart. Hearts from each group will be collected, total RNA will be extracted, and the amount of p53 mRNA will be quantitatively measured and compared. Furthermore, since ASOs do not easily accumulate in the heart when administered systemically, it may be easier to confirm their effects when perfused.

[0073] Example 3 Bleomycin-induced pulmonary fibrosis model (target organ: lung): It has been reported that bleomycin-induced pulmonary fibrosis is partly due to the activation of p53 and the associated autocrine downstream signaling (Enomoto Y., et al., 2023, Nat. commn.). Suppression of p53 expression during bleomycin administration may suppress the induction of pulmonary fibrosis. Eight- to ten-week-old C57BL / 6 mice were randomly divided into three groups: (1) negative control (untreated), (2) a group receiving systemic administration of p53 ASO, and (3) a group receiving lung-only perfusion of p53 ASO. The protocol was as follows: (1) group was left untreated on the day before or immediately after bleomycin administration; (2) group was administered only systemic p53 ASO; and (3) group was administered p53 ASO only in the lungs. Induction of pulmonary fibrosis with bleomycin is carried out, for example, as follows. Eight- to ten-week-old C57BL / 6 mice were anesthetized with intraperitoneal administration of 10% pentobarbital (100 μL / g weight), and bleomycin (3 μg (2.88 U / g weight)) was administered intratracheally under tracheotomy. Lungs will be collected from each group, total RNA will be extracted, and the amount of p53 mRNA will be quantitatively measured and compared. In addition, the efficacy of p53 will be evaluated using fibrosis markers, such as surfactant protein D concentration in bronchoalveolar lavage fluid. Furthermore, since ASOs are less likely to accumulate in the lungs when administered systemically, it may be easier to confirm their effects during reflux.

[0074] Reflux surgery: Perfusion is performed, for example, using a Mera cardiopulmonary bypass machine or ECMO. For example, when using ECMO, blood supply and drainage cannulas (19-25 Fr for blood supply and 17-23 Fr for blood supply) are inserted through the femoral vein (blood supply side) and the internal jugular vein (blood supply side) to access the right atrium. After cannulation, the pump is connected and started. The pump flow rate is maintained at 50-80 mL / kg / min in humans, with an SpO2 target of 85% or higher. The sweep gas volume is approximately 30-40 mmHg. Other control parameters include platelets of 20,000-50,000 / μL or higher, a PT-INR (prothrombin time-international normalized ratio) of 2.0 or lower, fibrinogen of 100-200 mg / dL or higher, hemoglobin (Hb) >7-10 g / dL, and ATIII >50%. Nucleic acid drugs can be efficiently delivered to the heart and lungs by mixing them with the return blood and returning it to the right atrium. [Explanation of symbols]

[0075] 10 1st tube 11 Second Tube 12 First opening of first tube 13 Second opening of second tube 14 Balloon 15 Balloon 16 Gases 17 Gases 20 1st Tube 21 Second Tube 22 Second opening of first tube 23 First opening of second tube 24 End 30 1st Tube 31 Second Tube 32 First opening of first tube 33 Second opening of second tube 34 Balloon 35 Balloon 36 Gas 37 Gas 40 1st Tube 41 Second Tube 42 Second opening of first tube 43 First opening of second tube 44 End 50 1st Tube 51 Second Tube 52 3rd Tube 53 Balloon support part of second tube 54 Balloon support part of third tube 55 First opening of first tube 56 Second opening of second tube 57 Second opening of third tube 58 Balloon 59 Balloon 501 Gas 502 Gas 503 Fixed part 504 Fixed part 60 1st Tube 61 Second Tube 62 3rd Tube 63 Balloon support part of second tube 64 Balloon support part of the third tube 65 First opening of first tube 66 Second opening of second tube 67 Second opening of third tube 68 Balloon 69 Balloon 601 Gas 602 Gas 603 Fixed part 604 Fixed part 70 1st Tube 71 2nd Tube 72 Second opening of first tube 73 First opening of second tube 81 Second Pump 82 First Pump

Claims

1. An apparatus for circulating a first liquid, which is different from the second liquid, in a part separate from a system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising: a shielding portion for shielding the partial area from the second liquid; a first pipe for passing a first liquid through it; a second pipe for passing a second liquid therethrough; Equipped with The first pipe and the second pipe extend along a line parallel to each other, A shielding portion is disposed along the railway line, the first pipe has an opening for the inflow of the first liquid and an opening for the outflow of the first liquid; the second pipe has an opening for the second liquid to flow in and an opening for the second liquid to flow out; the shielding portion is located downstream of an opening portion of the first pipe for allowing the first liquid to flow in, based on a direction in which the first liquid flows in the first pipe; an opening in the second pipe for allowing the second liquid to flow out is located downstream of the shielding portion with respect to a flow direction of the first liquid in the first pipe; an opening in the second pipe for allowing the second liquid to flow in is located downstream of the shielding portion with respect to the flow direction of the first liquid in the first pipe; Equipment.

2. An apparatus for circulating a first liquid, which is different from the second liquid, in a part separate from a system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising: a shielding portion for shielding the partial area from the second liquid; a first pipe for passing a first liquid through it; a second pipe for passing a second liquid therethrough; Equipped with The first pipe and the second pipe extend along a line parallel to each other, A shielding portion is disposed along the railway line, a direction in which the second liquid flows through the second pipe is opposite to a direction in which the first liquid flows through the first pipe; the first pipe has an opening for the inflow of the first liquid and an opening for the outflow of the first liquid; the second pipe has an opening for the second liquid to flow in and an opening for the second liquid to flow out; the shielding portion is located downstream of an opening portion of the first pipe for allowing the first liquid to flow in, based on a direction in which the first liquid flows in the first pipe; an opening in the second pipe for allowing the second liquid to flow out is located downstream of the shielding portion with respect to the flow direction of the first liquid in the first pipe; Equipment.

3. An apparatus for circulating a first liquid, which is different from the second liquid, in a part separate from a system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising: a shielding portion for shielding the partial area from the second liquid; a first pipe for passing a first liquid through it; a second pipe for passing a second liquid therethrough; Equipped with The first pipe and the second pipe extend along a line parallel to each other, A shielding portion is disposed along the railway line, the first pipe has an opening for the inflow of the first liquid and an opening for the outflow of the first liquid; the second pipe has an opening for the second liquid to flow in and an opening for the second liquid to flow out; the shielding portion is located upstream of an opening in the first pipe for allowing the first liquid to flow out, based on a direction in which the first liquid flows in the first pipe; an opening in the second pipe for allowing the second liquid to flow in is located upstream of the shielding portion with respect to the flow direction of the first liquid in the first pipe; Equipment.

4. An apparatus for circulating a first liquid, which is different from the second liquid, in a part separate from a system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising: a shielding portion for shielding the partial area from the second liquid; a first pipe for passing a first liquid through it; a second pipe for passing a second liquid therethrough; Equipped with The first pipe and the second pipe extend along a line parallel to each other, An apparatus in which the direction in which the second liquid flows in a second pipe for flowing the second liquid is opposite to the direction in which the first liquid flows in a first pipe for flowing the first liquid.

5. a first pipe for passing a first liquid therethrough is connected to a first pump for circulating the first liquid; a second pipe for passing a second liquid therethrough, the second pipe being connected to a second pump for circulating the second liquid; The device according to any one of claims 1 to 4.

6. 10. An apparatus comprising the device of claim 1 or 2, the device of claim 3, a first pump for circulating a first liquid, and a second pump for circulating a second liquid.

7. The device according to any one of claims 1 to 4, wherein the device is a catheter.

8. A method for circulating a second liquid in a system in which the second liquid is circulated, comprising circulating a first liquid, which is different from the second liquid, in a portion separate from a portion of the system in which the second liquid is circulated, the method comprising: Using the device according to any one of claims 1 to 4, A method that is not performed as a therapeutic intervention on humans.

9. the shielding portion is disposed around the first pipe; The device according to any one of claims 1 to 4, wherein an end of a second pipe for passing a second liquid compresses and stores the shielding portion disposed around the first pipe.

10. the shielding portion is disposed around the first pipe; The device according to any one of claims 1 to 4, wherein an end of a second pipe for passing a second liquid covers the shielding portion disposed around the first pipe, and the shielding portion is exposed by sliding toward the other end of the second pipe.

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