Method for local administration of drug

Abstract

The purpose of the present invention is to provide a technique that makes it possible to selectively administer a drug to a specific site, improves the efficiency of development of pharmaceutical products and clinical trials, and further increases the possibility of obtaining manufacturing and marketing approval and enhances feasibility from a medical economic perspective.　The present invention provides a method for producing a pharmaceutical composition for treating a specific disease, the pharmaceutical composition being subject to manufacturing and marketing approval, the method comprising a step for administering a drug only to a body site of a subject that has been isolated from the blood flow in the body of the subject.

Description

Method for Local Administration of a Drug

[0001] <First Invention> The present invention relates to a method for local administration of a drug.

[0002] <Second Invention> The present invention relates to an animal with independent perfusion of an internal body site.

[0003] <Third Invention> The present invention relates to a method for producing a pharmaceutical composition for treating a specific disease.

[0004] <First Invention / Third Invention> The main cause of toxicity exerted by pharmaceuticals on humans is that active ingredients act not only on lesions and target cells, but also on healthy tissues and cells. In addition, depending on factors such as differences in metabolic capacity due to individual variation, administration route, and preparation form, even the same drug may be more likely to cause severe side effects. If such toxicity becomes manifest, not only does it become difficult to continue treatment, but there is also a risk of significantly impairing the patient's QOL (quality of life). Therefore, ensuring efficacy while reducing toxicity is a very important issue in pharmaceutical development and clinical practice.

[0005] Examples of strategies for reducing toxicity include devising preparation designs and dosage forms. The use of sustained-release preparations or controlled-release preparations makes it possible to suppress rapid increases in blood drug concentration and alleviate side effects. In addition, methods for avoiding systemic toxicity by improving the administration route itself, such as inhalants, eye drops, and local injection, are also effective. Furthermore, by utilizing drug delivery systems (DDS) and prodrug design to introduce a mechanism that activates the drug only at the target site, drug exposure to unnecessary sites can be reduced. In particular, DDS using nanoparticles and liposomes can be used as a technique to intensively deliver drugs only to cancer tissue and minimize side effects. However, all of these are individual technologies that require optimization for each drug and treatment, and are not general-purpose.

[0006] Non-Patent Document 1 describes that mechanical perfusion technology and drug administration have been studied to reduce ischemia-reperfusion injury during renal transplantation. In Non-Patent Document 1, perfusion methods at low temperature, low-temperature oxygen supply, and normal temperature were compared, and antioxidants (NAC, quercetin), complement inhibitors (C1-INH, siRNA), hydrogen sulfide (H ２It is stated that the effects of S) were examined.

[0007] Non-patent document 2 explores the possibility of applying gene therapy during extracorporeal cardiac perfusion during heart transplantation. Non-patent document 2 states that while conventional static preservation methods pose problems such as myocardial damage and ischemia-reperfusion injury, mechanical perfusion may allow for the direct application of gene therapy and improvement of the cardiac condition. In particular, gene transfer using adenoviruses, adeno-associated viruses, and liposomes is being investigated, and it is stated that these can be used to mitigate ischemia-reperfusion injury, regulate immune responses, and correct pathogenic gene mutations.

[0008] Non-patent document 3 describes a study that verified that ambient temperature extracorporeal kidney perfusion reduces ischemia-reperfusion injury in kidney transplantation. In a study comparing ambient temperature extracorporeal kidney perfusion with conventional static refrigeration using a pig kidney transplantation model, the ambient temperature extracorporeal kidney perfusion group maintained mitochondrial function, had higher ATP levels, and suppressed oxidative stress and inflammation after transplantation. Furthermore, administration of the hydrogen sulfide donor AP39 during ambient temperature extracorporeal kidney perfusion further improved mitochondrial function and improved kidney function after transplantation. Non-patent document 3 suggests that the combined use of ambient temperature extracorporeal kidney perfusion and AP39 may be a new kidney preservation and transplantation strategy.

[0009] <Second Invention> Techniques for inserting a catheter into a blood vessel in an animal and performing contrast imaging, drug administration, or embolization are conventionally known.

[0010] For example, Non-Patent Document 4 discloses a model in which embolic stroke is induced in rats by inserting a microcatheter into the tail artery and transporting a thrombus to the middle cerebral artery region. While this technique offers excellent reproducibility of intravascular navigation and embolus creation under fluoroscopy, the animals maintain systemic circulation, and it is not intended to completely isolate specific internal body parts from the systemic circulation.

[0011] Furthermore, Non-Patent Document 5 describes a method in which angiography of the entire body or multiple organs can be performed in marmosets simply by percutaneously puncturing the tail artery and inserting a catheter, while maintaining systemic circulation. While this document is characterized by its minimally invasive approach to vascular access, the purpose of the contrast is to visualize blood vessels in vivo, and it does not isolate the target internal body part from the systemic circulation.

[0012] In other words, both Non-Patent Document 4 and Non-Patent Document 5 are classified as in vivo vascular access techniques that maintain systemic blood flow, and no animal model in which an internal organ is completely isolated from the systemic circulation and only that internal organ is externally perfused (isolated-organ perfusion model) is disclosed in these prior art documents.

[0013] Front Immunol. 2021 Jul 6:12:673562.Front Cardiovasc Med. 2023 Oct 16:10:1264449.Nat Commun. 2024 Sep 15;15(1):8086.Transl Stroke Res. 2025 Aug; 16(4):1331-1339.PLoS One. 2021 Apr 28; 16(4):e0250576.

[0014] <First Invention> The present invention aims to enhance the efficacy of a drug in a specific body part by treating that part with a high concentration, eliminate side effects in other parts of the body, and reduce drug costs by reducing the amount of drug used compared to systemic administration.

[0015] <Second Invention> However, in the development of drugs, contrast agents, drug delivery systems (DDS), and in the study of site-specific efficacy and toxicity evaluation, conventional in vivo systemic administration models have the following problems (1) to (6).

[0016] (1) If the drug's ability to reach the target site in the body is low, the drug's efficacy itself cannot be evaluated. Nucleic acid drugs, antibody drugs, etc., do not reach the target site in the body sufficiently, making it impossible to measure the true potential of their pharmacological activity. (2) Because systemic circulation exists, side effects due to exposure to other parts of the body hinder evaluation. Drug efficacy evaluation is often impossible due to off-target toxicity such as nephrotoxicity, hepatotoxicity, and myelotoxicity. (3) Local pharmacokinetics (uptake, retention, excretion) at a specific site in the body cannot be evaluated in isolation. Systemic blood flow interferes, making PK analysis at the site-by-site level difficult. (4) There are no models that observe the site-specific behavior of contrast agents, DDS, nanoparticles, etc., without the influence of other sites. (5) There are no systems that verify the safety and efficacy of high-concentration drug administration at a single site in the body. High-concentration evaluation is impossible because systemic toxicity appears first. (6) There are no in vivo models that apply therapeutic procedures only to a specific site in the body, such as pre-transplant treatment.

[0017] Thus, conventional technologies lacked a model for individually perfusing specific body parts in an in vivo state, making it impossible to perform truly site-specific pharmacological evaluations.

[0018] Therefore, the present invention aims to provide an in vivo model in which a specific internal body part of a target animal is completely isolated from the systemic circulation, and only that internal body part is circulated via an external perfusion circuit.

[0019] This model is expected to enable the achievement of objectives that were impossible with conventional technology, including: (1) evaluation of drug efficacy at individual sites within the body; (2) evaluation of local toxicity at specific sites within the body (pure measurement excluding systemic toxicity); (3) analysis of site-specific pharmacokinetics (uptake, retention, and excretion); (4) evaluation of the true pharmacological activity of nucleic acid drugs and antibody drugs; (5) evaluation of the localization of contrast agents, DDSs, nanoparticles, etc., at specific sites within the body; (6) verification of in situ gene therapy and drug therapy targeting specific sites within the body; and (7) construction of a local treatment model equivalent to pretreatment for transplantation at specific sites within the body.

[0020] <Third Invention> When applying a drug to a specific site in the body, it is desirable to enhance the drug's effect at that site while suppressing systemic effects.

[0021] However, since conventional drugs are designed and evaluated on the premise of systemic administration, development of even promising drugs may be discontinued due to systemic toxicity concerns. Furthermore, clinical trials based on systemic administration place a heavy burden on safety assessment, tending to increase development costs and time, and in particular, for highly toxic drugs, it may be difficult to even proceed to clinical trials.

[0022] Furthermore, if a drug is expensive, the dosage will be high if it is administered systemically, which may lead to restrictions on its use in actual medical practice for economic reasons. As a result, even drugs that are expected to be effective may become practically unavailable.

[0023] Furthermore, depending on the administration method and application form, it may be difficult to qualify for insurance coverage, potentially increasing the burden on patients.

[0024] Thus, there is a gap between optimizing the drug's action on a specific site and the development, clinical trials, approval, and commercialization of the drug.

[0025] Therefore, the present invention aims to provide a technology that enables selective drug administration to specific sites, improves the efficiency of drug development and clinical trials, and further enhances the feasibility of obtaining manufacturing and marketing approval and from a health economic perspective.

[0026] <First Invention> The inventors have conducted diligent research and found that by isolating a specific body part from the body's blood flow and administering a drug to that body part, the drug can be localized only to that body part and not to other areas, thereby suppressing drug side effects. The inventors have found that by temporarily isolating a specific body part from the body's blood flow, treating that body part with a drug, and then reconnecting it to the blood flow, it is possible to treat only that specific body part with a high concentration of drug, thereby not only enhancing the drug's efficacy in that body part but also eliminating side effects in other body parts. Furthermore, they have found that the amount of drug used, such as antisense oligonucleotides (hereinafter sometimes referred to as ASOs), which have high manufacturing costs, can be reduced compared to systemic administration, thereby suppressing drug costs. The inventors have also developed a device used to temporarily isolate a specific body part from the body's blood flow, treat that body part with a drug, and then reconnect it to the blood flow.

[0027] Since methods such as pulmonary perfusion (EVLP) are already established in transplantation, it is possible to temporarily isolate specific parts of the body from the body's blood flow and administer drugs to them.

[0028] <Second Invention> After diligent research, the inventors have found that the above problem can be solved by constructing an isolated-organ perfusion system in which a specific internal organ of an animal is isolated from the systemic circulation while remaining in vivo, a catheter inserted into the internal organ artery and internal organ vein is connected to an external perfusion circuit, and a perfusion fluid (drug, contrast agent, etc.) supplied from the outside is circulated only within the internal organ.

[0029] More specifically, we established a model in which only the kidney is circulated by an external circuit by cannulating catheters into the renal artery and renal vein, then ligating the renal artery and renal vein along with the catheters, pumping perfusion fluid from the introduction catheter, and collecting the perfusion fluid from the return catheter.

[0030] This configuration is fundamentally different from conventional ex vivo perfusion models and in vivo systemic administration models in that it maintains the presence of internal organs within the body while completely eliminating interference from other parts of the body and systemic blood flow.

[0031] <Third Invention> In order to solve the above problems, the present invention provides a method for producing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, and which includes a step of administering the drug only to an internal body part that is independent of the blood flow in the body of the target.

[0032] According to the present invention, it becomes possible to design and develop pharmaceutical compositions based on the premise that the drug will act only on specific sites within the body, freeing oneself from the conventional constraints that dictate systemic administration. As a result, it becomes possible to apply drugs that were difficult to evaluate from the perspective of systemic toxicity, thereby expanding the scope of pharmaceutical development.

[0033] Furthermore, because this configuration can suppress systemic effects, the burden of safety evaluation is reduced, and the efficiency of clinical trials can be improved. In addition, even for drugs that were previously difficult to obtain manufacturing and marketing approval for from a toxicity standpoint, the possibility of obtaining approval can be increased by using the method of the present invention.

[0034] In addition, by limiting the target of drug administration to specific body parts, the required amount of drug can be reduced, making even expensive drugs usable at a realistic cost. Thus, the present invention has a configuration that simultaneously alleviates the constraints of both drug toxicity and economic feasibility.

[0035] Furthermore, by employing a configuration in which the drug is recovered after administration, the impact on systemic circulation can be controlled more appropriately, and the system can be implemented in a manner that is also feasible from the standpoint of medical costs.

[0036] In other words, the present invention provides the following: <First Invention> [Aspect A-1] A drug for administration to a body site independent of the blood flow within the body of a target. [Aspect A-2] The drug according to Aspect A-1, wherein the target is a mammal. [Aspect A-3] The drug according to Aspect A-1, wherein the target is a human. [Aspect A-4] The drug according to Aspect A-1, wherein the body site is the liver, heart, lungs, pancreas, spleen, kidney, brain, spinal cord, small intestine, lower limb, upper arm, bladder, or pelvis. [Aspect A-5] The drug according to Aspect A-1, wherein the drug is a low molecular weight drug or a high molecular weight drug. [Aspect A-6] The drug according to Aspect A-5, wherein the high molecular weight drug is an antibody drug, protein, peptide drug, or nucleic acid drug. [Aspect A-7] The drug according to Aspect A-6, wherein the nucleic acid drug is an antisense oligonucleotide, siRNA, miRNA, aptamer, decoy, CpG oligo, or mRNA. [Aspect A-8] The drug according to Aspect A-7, wherein the antisense oligonucleotide is a p53 antisense oligonucleotide. [Aspect A-9] The drug according to Aspect A-5, wherein the small molecule drug is an anticancer drug, an anti-infective drug, an immunosuppressant, an anti-inflammatory drug, or a steroid. [Aspect A-10] The drug according to Aspect A-1, wherein the subject is suffering from a disease. [Aspect A-11] The drug according to Aspect A-10, wherein the disease is lung cancer, osteosarcoma, bladder cancer, cervical cancer, renal pelvis cancer, kidney cancer, autoimmune hepatitis, neuroendocrine tumor, glioma, bacterial and viral hepatitis, or pulmonary fibrosis. [Aspect A-12] The drug according to Aspect A-1, for use in combination with a transfection reagent. [Aspect A-13] The drug according to Aspect A-1, for reconnecting an internal body part isolated from the blood flow in the subject to the blood flow again. [Aspect A-14] A device for circulating a first liquid, 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 excluding the part in question, the device comprising: a shielding part for shielding the part in question; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid.[Aspect A-15] The apparatus according to aspect A-14, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the shielding portion is located downstream of the opening for introducing the first liquid in the first pipe with reference to the direction in which the first liquid flows in the first pipe, and the opening for discharging the second liquid in the second pipe is located downstream of the shielding portion with reference to the direction in which the first liquid flows in the first pipe. [Aspect A-16] The apparatus according to aspect A-14, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the shielding portion is located upstream of the opening for discharging the first liquid in the first pipe, with reference to the direction in which the first liquid flows in the first pipe, and the opening for introducing the second liquid in the second pipe is located upstream of the shielding portion, with reference to the direction in which the first liquid flows in the first pipe. [Aspect A-17] The apparatus according to aspect A-14, wherein in the second pipe for introducing the second liquid, the direction in which the second liquid flows is reversed with reference to the direction in which the first liquid flows in the first pipe for introducing the first liquid. [Aspect A-18] The apparatus according to aspect A-14, wherein a first pipe for circulating a first liquid is connected to a first pump for circulating the first liquid, and a second pipe for circulating a second liquid is connected to a second pump for circulating the second liquid. [Aspect A-19] An apparatus comprising the apparatus according to aspect A-15, the apparatus according to aspect A-16, a first pump for circulating a first liquid, and a second pump for circulating a second liquid. [Aspect A-20] The apparatus according to aspect A-14, wherein the apparatus is a catheter.[Aspect A-21] A method for circulating a second liquid, different from the first liquid, in a part of a system through which the first liquid circulates, and circulating the first liquid in a part of the system through which the first liquid circulates, excluding that part, the method using the apparatus described in Aspect A-14. [Aspect A-22] The apparatus described in Aspect A-14, wherein the end of the second pipe for circulating the second liquid compresses and stores the shielding portion. [Aspect A-23] The apparatus described in Aspect A-14, wherein the end of the second pipe for circulating the second liquid covers the shielding portion and exposes the shielding portion by sliding toward the other end of the second pipe.

[0037] [Aspect B-1] A device for circulating a first liquid, different from the second liquid, in a part of the 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 part for shielding the part of the system from the second liquid; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along a line toward each other, the shielding part is positioned along the line, the first pipe has an opening for the first liquid to flow in and an opening for the first liquid to flow out, the second pipe has an opening for the second liquid to flow in and an opening for the second liquid to flow out, and the shielding part is located downstream of the opening for the first liquid to flow in the first pipe, with reference to the direction in which the first liquid flows in the first pipe. An apparatus wherein the opening in the second pipe for discharging the second liquid is located downstream of the shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the opening in the second pipe for inflowing the second liquid is located downstream of the shielding portion with reference to the direction in which the first liquid flows in the first pipe.[Aspect B-2] A device for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and in the system in which the second liquid circulates, the device comprises: a shielding part for shielding the part of the system from the second liquid; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along a line toward each other, the shielding part is positioned along the line, the direction in which the second liquid circulates in the second pipe for circulating the second liquid is opposite to the direction in which the first liquid circulates in the first pipe for circulating the first liquid, the first pipe has an opening for the first liquid to flow in and an opening for the first liquid to flow out, and 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 the opening in the first pipe for the inflow of the first liquid, with reference to the direction in which the first liquid flows through the first pipe, and the opening in the second pipe for the outflow of the second liquid is located downstream of the shielding portion, with reference to the direction in which the first liquid flows through the first pipe.[Aspect B-3] A device for circulating a first liquid different from the second liquid in a part of the system in which the second liquid circulates, wherein the device comprises: a shielding part for shielding the part from the second liquid; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along a line toward each other, the shielding part is positioned along the line, the first pipe has an opening for the first liquid to flow in and an opening for the first liquid to flow out, the second pipe has an opening for the second liquid to flow in and an opening for the second liquid to flow out, and the shielding part is located upstream of the opening for the first liquid to flow out in the first pipe, with reference to the direction in which the first liquid flows in the first pipe. Apparatus B-4: An apparatus for circulating a first liquid, which is different from the second liquid, in a part of the 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 part for shielding the part from the second liquid; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along each other, and in the second pipe for circulating the second liquid, the direction in which the second liquid circulates is opposite to the direction in which the first liquid circulates in the first pipe for circulating the first liquid. [Aspect B-5] The apparatus according to any one of aspects B-1 to B-4, wherein a first pipe for circulating a first liquid is connected to a first pump for circulating the first liquid, and a second pipe for circulating a second liquid is connected to a second pump for circulating the second liquid.[Aspect B-6] An apparatus comprising the instrument described in Aspect B-1 or 2, the instrument described in Aspect B-3, a first pump for circulating a first liquid, and a second pump for circulating a second liquid. [Aspect B-7] The instrument described in any one of Aspects B-1 to B-4, wherein the instrument is a catheter. [Aspect B-8] A method for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, the method being performed using the instrument described in any one of Aspects B-1 to B-4, and not performed as a medical treatment on a human being. [Aspect B-9] The instrument described in any one of Aspects B-1 to B-4, wherein the shielding portion is arranged around the first pipe, and the end of the second pipe for circulating the second liquid compresses and stores the shielding portion arranged around the first pipe. [Aspect B-10] The apparatus according to any one of aspects B-1 to B-4, wherein the shielding portion is arranged around the first pipe, and the end of the second pipe for circulating the second liquid covers the shielding portion arranged around the first pipe, and the shielding portion is exposed by sliding toward the other end of the second pipe.

[0038] [Aspect C-1] A site-specific localization agent for administration to a site in the body of a subject that is independent of the blood flow within the subject, wherein the site in the body that is independent of the blood flow within the subject is designed to reconnect with the blood flow within the subject. [Aspect C-2] The agent according to Aspect C-1, wherein the subject is a mammal. [Aspect C-3] The agent according to Aspect C-1, wherein the site in the body is the liver, heart, lungs, pancreas, spleen, kidney, brain, spinal cord, small intestine, lower limb, upper arm, bladder, or pelvis. [Aspect C-4] The agent according to Aspect C-1, wherein the drug is a low-molecular-weight drug or a high-molecular-weight drug. [Aspect C-5] The agent according to Aspect C-1, wherein the drug is a liquid. [Aspect C-6] The agent according to Aspect C-1, wherein, in the subject, the blood flow within the subject is not inhibited, except for the blood flow within the subject that is independent of the aforementioned site in the body. [Aspect C-7] A method for preparing a site-specific localization agent for administration to a site in the body isolated from the blood flow within the body of a subject, comprising the step of preparing the drug, wherein the site in the body isolated from the blood flow within the body of the subject is intended to reconnect with the blood flow within the subject. [Aspect C-8] The method according to Aspect C-7, wherein the drug is a liquid. [Aspect C-9] The method according to Aspect C-7, wherein the blood flow within the body of the subject is not inhibited, except for the blood flow within the body of the subject isolated from the site in the body. [Aspect C-10] A use of the drug in the manufacture of a site-specific localization agent for administration to a site in the body isolated from the blood flow within the body of a subject, wherein the site in the body isolated from the blood flow within the body of the subject is intended to reconnect with the blood flow within the subject. [Aspect C-11] The use according to Aspect C-10, wherein the drug is a liquid. [Aspect C-12] The use according to aspect C-10, wherein, in the subject, the blood flow within the subject's body is not obstructed, except for the blood flow within the subject's body that is independent of the internal body part.

[0039] [Aspect D-1] A site-specific localizing agent containing a drug, for administration to a site in the body that is independent of the blood flow within the body of the target, wherein the site in the body that is independent of the blood flow within the body of the target is connected to the blood flow again in the target, and a device for circulating a first liquid different from the second liquid in a part of the body separate from the 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 part for shielding the part of the body from the second liquid, a first pipe for circulating the first liquid, and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along a line toward each other, the shielding part is positioned along the line, the first pipe has an opening for the inflow of the first liquid and an opening for the outflow of the first liquid, and the second pipe has an opening for the inflow of the second liquid and an opening for the outflow of the second liquid. An agent for administration by a device, wherein the shielding portion is located downstream of the opening in the first pipe for introducing the first liquid, with reference to the direction in which the first liquid flows through the first pipe; the opening in the second pipe for discharging the second liquid is located downstream of the shielding portion, with reference to the direction in which the first liquid flows through the first pipe; and the opening in the second pipe for introducing the second liquid is located downstream of the shielding portion, with reference to the direction in which the first liquid flows through the first pipe.[Aspect D-2] A site-specific localizing agent for administration to a site in the body of a target that is independent of the blood flow within the target body, wherein the site in the body that is independent of the blood flow within the target body is connected to the blood flow again within the target, and a device for circulating a first liquid different from the second liquid in a part of the body separate from the 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 part for shielding the part of the body from the second liquid, a first pipe for circulating the first liquid, and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along a line toward each other, the shielding part is positioned along the line, and in the second pipe for circulating the second liquid, the direction in which the second liquid circulates is opposite to the direction in which the first liquid circulates in the first pipe for circulating the first liquid. An agent for administration by a device, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the shielding portion is located downstream of the opening for introducing the first liquid in the first pipe, with reference to the direction in which the first liquid flows in the first pipe, and the opening for discharging the second liquid in the second pipe is located downstream of the shielding portion, with reference to the direction in which the first liquid flows in the first pipe.[Aspect D-3] A site-specific localizing agent containing a drug, for administration to a site in the body that is independent of the blood flow within the body of the target, wherein the site in the body that is independent of the blood flow within the body of the target is connected to the blood flow again in the target, and a device for circulating a first liquid different from the second liquid in a part of the body separate from the 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 part for shielding the part of the body from the second liquid, a first pipe for circulating the first liquid, and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along a line toward each other, the shielding part is positioned along the line, the first pipe has an opening for the inflow of the first liquid and an opening for the outflow of the first liquid, and the second pipe has an opening for the inflow of the second liquid and an opening for the outflow of the second liquid, The shielding portion is located upstream of the opening in the first pipe for discharging the first liquid, with reference to the direction in which the first liquid flows through the first pipe, and the opening in the second pipe for letting in the second liquid is located upstream of the shielding portion, with reference to the direction in which the first liquid flows through the first pipe, for administration by an instrument.[Aspect D-4] A site-specific localized agent containing a drug, for administration to a site in the body that is independent of the blood flow within the body of a target, wherein the site in the body that is independent of the blood flow within the body of the target is connected to the blood flow again in the target, and the device circulates a first liquid different from the second liquid in a part of the body separate from the system in which the second liquid circulates, and circulates the second liquid in the system in which the second liquid circulates, comprising: a shielding part for shielding the part of the body from the second liquid; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid, wherein the first pipe and the second pipe extend along each other's lines, and the direction in which the second liquid circulates in the second pipe for circulating the second liquid is opposite to the direction in which the first liquid circulates in the first pipe for circulating the first liquid, for administration by the device. [Aspect D-5] The agent according to any one of aspects D-1 to D-4, wherein the device has a first pipe for circulating a first liquid which is connected to a first pump for circulating the first liquid, and a second pipe for circulating a second liquid which is connected to a second pump for circulating the second liquid. [Aspect D-6] A site-specific localized agent containing a drug, for administration to a site in the body that is isolated from the blood flow in the body of a subject, wherein the site in the body that is isolated from the blood flow in the body of the subject is connected to the blood flow again in the subject, and the agent is for administration by a device that includes the device according to aspect D-1 or aspect D-2, the device according to aspect D-3, a first pump for circulating a first liquid, and a second pump for circulating a second liquid. [Aspect D-7] The agent according to any one of aspects D-1 to D-4, wherein the device is a catheter. [Aspect D-8] A method for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, using the agent described in any one of aspects D-1 to D-4, and not performed as a medical treatment for a human being.[Aspect D-9] The agent according to any one of aspects D-1 to D-4, wherein the shielding portion is arranged around the first pipe, and the end of the second pipe for circulating the second liquid compresses and stores the shielding portion arranged around the first pipe. [Aspect D-10] The agent according to any one of aspects D-1 to D-4, wherein the shielding portion is arranged around the first pipe, and the end of the second pipe for circulating the second liquid covers the shielding portion arranged around the first pipe, and exposes the shielding portion by sliding toward the other end of the second pipe.

[0040] [Aspect E-1] An apparatus comprising an apparatus for administering a drug to an internal organ separated from the blood flow within a target body, and an apparatus for circulating the blood flow separated from the internal organ by bypassing the internal organ, wherein the internal organ separated from the blood flow within the target body is for reconnecting to the blood flow within the target body. [Aspect E-2] An apparatus for administering a drug to an internal organ separated from the blood flow within a target body, wherein the internal organ separated from the blood flow within the target body is for reconnecting to the blood flow within the target body, and the internal organ is a kidney. [Aspect E-3] An apparatus for administering a drug to an internal organ separated from the blood flow within a target body, wherein the internal organ separated from the blood flow within the target body is for reconnecting to the blood flow within the target body, and the apparatus is an apparatus for washing the internal organ with a secondary fluid that does not contain the drug, detoxifying the drug in the internal organ, or neutralizing the drug in the internal organ, in a step prior to reconnecting to the blood flow. [E-4] A device comprising: a device for administering a drug to an internal organ separated from the blood flow within the subject; and a device for recovering the drug administered to the internal organ separated from the blood flow within the subject, wherein the internal organ separated from the blood flow within the subject is intended to be reconnected to the blood flow within the subject (excluding a device that includes a device for filtering the recovered drug).

[0041] [Aspect F-1] An apparatus for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising: a first shielding part for shielding the part from the second liquid; a second shielding part for shielding the part from the second liquid; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid. [Aspect F-2] The apparatus according to aspect F-1, wherein the first pipe and the second pipe extend along a line, the first shielding part is located along the line, and the second shielding part is located along the line. [Aspect F-3] The apparatus according to aspect F-1, wherein in the second pipe for circulating the second liquid, the direction in which the second liquid circulates is reversed with respect to the direction in which the first liquid circulates in the first pipe for circulating the first liquid. [Aspect F-4] The apparatus according to aspect F-1, wherein in the second pipe for circulating the second liquid, the direction in which the second liquid circulates is the same with respect to the direction in which the first liquid circulates in the first pipe for circulating the first liquid. [Aspect F-5] The apparatus according to aspect F-1, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the opening in the first pipe for introducing the first liquid is located upstream of the first shielding portion with respect to the direction in which the first liquid flows in the first pipe, the first shielding portion is located upstream of the opening in the first pipe for discharging the first liquid with respect to the direction in which the first liquid flows in the first pipe, and the opening in the first pipe for discharging the first liquid is located upstream of the second shielding portion with respect to the direction in which the first liquid flows in the first pipe.[Aspect F-6] The apparatus according to aspect F-1, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the opening for discharging the first liquid in the first pipe is located downstream of the first shielding part with respect to the direction in which the first liquid flows in the first pipe, the first shielding part is located downstream of the opening for introducing the first liquid in the first pipe with respect to the direction in which the first liquid flows in the first pipe, and the opening for introducing the first liquid in the first pipe is located downstream of the second shielding part with respect to the direction in which the first liquid flows in the first pipe. [Aspect F-7] The apparatus according to aspect F-1, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is located upstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe, the first shielding portion is located upstream of the second shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located upstream of the opening for introducing the second liquid in the second pipe with reference to the direction in which the first liquid flows in the first pipe.[Aspect F-8] The apparatus according to aspect F-1, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is located downstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe, the first shielding portion is located downstream of the second shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located downstream of the opening for introducing the second liquid in the second pipe with reference to the direction in which the first liquid flows in the first pipe. [Aspect F-9] The apparatus according to aspect F-1, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is located upstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe, the first shielding portion is located upstream of the second shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located upstream of the opening in the second pipe for discharging the second liquid with reference to the direction in which the first liquid flows in the first pipe.[Aspect F-10] The apparatus according to aspect F-1, wherein the first pipe has an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe has an opening for introducing a second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is located downstream of the first shielding portion with respect to the direction in which the first liquid flows in the first pipe, the first shielding portion is located downstream of the second shielding portion with respect to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located downstream of the opening in the second pipe for discharging the second liquid with respect to the direction in which the first liquid flows in the first pipe. [Aspect F-11] The apparatus according to aspect F-1, further comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is connected to the opening for introducing the second liquid in the third pipe, and the opening for discharging the second liquid in the third pipe is located upstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe.[Aspect F-12] The apparatus according to aspect F-1, further comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is connected to the opening for introducing the second liquid in the third pipe, and the opening for discharging the second liquid in the third pipe is located downstream of the first shielding portion with reference to the direction in which the first liquid flows through the first pipe. [Aspect F-13] The apparatus according to aspect F-1, further comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is connected to the opening in the third pipe for discharging the second liquid, and the opening in the third pipe for introducing the second liquid is located upstream of the first shielding portion with reference to the direction in which the first liquid flows through the first pipe.[Aspect F-14] The apparatus according to aspect F-1, further comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is connected to the opening in the third pipe for discharging the second liquid, and the opening in the third pipe for introducing the second liquid is located downstream of the first shielding portion with reference to the direction in which the first liquid flows through the first pipe. [Aspect F-15] The apparatus according to aspect F-1, wherein the first pipe has a first side wall, the second pipe has a second side wall, and all or part of the first side wall surrounds part of the second side wall. [Aspect F-16] The apparatus according to any one of aspects F-11 to F-14, wherein the third pipe has a third side wall, and all or part of the third side wall surrounds part of the first side wall. [Aspect F-17] The apparatus according to aspect F-1, wherein the first pipe has a first side wall, the second pipe has a second side wall, and part of the second side wall is in contact with the second shielding portion. [Aspect F-18] The apparatus according to aspect F-1, wherein the first pipe for circulating the first liquid is for connecting to a first pump for circulating the first liquid. [Aspect F-19] The apparatus according to aspect F-1, wherein a second pipe for circulating a second liquid is connected to a second pump for circulating the second liquid. [Aspect F-20] An apparatus comprising the apparatus according to aspect F-1 and a first pump for circulating a first liquid. [Aspect F-21] The apparatus according to aspect F-1, wherein the apparatus is a catheter. [Aspect F-22] A method for circulating a second liquid in a system in which the second liquid circulates, by circulating a first liquid different from the second liquid in a part of the system in which the second liquid circulates, the method using the apparatus according to aspect F-1.[Aspect F-23] The method according to aspect F-22, which is not performed as a medical treatment on a human being. [Aspect F-24] An apparatus for circulating a first liquid, different from the second liquid, in a part separate from the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, the apparatus comprising a pipe for circulating the first liquid. [Aspect F-25] The apparatus according to aspect F-24, wherein the pipe for circulating the first liquid is for connecting to the part. [Aspect F-26] The apparatus according to aspect F-24, comprising a shielding part for shielding the part from the second liquid. [Aspect F-27] The apparatus according to aspect F-24, comprising a pipe for circulating the second liquid. [Aspect F-28] An apparatus for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising a pipe for introducing the first liquid and a pipe for discharging the first liquid. [Aspect F-29] The apparatus according to aspect F-28, wherein the pipe for introducing the first liquid is for connecting to the part of the system. [Aspect F-30] The apparatus according to aspect F-28, wherein the pipe for discharging the first liquid is for connecting to the part of the system. [Aspect F-31] The apparatus according to aspect F-28, comprising a shielding part for shielding the part of the system from the second liquid. [Aspect F-32] The apparatus according to aspect F-28, wherein the part is a part created by damming a system through which the second liquid circulates, and the part is equipped with a shielding portion to shield from the second liquid the part through which the second liquid flowed before the damming. [Aspect F-33] The apparatus according to aspect F-28, wherein the part is a part created by damming a system through which the second liquid circulates, and the part is equipped with a shielding portion to shield from the second liquid the part through which the second liquid flowed before the damming.[Aspect F-34] The apparatus according to Aspect F-28, wherein the part is a part created by damming a system through which the second liquid circulates, the part is provided with a shielding part for shielding from the second liquid a part through which the second liquid flowed before the damming, and the part is provided with a shielding part for shielding from the second liquid a part through which the second liquid flowed before the damming. [Aspect F-35] The apparatus according to Aspect F-28, further comprising a pipe for circulating the second liquid. [Aspect F-36] A method for circulating the second liquid in a system through which the second liquid circulates by circulating a first liquid different from the second liquid in a part separate from the system through which the second liquid circulates, the method using the apparatus according to Aspect F-24 or Aspect F-28. [Aspect F-37] The method according to Aspect F-36, which is not performed as a medical treatment for a human being.

[0042] <Second Invention> [Aspect G-1] A site-independent perfusion animal in which a specific internal body part of the animal is isolated from the systemic circulation of the animal, wherein a perfusion fluid circulating only to the specific internal body part is supplied and collected by an external perfusion circuit via an introduction device and an discharge device connected to the specific internal body part. [Aspect G-2] The site-independent perfusion animal according to Aspect G-1, wherein the device is a catheter. [Aspect G-3] The site-independent perfusion animal according to Aspect G-1, wherein the specific internal body part is a kidney. [Aspect G-4] The site-independent perfusion animal according to Aspect G-1, wherein isolation from the systemic circulation is performed by ligation of an internal artery and an internal vein. [Aspect G-5] The site-independent perfusion animal according to Aspect G-4, wherein the internal artery and internal vein, including the blood vessel and catheter, are ligated with silk thread. [Aspect G-6] The site-independent perfusion animal according to Aspect G-1, wherein the device is inserted under X-ray fluoroscopy. [Aspect G-7] An internal site-independent perfusion animal according to Aspect G-1, prepared by a method including the step of using a contrast agent as the perfusion fluid and taking a perfusion image within the specific internal site. [Aspect G-8] An internal site-independent perfusion animal according to Aspect G-1, wherein the introduction device is inserted into an internal site artery and the discharge device is inserted into an internal site vein. [Aspect G-9] An internal site-independent perfusion animal according to Aspect G-1, wherein the external perfusion circuit is equipped with a pump for circulating the perfusion fluid and is configured as a circuit that prevents the perfusion fluid from leaking into the systemic circulation. [Aspect G-10] A method for evaluating the internal site-specific efficacy, toxicity, or pharmacokinetics of a drug contained in a perfusion fluid using an internal site-independent perfusion animal according to any one of Aspects G-1 to G-9. [Aspect G-11] A method for evaluating the internal site-specific accumulation or distribution of a substance using an internal site-independent perfusion animal according to any one of Aspects G-1 to G-9. [Aspect G-12] The method according to aspect G-11, wherein the substance is a contrast agent. [Aspect G-13] A method for administering a drug to a specific body site while reducing systemic toxicity, using an internal site independent perfusion animal as described in any one of aspects G-1 to G-9, and measuring the drug reactivity at the specific body site.[Aspect G-14] A method for treating an internal body part as a pretreatment for transplantation, wherein a substance is perfused to an internal body part in an animal perfused to an internal body part as described in any one of aspects G-1 to G-9, while the internal body part is isolated from the systemic circulation. [Aspect G-15] The method according to aspect G-14, wherein the substance is a therapeutic agent, a gene transfer agent, a protective agent, or a washing solution. [Aspect G-16] A drug for use in the method according to aspect G-10. [Aspect G-17] A substance for use in the method according to aspect G-11. [Aspect G-18] A drug for use in the method according to aspect G-13. [Aspect G-19] A substance for use in the method according to aspect G-14.

[0043] <Third Invention> [Aspect H-1] A method for producing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, the method comprising the step of administering the drug only to a part of the body of the target, which is independent of the blood flow within the body of the target. [Aspect H-2] The method according to Aspect H-1, which does not involve a medical treatment to a human being. [Aspect H-3] The method according to Aspect H-1, wherein the part of the body of the target is an organ. [Aspect H-4] The method according to Aspect H-1, wherein the part of the body of the target, which is independent of the blood flow within the body of the target, is for reconnecting to the blood flow in the target. [Aspect H-5] The method according to Aspect H-1, wherein the drug has been confirmed to exhibit toxicity in a part of the body other than the affected area for treating the specific disease. [Aspect H-6] The method according to Aspect H-1, wherein the drug has been confirmed to exhibit toxicity throughout the body. [Aspect H-7] The method according to Aspect H-1, wherein the drug is avoided for use in pharmaceutical compositions for treating the specific disease due to its high unit cost. [Aspect H-8] The method according to aspect H-1, wherein in the step of administering the drug, a site-independent perfusion animal is used, wherein a site-independent perfusion animal is used in which a specific internal part of the animal is isolated from the systemic circulation of the animal, and a perfusion fluid circulating only to that specific internal part is supplied by an external perfusion circuit via an introduction device connected to that specific internal part. [Aspect H-9] The method according to aspect H-1, wherein in the step of administering the drug, a site-independent perfusion animal is used in which a specific internal part of the animal is isolated from the systemic circulation of the animal, and a perfusion fluid circulating only to that specific internal part is supplied and collected by an external perfusion circuit via an introduction device and an discharge device connected to that specific internal part. [Aspect H-10] The method according to aspect H-1, wherein in the step of administering the drug, a device is used for administering the drug only to an internal part that is isolated from the blood flow in the target body. [Aspect H-11] The method according to aspect H-10, wherein the device for administering a drug to an internal body part, independent of the blood flow within the target body, is a device connected to the internal body part.[Aspect H-12] The method according to Aspect H-1, wherein in the step of administering the aforementioned medicament, an instrument for circulating blood flow independent from the aforementioned in-vivo site by bypassing said in-vivo site is used. [Aspect H-13] The method according to Aspect H-1, comprising a step of reconnecting an in-vivo site independent from blood flow in a subject to the blood flow in the subject, comprising, as a step prior to said step of reconnecting to blood flow, a step of washing said in-vivo site with a secondary fluid that does not contain the medicament, a step of detoxifying the medicament in said in-vivo site, or a step of neutralizing the medicament in said in-vivo site. [Aspect H-14] The method according to Aspect H-1, wherein in the step of administering the aforementioned medicament, an instrument for recovering the administered medicament only from the in-vivo site independent from blood flow in a subject is used. [Aspect H-15] The method according to Aspect H-14, wherein the instrument for recovering the administered medicament only from the in-vivo site independent from blood flow in a subject is an instrument connected to said in-vivo site. [Aspect H-16] The method according to Aspect H-1, comprising a step of recovering the administered medicament only from the in-vivo site independent from blood flow in a subject. [Aspect H-17] The method according to Aspect H-16, wherein a device for filtering the recovered medicament is not used. [Aspect H-18] A method of screening for a pharmaceutical composition for treating a specific disease, which is subject to marketing approval, comprising a step of administering a medicament only to an in-vivo site of a subject that is independent from blood flow in the subject.

[0044] <First Invention> According to the present invention, since a medicament can be applied at high concentration only to a specific in-vivo site, not only can the medicinal efficacy at that in-vivo site be enhanced, but also side effects on other in-vivo sites can be eliminated. According to the present invention, the usage amount of a medicament with high manufacturing cost such as ASO can be reduced compared to systemic administration, and the cost of the medicament can be suppressed. In the present invention using a nucleic acid medicament such as ASO, a transfection reagent may possibly be used, and higher effectiveness can be expected in such a case. Among the present invention, according to the instrument of the present invention, adopting a configuration provided with a shielding part can prevent the medicament from flowing into a non-target in-vivo site, and avoid side effects.

[0045] Furthermore, the present method is less invasive than surgical procedures targeting an internal site of a subject, thereby reducing the physical and mental burden on a patient. For example, by applying the present method without performing thoracotomy on the lung, treatment can be provided even to patients with weaker physical strength.

[0046] Furthermore, unlike individual drug delivery methods that have been conventionally studied separately for each drug and each therapy, the present method has generality, so it has a wide application range, including the use of already approved drugs. In such individual drug delivery methods, chemical ligands having affinity for the target internal site, or polymers such as micelles for safely delivering a pharmaceutical agent to the target internal site may be used. In this case, the chemical ligands and polymers such as micelles themselves may also have toxicity. Therefore, physically delivering a pharmaceutical agent directly to an internal site of the body by the present method can also avoid such toxicity risks.

[0047] According to the present invention, first, only a small amount of the drug is required. Even when used for treatment with expensive drugs or drugs that are difficult to produce, the present invention can save more patients at low cost.

[0048] Next, according to the present invention, the invasiveness of surgery can be reduced. For example, when operating on the lung, it is only necessary to insert several catheters, without thoracotomy and rib resection.

[0049] Furthermore, according to the present invention, the drug can be prevented from circulating throughout the body. Therefore, if the drug is washed away after the operation, the amount of the drug circulating throughout the body can be suppressed to a minimum. As a result, only microdose toxicity tests are required for clinical trials, and drastic reductions in the cost and duration of clinical development can be expected, allowing medical care to reach patients earlier.

[0050] Furthermore, according to the present invention, toxicity derived from drug delivery can be reduced by not using unknown chemical delivery technologies.

[0051] According to the present invention, since the drug can be administered only to a specific internal site of the body, the drug can be administered at a high concentration while suppressing concerns about systemic toxicity. Therefore, high drug efficacy can be expected.

[0052] Furthermore, while conventional technologies are all individual techniques that require optimization for each drug or treatment and are not generally applicable, the method of the present invention is generally applicable.

[0053] Devices such as catheters shown in Figures 1 to 10 and Figures 25 to 29, which may also serve as devices for administering drugs to internal sites or for recovering drugs from internal sites, allow for the circulation of blood flow that is independent of an internal site, bypassing that site. This enables the circulation of blood flow within the target body, independent of an internal site, bypassing that site. As a result, it is possible to exert excellent effects while reducing damage to surrounding tissues, and to maximize the effect by allowing for longer perfusion times.

[0054] In this invention, two independent environments are provided: internal site perfusion and internal circulation, allowing for separate treatments for each. Specifically, for internal circulation, for example, at least an anticoagulant can be administered, which constitutes treatment. In other words, this invention incorporates not only the concept of internal circulation but also the concept of performing treatment within internal circulation. Therefore, this invention can also be described as a perfusion device for performing multiple independent treatments on the same person. Specifically, by using catheters as shown in Figures 1 to 10 and Figures 25 to 29, two or more perfusions (systemic circulation and internal site perfusion) can be created and incorporated into the device. It should be noted that patients may be taking multiple medications and undergoing multiple treatments, and multiple treatments may be performed simultaneously during surgery. According to this invention, independent and separate treatments can be performed under each perfusion.

[0055] Furthermore, according to the present invention, for example, it is possible to deliver a drug to a location other than a specific body site, rather than to a specific body site. In cancer patients, metastasis from the primary tumor is common, and anticancer drugs are often administered systemically to treat these multiple locations together. However, on the other hand, certain body sites such as the liver, small intestine, and bone marrow are prone to side effects unique to anticancer drugs, and many anticancer drugs cause similar side effects in these areas. Therefore, if metastasis has not spread to these body sites, it is possible to exclude these body sites and deliver the drug into the systemic circulation line, thereby maintaining the therapeutic effect on areas other than these body sites while suppressing side effects.

[0056] <Second Invention> According to the present invention, site-specific drug efficacy can be evaluated purely. According to the present invention, the effectiveness of nucleic acid drugs, antibody drugs, etc. can be accurately measured because the drug is delivered to the target site in the body at a high concentration. According to the present invention, systemic toxicity can be eliminated and local toxicity of a site in the body can be evaluated. According to the present invention, pharmacokinetic analysis (uptake, retention, excretion) of a single site in the body is possible. The present invention is extremely useful for evaluating the site-specific localization of contrast agents and DDSs. According to the present invention, the safety and efficacy of high-concentration drugs can be examined without systemic effects. According to the present invention, it can be used in clinical application research such as pretreatment for transplantation of a site in the body and site-specific gene therapy. The present invention functions as a unique novel research platform that sits between in vivo and ex vivo.

[0057] In other words, this invention makes it possible for the first time to perform pharmacological evaluation of individual body parts, which was impossible with conventional in vivo models, and has value in an extremely wide range of fields, including drug development, drug delivery system (DDS) development, contrast agent development, transplant medicine, and research on the function of body parts.

[0058] <Third Invention> According to the present invention, by administering a drug only to a specific site in the body, it is possible to exert a high drug effect at that site, and by suppressing or controlling the inflow of the drug into the systemic circulation, the effects on the entire body can be reduced.

[0059] Furthermore, this invention can be applied to drugs that were previously difficult to develop or approve from the standpoint of systemic toxicity, thereby increasing the likelihood of developing pharmaceuticals and obtaining manufacturing and marketing approval. In addition, by reducing the burden of safety evaluation, it becomes possible to improve the efficiency of clinical trials and reduce development costs.

[0060] Furthermore, because the dosage of drugs can be reduced according to the present invention, drugs that were previously limited in use in actual medical practice due to their high cost can now be practically used. As a result, the scope of application for pharmaceuticals can be expanded to include drugs that were not previously used.

[0061] Furthermore, by reducing drug usage and minimizing side effects, it can also contribute to lowering medical costs.

[0062] Furthermore, in the present invention, clinical trials of the pharmaceutical composition are conducted on the premise of administration via the body site perfusion system, and since the burden of safety evaluation is reduced compared to systemic administration, it may be possible to reduce the scale or shorten the duration of clinical trials. In addition, it may be possible to reduce the number of cases and simplify toxicity evaluation (e.g., low-dose trials).

[0063] Since the pharmaceutical compositions in this invention are evaluated on the premise of administration within the body site perfusion system, the likelihood of obtaining approval increases even for drugs that were previously difficult to approve.

[0064] Furthermore, the pharmaceutical composition of the present invention can be introduced to the market on the premise that it will be provided as part of insured medical treatment. This is because it is expected to reduce medical costs by reducing the amount of drug used and reducing side effects, and will also contribute to reducing the burden on patients.

[0065] Thus, the present invention provides a series of steps, including the construction of an in-body site perfusion system, the development of a pharmaceutical composition suitable for said perfusion system, the acquisition of clinical trials and manufacturing and marketing approval for said pharmaceutical composition, and the provision of said pharmaceutical composition as a medical treatment covered by health insurance.

[0066] As described above, the present invention makes it possible to practically use drugs that were previously difficult to utilize from the standpoint of toxicity or economic feasibility, and also provides a new framework for drug development and medical care provision.

[0067] Figure 1 is a cross-sectional view showing one end of a catheter according to an embodiment of the present invention. Figure 2 is a cross-sectional view showing the other end of a catheter according to an embodiment of the present invention. Figure 3 is a cross-sectional view showing one end of a catheter according to an embodiment of the present invention. Figure 4 is a cross-sectional view showing the other end of a catheter according to an embodiment of the present invention. Figure 5 is a cross-sectional view showing one end of a catheter according to an embodiment of the present invention. In Figure 5, the balloon support is compressing the balloon. Figure 6 is a cross-sectional view showing one end of a catheter according to an embodiment of the present invention. In Figure 6, the balloon support is releasing the balloon. Figure 7 is a cross-sectional view showing the other end of a catheter according to an embodiment of the present invention. Figure 8 is a diagram showing the configuration when a catheter according to an embodiment of the present invention is applied to the human body. Figure 9 is a magnified view of one end of the first catheter in Figure 8. Figure 10 is a magnified view of one end of the second catheter in Figure 8. Figure 11 is a photograph showing the insertion of an intravenous catheter into the tail artery and tail vein. Figure 12 is a photograph obtained by abdominal angiography. Figure 13 is a photograph of cannulation into the renal artery and renal vein. Figure 14 is a photograph of the renal artery and vein exposed and taped after a midline abdominal incision. Figure 15 is an image showing an independent circulatory system in which the target substance is injected through a catheter cannulated into the renal artery and retrieved through a catheter cannulated into the renal vein. Figure 16 is a still image (0 seconds) taken from an 8-second video of the kidney and surrounding areas when a contrast agent was perfused, with each frame being inserted at a time. Figure 17 is a still image (1 second) taken from an 8-second video of the kidney and surrounding areas when a contrast agent was perfused, with each frame being inserted at a time. Figure 18 is a still image (2 seconds) taken from an 8-second video of the kidney and surrounding areas when a contrast agent was perfused, with each frame being inserted at a time. Figure 19 is a still image (3 seconds) taken from an 8-second video of the kidney and surrounding areas when a contrast agent was perfused, with each frame being inserted at a time. Figure 20 shows still images (4 seconds) taken from an 8-second video of the kidney and surrounding areas after perfusion with contrast agent, frame by frame (1 second each). Figure 21 shows still images (5 seconds) taken from an 8-second video of the kidney and surrounding areas after perfusion with contrast agent, frame by frame (1 second each).Figure 22 is a series of still images (6 seconds) taken from an 8-second video showing the kidney and surrounding areas when a contrast agent was perfused. Figure 23 is a series of still images (7 seconds) taken from an 8-second video showing the kidney and surrounding areas when a contrast agent was perfused. Figure 24 is a series of still images (8 seconds) taken from an 8-second video showing the kidney and surrounding areas when a contrast agent was perfused. Figure 25 is a cross-sectional view showing a catheter according to an embodiment of the present invention. Figure 26 is a cross-sectional view showing a catheter according to an embodiment of the present invention. Figure 27 is a cross-sectional view showing a catheter according to an embodiment of the present invention. Figure 28 is a cross-sectional view showing a catheter according to an embodiment of the present invention. Figure 29 is a cross-sectional view showing a catheter according to an embodiment of the present invention.

[0068] <First Invention> Explanation of Terms: Ischemia-reperfusion injury: Tissue damage that occurs when blood flows again to tissue that has been in an ischemic or hypoxic state for a certain period of time.

[0069] ASO: Antisense Oligonucleotide. A single-stranded nucleic acid designed to hybridize (complementarily) with a target mRNA.

[0070] EVLP: ex vivo lung perfusion. A method of preserving excised organs while maintaining ventilation and perfusion.

[0071] siRNA: Double-stranded RNA consisting of 21-23 base pairs. It suppresses the expression of target mRNA by degrading it through RNA interference.

[0072] mRNA: A molecule composed of ribonucleic acid that corresponds to a gene sequence. This sequence is read by ribosomes, leading to the synthesis of proteins corresponding to the gene.

[0073] Transfection: The process of introducing nucleic acids such as DNA or RNA into cultured cells.

[0074] S100 proteins: A group of proteins that possess an EF hand-shaped calcium-binding domain (loop-helix-loop).

[0075] Bleomycin: A type of drug used in cancer treatment that induces cell death in cancer cells by cleaving or inhibiting DNA synthesis.

[0076] Bronchoalveolar lavage: A method in which saline solution is injected into the bronchi via a bronchoscope to lavage the alveoli and peripheral airways, and the cellular and humoral components of the recovered fluid are analyzed.

[0077] Surfactant protein D: A glycoprotein produced in alveolar type II epithelial cells, and a lung-specific marker used for diagnosing, monitoring, and predicting the prognosis of lung diseases.

[0078] ECMO stands for extracorporeal membrane oxygenation, which is an extracorporeal membrane oxygenation device.

[0079] SpO2: Blood oxygen saturation (the percentage of oxygen bound to hemoglobin in arterial blood). It can be measured with a pulse oximeter, and the normal range is 96-98%.

[0080] Sweep Gas Volume: The flow rate of oxygen delivered to the artificial lung. Used when introducing an extracorporeal membrane oxygenation (ECMO) device.

[0081] PT-INR (prothrombin time - international normalized ratio) is an abbreviation for prothrombin time - international normalized ratio. It indicates the blood's clotting ability and is primarily used for managing the dosage of the anticoagulant warfarin.

[0082] Drug: The present invention provides a drug for administration to a body site independent of the blood flow within the target body.

[0083] Examples of subjects include vertebrates. Examples of vertebrates include mammals such as mice, rats, rabbits, pigs, cattle, monkeys, and humans. Mammals are preferably humans. Subjects can be of any age, including fetuses, infants, young adults, adolescents, adults, and the elderly. Deceased subjects can also be included.

[0084] Internal organs are examples of internal organs. These include the liver, heart, lungs, pancreas, spleen, kidneys, brain, spinal cord, small intestine, lower limbs, upper arms, bladder, and pelvic cavity. Devices for perfusion of drugs into organs already exist (e.g., OrganOx for the liver; OrganOx-OrganOx).

[0085] Examples of drugs include small molecule drugs and large molecule drugs. Drugs may also be included in pharmaceutical compositions. Furthermore, drugs may be drugs for cell therapy or drugs for gene therapy. Examples of drugs for cell therapy and drugs for gene therapy include cells, viruses, and viral vectors.

[0086] Examples of macromolecular-weight pharmaceuticals include antibody drugs, protein drugs, peptide drugs, and nucleic acid drugs. Since nucleic acid drugs are generally highly toxic, topical administration according to the present invention is effective.

[0087] Nucleic acid drugs include, for example, antisense oligonucleotides, siRNA, miRNA, aptamers, decoys, CpG oligonucleotides, and mRNA. Antibody drugs include, for example, antibody-drug conjugates (ADCs).

[0088] Examples of antisense oligonucleotides include p53 antisense oligonucleotides, EWS / FLI1 (Ewing's sarcoma) antisense oligonucleotides, VPS4A / 4B (VPS4B deficiency 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.

[0089] 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-based drugs, anti-obesity drugs, antiviral drugs, enzymes, peptide drugs, and antibody drugs.

[0090] Examples of target groups include individuals suffering from a disease.

[0091] Diseases that may be treated include, for example, lung cancer, osteosarcoma, bladder cancer, cervical cancer, renal pelvis cancer, kidney cancer, autoimmune hepatitis, neuroendocrine tumors, glioma, bacterial and viral hepatitis, pulmonary fibrosis, various cancers including liver cancer and triple-negative breast cancer, Alport syndrome, intranuclear inclusion disease, amyloidosis, pustular psoriasis, asthma, ALS, obesity, infections, and enzyme deficiencies such as mucopolysaccharidosis. Diseases that may be treated include cancers of the nervous system and hepatitis caused by infections. Regarding cancers of the nervous system, anticancer drugs tend to cause side effects in proliferating cells, so it is thought that the effect will be even greater if the cancer is a non-proliferating nervous system cancer. On the other hand, regarding infections, infectious disease drugs are effective in a short time in cell experiments. However, in administration to animals and humans, they are administered for more than a week, which presents challenges in balancing side effects and ensuring that the drug reaches the necessary site.

[0092] The agents of the present invention are intended for use in combination with transfection reagents, for example. Examples of transfection reagents include Lipofectamine and i-Fect, which are based on cationic lipids; jetPEI and PEI MAX, which are based on cationic polymers (such as polyethyleneimine); TransIT, a non-liposomal reagent composed of lipids and proteins; GenomeONE, a non-viral transfection reagent; CalFectin, which uses the calcium phosphate method; and methods using DEAE-dextran. Generally, transfection reagents are not considered suitable for use in living organisms, and are typically used in vitro. The present invention can solve these problems as well.

[0093] In the present invention, the internal body part that has been isolated from the blood flow within the target body is preferably intended to be reconnected to the blood flow.

[0094] The present invention provides a method for treating a target, which includes the step of administering a drug to a body part isolated from the blood flow within the target body. The present invention also provides a method for treating a target disease, which includes the step of administering a drug to a body part isolated from the blood flow within the target body. These methods may include the step of isolating the body part from the blood flow within the target body. These methods may include the step of reconnecting the body part, which is isolated from the blood flow within the target body and to which the drug has been administered, back to the blood flow. Furthermore, as a pre-step to reconnect to the blood flow, there may be a step of washing with a secondary fluid that does not contain the drug used, a step of detoxifying or neutralizing the drug, and these may be performed individually or in combination. Examples of steps for detoxifying or neutralizing the drug include a step of removing the drug and a step of decomposing the drug. An example of a step of removing the drug is a step of removing the drug by dialysis. More specifically, a step of washing with a secondary fluid that does not contain the drug used may include delivering a liquid that does not contain the drug used, or a liquid with a low content of the drug used, to the body part, and then recovering the liquid from the body part to reduce the amount of the drug in the body part. Disease management includes treating the disease, pre-transplant preparation, and disease prevention. Disease treatment also includes complete cure, improvement of symptoms, and alleviation of symptoms.

[0095] The present invention provides a pharmaceutical composition for administration to a body site independent of the blood flow within the target body. Furthermore, the present invention provides a pharmaceutical composition for treating a target, for administration to a body site independent of the blood flow within the target body. Moreover, the present invention provides a pharmaceutical composition for treating a target disease, for administration to a body site independent of the blood flow within the target body.

[0096] The present invention provides the use of a drug in the manufacture of a pharmaceutical composition for administration to a body site independent of the blood flow within the target body. The present invention provides the use of a drug in the manufacture of a pharmaceutical composition for treating a target, for administration to a body site independent of the blood flow within the target body. Furthermore, the present invention provides the use of a drug in the manufacture of a pharmaceutical composition for treating a target disease, for administration to a body site independent of the blood flow within the target body.

[0097] Devices: Below, with reference to Figures 1 to 10, examples of embodiments of the invention of devices such as catheters will be described. However, the present invention is not limited to the forms shown in Figures 1 to 10.

[0098] The catheter shown in Figures 1 and 2 comprises 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 configuration is omitted on the left side of Figure 1, and the configuration is omitted on the right side of Figure 2, but the left side of Figure 1 and the right side of Figure 2 are continuous.

[0099] The catheter shown in Figures 1 and 2 includes balloon 14 and balloon 15 in Figure 1. These are donut-shaped balloons surrounding the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. In Figure 1, balloon 14 is filled with gas 16. In Figure 1, balloon 15 is filled with gas 17. Although not shown in Figure 1, the catheter shown in Figures 1 and 2 may also include a third tube for filling balloon 14 with gas 16. Although not shown in Figure 1, the catheter shown in Figures 1 and 2 may also 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.

[0100] In the catheter shown in Figures 1 and 2, the first tube 10 comprises a first opening 12 and a second opening 22. A first liquid flows in from the first opening 12 of the first tube in the direction of the solid arrows in Figures 1 and 2, and the first liquid flows out from the second opening 22 of the first tube in the direction of the solid arrows in Figures 1 and 2.

[0101] In the catheter shown in Figures 1 and 2, the second tube 11 comprises a first opening 23, a second opening 13, and an end portion 24. The second liquid flows in from the first opening 23 of the second tube in the direction of the dotted arrows in Figures 1 and 2, and flows out from the second opening 13 of the second tube in the same direction.

[0102] The first liquid preferably contains a drug.

[0103] The second liquid preferably does not contain all or part of the drugs contained in the first liquid. However, when using ECMO or the like, drugs that improve blood fluidity, such as antiplatelet agents and anticoagulants, may be included.

[0104] The catheter shown in Figures 3 and 4 comprises 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 configuration is omitted on the left side of Figure 3, and the configuration is omitted on the right side of Figure 4, but the left side of Figure 3 and the right side of Figure 4 are continuous.

[0105] The catheter shown in Figures 3 and 4 includes a balloon 34 and a balloon 35 in Figure 3. These are donut-shaped balloons surrounding the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. 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 also 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 also 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.

[0106] In the catheter shown in Figures 3 and 4, the first tube 30 comprises a first opening 32 and a second opening 42. The first liquid flows in from the first opening 32 of the first tube in the direction of the solid arrows in Figures 3 and 4, and the first liquid flows out from the second opening 42 of the first tube in the direction of the solid arrows in Figures 3 and 4.

[0107] In the catheter shown in Figures 3 and 4, the second tube 31 comprises a first opening 43, a second opening 33, and an end portion 44. The second liquid flows in from the first opening 43 of the second tube in the direction of the dotted arrow in Figures 3 and 4, and flows out from the second opening 33 of the second tube 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 is in contact not only with the inner wall of the second tube 31 but also with the outer wall of the first tube 30.

[0108] The first liquid preferably contains a drug.

[0109] The second liquid preferably does not contain all or part of the drugs contained in the first liquid. However, when using ECMO or the like, drugs that improve blood fluidity, such as antiplatelet agents and anticoagulants, may be included.

[0110] In Figure 4, the end portion 44 of the second tube 41 surrounds the first tube 40. The portion of the second tube 41 that contacts the first tube 40 has a flexible, seamless, and tightly fitting structure so as to be airtight, but the first tube 40 is allowed to move slightly.

[0111] The catheter shown in Figures 5 to 7 comprises 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 configuration is omitted on the left side of Figures 5 and 6, and the configuration is omitted on the right side of Figure 7, but the left side of Figures 5 and 6 and the right side of Figure 7 are continuous. In Figure 5, the balloon support portion 53 of the second tube compresses balloon 58, and the balloon support portion 54 of the third tube compresses balloon 59. In Figure 6, the balloon support portion 53 of the second tube releases balloon 58, and the balloon support portion 54 of the third tube releases balloon 59.

[0112] The catheter shown in Figures 5 to 7 includes a balloon 58 and a balloon 59 in Figure 5. These are donut-shaped balloons surrounding the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. In Figure 5, balloon 58 is filled with gas 501. In Figure 5, balloon 59 is filled with gas 502. Although not shown in Figure 5, the catheter shown in Figures 5 to 7 may include a third tube for filling balloon 58 with gas 501. Although not shown in Figure 5, the catheter shown in Figures 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, as will be described later, with the catheter shown in Figures 5 to 7, the balloon 58 is compressed and released using the balloon support portion 53 of the second tube, and the balloon 59 is compressed and released using the balloon support portion 54 of the third tube, so there is no need to provide a third tube and a fourth tube.

[0113] In the catheter shown in Figures 5 to 7, the first tube 50 comprises first openings 55 and 65 and a second opening 72. The first liquid flows in from the first openings 55 and 65 of the first tube in the direction of the solid arrows in Figures 5 to 7, and the first liquid flows out from the second opening 65 of the first tube in the direction of the solid arrows in Figures 5 to 7.

[0114] In the catheter shown in Figures 5 to 7, the second tube 71 branches into second tubes 51 and 61 and third tubes 52 and 62 at the end shown in Figures 5 and 6. The second tube 71 has a first opening 73. The second tubes 51 and 61 have a balloon support portion 53 and a second opening 56. The second tubes 51 and 61 are fixed to the first tube 50 at least at a fixing portion 503. The third tubes 52 and 62 have a balloon support portion 54 and a second opening 57. The third tubes 52 and 62 are fixed to the first tube 50 at least at a fixing portion 504. The balloon support portion 53 of the second tube shown in Figure 5 is made of a rigid material. The balloon support portion 53 of the second tube shown in Figure 5 slides when the end shown in Figure 7 is pulled, and transitions to the balloon support portion 63 of the second tube shown in Figure 6. As a result, the balloon support portion 53 of the second tube can release the balloon 58. The balloon support portion 54 of the second tube shown in Figure 5 is made of a rigid material. The balloon support portion 54 of the second tube shown in Figure 5 slides when the end shown in Figure 7 is pulled, and transitions to the balloon support portion 64 of the second tube shown in Figure 6. As a result, the balloon support portion 54 of the second tube can 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 Figures 5 to 7, the second liquid flows out from the second openings 56, 66 of the second tube in the direction of the dotted arrows in Figures 5 to 7, and the second liquid flows out from the second openings 57, 67 of the third tube in the direction of the dotted arrows in Figures 5 to 7. The second tubes 51, 61, 71 and the third tubes 52, 62 surround the first tube 50.

[0115] 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.

[0116] The first liquid preferably contains a drug.

[0117] The second liquid preferably does not contain all or part of the drugs contained in the first liquid. However, when using ECMO or the like, drugs that improve blood fluidity, such as antiplatelet agents and anticoagulants, may be included.

[0118] In the catheters shown in Figures 1 to 7, a mechanical umbrella-shaped blood flow stopper may be used instead of a balloon to avoid balloon-related risks such as balloon rupture. In other words, the shielding portion in the device of the present invention is not limited to a balloon.

[0119] The catheters shown in Figures 1 to 7 may include a pin for rupturing the balloon. Preferably, a flexible pin is positioned within the sheath and is bent outward. During insertion, the pin does not obstruct movement. In addition, to avoid damage from friction with the blood vessel between the sheath and the balloon, the sleeve can be pulled or pushed. To rupture the balloon, the sheath can be pushed toward the balloon.

[0120] Figures 8 to 10 show the configuration when a catheter according to an embodiment of the present invention is applied to the human body. When a catheter according to an embodiment of the present invention is applied to the human body, two catheters according to an embodiment of the present invention are used. Here, the two catheters used are referred to as the first catheter and the second catheter. The first catheter refers to the upper of the two catheters shown in Figure 8. The second catheter refers to the lower of the two catheters shown in Figure 8. The catheter shown in Figure 9 represents the first catheter. The catheter shown in Figure 10 represents the second catheter.

[0121] As shown in Figures 8 to 10, the first fluid is supplied to the organ from the first opening of the first tube of the first catheter. The first fluid is recovered from the organ from the first opening of the first tube of the second catheter. The first fluid recovered from 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 the first pump 82. This makes it possible to circulate the first fluid only within the organ. The organ is shielded by the balloons in the first catheter and the balloon in the second catheter. The first fluid preferably contains a drug. The first pump may be connected to equipment such as ECMO, which introduces oxygen or the like into the blood to keep the isolated organ alive. The first pump may also include a sensor to monitor the drug concentration. Furthermore, the first pump may include an injection system for administering the drug. It is preferable that the first pump has these configurations.

[0122] As shown in Figures 8 to 10, the second fluid is collected from the second opening of the second tube of the first catheter. The second fluid 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 makes it possible to circulate the second fluid, which was dammed up to circulate the first fluid only in the organ. The second pump may include a device that replaces the function that the isolated organ provided to the whole body (for example, ECMO if the lungs are isolated). The second pump may include a sensor that monitors the health of the blood throughout the body. The second pump may include a syringe for administering drugs that improve blood fluidity. It is preferable that the second pump has these components.

[0123] When applying a catheter according to an embodiment of the present invention to the human body, three or more catheters according to the embodiment of the present invention may be used simultaneously. Examples of three or more include four or more, five or more, six or more, seven or more, eight or more, nine or more, etc. Examples of three or more include nine or fewer, eight or fewer, seven or fewer, six or fewer, five or fewer, four or fewer, etc. For example, when applying a catheter according to an embodiment of the present invention to a branching artery, the catheter according to the embodiment of the present invention may be applied to the artery before branching and to all or part of the artery after branching. For example, when applying a catheter according to an embodiment of the present invention to a converging vein, the catheter according to the embodiment of the present invention may be applied to all or part of the vein before converging and to the vein after converging. For example, when applying a catheter according to an embodiment of the present invention to a branching artery, three or more catheters according to the embodiment of the present invention may be used simultaneously. For example, when applying a catheter according to an embodiment of the present invention to a converging vein, three or more catheters according to the embodiment of the present invention may be used simultaneously. For example, when a catheter according to an embodiment of the present invention is applied to a branching artery and a merging vein, six or more catheters according to the embodiment of the present invention may be used simultaneously. An example of applying a catheter according to an embodiment of the present invention to a branching artery and a merging vein is when the catheter according to the embodiment of the present invention is applied within the pelvis.

[0124] When applying a catheter according to an embodiment of the present invention to the human body, the pressure conditions are preferably 66.6 kPa (500 mmHg) or less, the temperature conditions are preferably in the range of 4 to 45°C, the oxygen conditions are preferably blood oxygen saturation of 20% to 100%, and the pH conditions are preferably in the range of 6.8 to 7.8.

[0125] Regarding pressure conditions, examples of pressures below 500 mmHg include 450 mmHg or less, 400 mmHg or less, 350 mmHg or less, 300 mmHg or less, 250 mmHg or less, and 200 mmHg or less. Regarding pressure conditions below 500 mmHg, examples of pressures above 200 mmHg, 250 mmHg or more, 300 mmHg or more, 350 mmHg or more, 400 mmHg or more, and 450 mmHg or more.

[0126] Regarding temperature conditions, 4 to 45°C can be defined as, for example, 4°C or higher, 5°C or higher, 6°C or higher, 7°C or higher, 8°C or higher, 9°C or higher, 10°C or higher, 11°C or higher, 12°C or higher, 13°C or higher, 14°C or higher, 15°C or higher, 16°C or higher, 17°C or higher, 18°C ​​or higher, 19°C or higher, 20°C or higher, 21°C or higher, 22°C or higher, 23°C or higher, 24°C or higher, 25°C or higher, 26°C or higher, 27°C or higher, 28°C or higher, 29°C or higher, 30°C or higher, 31°C or higher, 32°C or higher, 33°C or higher, 34°C or higher, 35°C or higher, 36°C or higher, 37°C or higher, 38°C or higher, 39°C or higher, 40°C or higher, 41°C or higher, 42°C or higher, 43°C or higher, 44°C or higher, 45°C or higher, and so on. Regarding temperature conditions, 4 to 45°C can include, for example, 45°C or below, 44°C or below, 43°C or below, 42°C or below, 41°C or below, 40°C or below, 39°C or below, 38°C or below, 37°C or below, 36°C or below, 35°C or below, 34°C or below, 33°C or below, 32°C or below, 31°C or below, 30°C or below, 29°C or below, 28°C or below, 27°C or below, 26°C or below, 25°C or below, 24°C or below, 23°C or below, 22°C or below, 21°C or below, 20°C or below, 19°C or below, 18°C ​​or below, 17°C or below, 16°C or below, 15°C or below, 14°C or below, 13°C or below, 12°C or below, 11°C or below, 10°C or below, 9°C or below, 8°C or below, 7°C or below, 6°C or below, 5°C or below, and 4°C or above.

[0127] Regarding blood oxygen saturation, the range of 20% to 100% includes, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, and 100%. Regarding blood oxygen saturation, the range of 20% to 100% includes, for example, 100% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, and 20% or less.

[0128] Regarding pH conditions, examples of values ​​between 6.8 and 7.8 include 6.8 or higher, 6.9 or higher, 7.0 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, 7.5 or higher, 7.6 or higher, 7.7 or higher, and 7.8 or higher. Regarding pH conditions between 6.8 and 7.8, examples of values ​​between 7.8 or lower include 7.8 or lower, 7.7 or lower, 7.6 or lower, 7.5 or lower, 7.4 or lower, 7.3 or lower, 7.2 or lower, 7.1 or lower, 7.0 or lower, 6.9 or lower, and 6.8 or lower.

[0129] The present invention allows for the circulation of a secondary fluid within a single internal body part by confining it to a region enclosed by shielding, with the upstream end representing the arterial side and the downstream end representing the venous side, if the pipes represent the blood vessels of the human body. In this case, the internal body part is separated from the body, so it is necessary to replace the role that the internal body part played by a predetermined process. For example, if the lungs are separated, oxygen is taken into the blood by connecting an ECMO machine. The present invention can be applied to a method of treating only a specific internal body part using a fluid to which a pharmaceutical drug has been added as a secondary fluid. Furthermore, the present invention can be applied to more effective treatment by monitoring the secondary fluid with a sensor and maintaining the concentration of the pharmaceutical drug at the highest possible concentration. In treatments that always use the highest concentration of pharmaceutical drugs approved for use in the human body, the amount of pharmaceutical drug introduced into the human body can be minimized by using sufficient secondary fluid.

[0130] Although Figures 1 to 10 above show examples of catheters, the instruments of the present invention are not limited to catheters and may be used, for example, for cleaning or painting pipes. Therefore, among the methods of the present invention, a second liquid different from the first liquid is circulated in a part of the system in which the first liquid circulates, and the first liquid is circulated in the part of the system excluding that part, can be said to be acts performed as medical treatment on humans, as well as acts that are not performed as medical treatment on humans.

[0131] Hereinafter, with reference to Figures 25 to 29, examples of embodiments of the present invention, specifically regarding devices such as catheters, will be described. However, the present invention is not limited to the embodiments shown in Figures 25 to 29.

[0132] The catheter shown in Figure 25 comprises a first tube 80, a second tube 81, a first balloon 85, a first balloon 86, a second balloon 87, and a second balloon 88.

[0133] The catheter shown in Figure 25 includes a first balloon 85 and a first balloon 86. These are donut-shaped balloons covering the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of first balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. The catheter shown in Figure 25 also includes a second balloon 87 and a second balloon 88. These are donut-shaped balloons covering the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of second balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. In Figure 25, the first balloon 85 and the first balloon 86 are filled with gas. In Figure 25, the second balloon 87 and the second balloon 88 are filled with gas. Although not shown in Figure 25, the catheter shown in Figure 25 may be equipped with a tube for filling the first balloon 85 with gas. Although not shown in Figure 25, the catheter shown in Figure 25 may be equipped with a tube for filling the first balloon 86 with gas. Although not shown in Figure 25, the catheter shown in Figure 25 may be equipped with a tube for filling the second balloon 87 with gas. Although not shown in Figure 25, the catheter shown in Figure 25 may be equipped with a tube for filling the second balloon 88 with gas.

[0134] In the catheter shown in Figure 25, the first tube 80 includes a first opening 82 and a second opening. The first liquid flows in from the second opening of the first tube in the direction of the solid arrow in Figure 25, and the first liquid flows out from the first opening 82 of the first tube in the direction of the solid arrow in Figure 25. However, the direction in which the first liquid flows through the first tube 80 may be the opposite.

[0135] In the catheter shown in Figure 25, the second tube 81 comprises a first opening 83 and a second opening 84. The second liquid flows in from the first opening 83 in the direction of the dotted arrow in Figure 25, and flows out from the second opening 84 in the same direction. However, the direction in which the second liquid flows through the second tube 81 may be the opposite.

[0136] The first liquid preferably contains a drug.

[0137] The second liquid preferably does not contain all or part of the drugs contained in the first liquid. However, when using ECMO or the like, drugs that improve blood fluidity, such as antiplatelet agents and anticoagulants, may be included.

[0138] In the catheter shown in Figure 25, with reference to the direction in which the first liquid flows through the first pipe 80, the first balloon 85 and the first balloon 86 are located downstream of the second opening of the first tube and upstream of the first opening 82 of the first tube. In the catheter shown in Figure 25, with reference to the direction in which the first liquid flows through the first pipe 80, the first opening 82 of the first tube is located upstream of the second balloon 87 and the second balloon 88.

[0139] In the catheter shown in Figure 25, the first balloon 85 and the first balloon 86 are located downstream of the second opening 84 of the second tube, with reference to the direction in which the first liquid flows through the first pipe 80. In the catheter shown in Figure 25, the second balloon 87 and the second balloon 88 are located downstream of the first balloon 85 and the first balloon 86, with reference to the direction in which the first liquid flows through the first pipe 80. In the catheter shown in Figure 25, the first opening 83 of the second tube is located downstream of the second balloon 87 and the second balloon 88, with reference to the direction in which the first liquid flows through the first pipe 80.

[0140] The catheter shown in Figure 25 can be applied to the human body in general as shown in Figures 8 to 10, but more specifically, it is placed in a branched blood vessel. Although not shown in Figure 25, the first opening 83 of the second tube is placed in the blood vessel before branching, the second opening 84 of the second tube is placed in one of the blood vessels after branching, and the first opening 82 of the first tube is placed in the other blood vessel after branching. As a result, the second fluid, such as blood, which was flowing from the blood vessel before branching to one of the blood vessels after branching and the other blood vessel after branching, will now flow only to one of the blood vessels after branching, while the first fluid will flow to the other blood vessel after branching. The catheter shown in Figure 25 is useful because it can be applied even when the blood vessel to the organ is short and the balloon cannot be expanded. Although not shown in Figure 25, the second opening of the first tube may be connected to a first pump for circulating the first fluid. The first pump may be connected to equipment such as ECMO, which introduces oxygen and other substances into the bloodstream to keep the isolated organs alive. The first pump may also include a sensor to monitor drug concentration. Furthermore, the first pump may include an injection system for administering drugs. It is preferable that the first pump has these configurations.

[0141] The catheter shown in Figure 26 comprises a first tube 91, a second tube 90, a third tube 92, a first balloon 96, a first balloon 97, a second balloon 98, and a second balloon 99. The third tube 92 surrounds the first tube 91. The first tube 91 surrounds the second tube 90.

[0142] The catheter shown in Figure 26 includes a first balloon 96 and a first balloon 97. These are donut-shaped balloons covering the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of first balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. The catheter shown in Figure 26 also includes a second balloon 98 and a second balloon 99. These are donut-shaped balloons covering the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of second balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. In Figure 26, the first balloon 96 and the first balloon 97 are filled with gas. In Figure 26, the second balloon 98 and the second balloon 99 are filled with gas. Although not shown in Figure 26, the catheter shown in Figure 26 may be equipped with a tube for filling the first balloon 96 with gas. Although not shown in Figure 26, the catheter shown in Figure 26 may be equipped with a tube for filling the first balloon 97 with gas. Although not shown in Figure 26, the catheter shown in Figure 26 may be equipped with a tube for filling the second balloon 98 with gas. Although not shown in Figure 26, the catheter shown in Figure 26 may be equipped with a tube for filling the second balloon 99 with gas.

[0143] In the catheter shown in Figure 26, the first tube 91 comprises a first opening 94 and a second opening. The first liquid flows in from the second opening of the first tube in the direction of the solid arrow in Figure 26, and the first liquid flows out from the first opening 94 of the first tube in the direction of the solid arrow in Figure 26. However, the direction in which the first liquid flows through the first tube 91 may be the opposite.

[0144] In the catheter shown in Figure 26, the second tube 90 comprises a first opening 93 and a second opening. The second liquid flows in from the first opening 93 of the second tube in the direction of the dotted arrow in Figure 26, and flows out from the second opening of the second tube in the same direction. However, the direction in which the second liquid flows through the second tube 90 may be the opposite.

[0145] In the catheter shown in Figure 26, the third tube 92 comprises a first opening 95 and a second opening. Although not shown in Figure 26, the second opening of the third tube is connected to the second opening of the second tube, and the second liquid that flows out from the second opening of the second tube flows into the second opening of the third tube, and the second liquid flows out from the first opening 95 of the third tube in the direction of the dotted arrow in Figure 26. However, the direction in which the second liquid flows through the third tube 92 may be the opposite.

[0146] The first liquid preferably contains a drug.

[0147] The second liquid preferably does not contain all or part of the drugs contained in the first liquid. However, when using ECMO or the like, drugs that improve blood fluidity, such as antiplatelet agents and anticoagulants, may be included.

[0148] In the catheter shown in Figure 26, with reference to the direction in which the first liquid flows through the first pipe 91, the first balloon 96 and the first balloon 97 are located downstream of the second opening of the first tube and upstream of the first opening 94 of the first tube. In the catheter shown in Figure 26, with reference to the direction in which the first liquid flows through the first pipe 91, the first opening 94 of the first tube is located upstream of the second balloon 98 and the second balloon 99.

[0149] In the catheter shown in Figure 26, the first balloon 96 and the first balloon 97 are located downstream of the second opening of the second tube, with reference to the direction in which the first liquid flows through the first pipe 91. In the catheter shown in Figure 26, the second balloon 98 and the second balloon 99 are located downstream of the first balloon 96 and the first balloon 97, with reference to the direction in which the first liquid flows through the first pipe 91. In the catheter shown in Figure 26, the first opening 93 of the second tube is located downstream of the second balloon 98 and the second balloon 99, with reference to the direction in which the first liquid flows through the first pipe 91.

[0150] In the catheter shown in Figure 26, the second opening of the third tube is located upstream of the first opening 95 of the third tube, with reference to the direction in which the first liquid flows through the first pipe 91. In the catheter shown in Figure 26, the first opening 95 of the third tube is located upstream of the first balloon 96 and the first balloon 97, with reference to the direction in which the first liquid flows through the first pipe 91.

[0151] The catheter shown in Figure 26 can be applied to the human body in general as shown in Figures 8 to 10, but more specifically, it is placed in a branched blood vessel. Although not shown in Figure 26, the first opening 93 of the second tube is placed in the blood vessel before branching, the first opening 95 of the third tube is placed in one of the blood vessels after branching, and the first opening 94 of the first tube is placed in the other blood vessel after branching. As a result, the second fluid, such as blood, which was flowing from the blood vessel before branching to one of the blood vessels after branching and the other blood vessel after branching, will now flow only to one of the blood vessels after branching, while the first fluid will flow to the other blood vessel after branching. The catheter shown in Figure 26 is useful because it can be applied even when the blood vessel to the organ is short and the balloon cannot be expanded. Although not shown in Figure 26, the second opening of the first tube may be connected to a first pump for circulating the first fluid. The first pump may be connected to equipment such as ECMO, which introduces oxygen and other substances into the bloodstream to keep the isolated organs alive. The first pump may also include a sensor to monitor drug concentration. Furthermore, the first pump may include an injection system for administering drugs. It is preferable that the first pump has these configurations.

[0152] Figure 27 shows the catheter shown in Figure 26 when used in combination with the guidewire 100. As shown in Figure 27, the catheter shown in Figure 26 can be supported as a whole by the guidewire 100, making it easier to position at the required site.

[0153] The catheter shown in Figure 28 comprises a first tube 110, a second tube 111, a first balloon 115, a first balloon 116, a second balloon 117, and a second balloon 118.

[0154] The catheter shown in Figure 28 includes a first balloon 115 and a first balloon 116. These are donut-shaped balloons covering the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of first balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. The catheter shown in Figure 28 also includes a second balloon 117 and a second balloon 118. These are donut-shaped balloons covering the catheter, shown in a cross-sectional view. This allows for well-balanced shielding, but the number of second balloons is not limited to one; there may be two or more. The balloons are preferably hollow cylindrical. In Figure 28, the first balloon 115 and the first balloon 116 are filled with gas. In Figure 28, the second balloon 117 and the second balloon 118 are filled with gas. Although not shown in Figure 28, the catheter shown in Figure 28 may be equipped with a tube for filling the first balloon 115 with gas. Although not shown in Figure 28, the catheter shown in Figure 28 may be equipped with a tube for filling the first balloon 116 with gas. Although not shown in Figure 28, the catheter shown in Figure 28 may be equipped with a tube for filling the second balloon 117 with gas. Although not shown in Figure 28, the catheter shown in Figure 28 may be equipped with a tube for filling the second balloon 118 with gas.

[0155] In the catheter shown in Figure 28, the first tube 110 includes a first opening 112 and a second opening. The first liquid flows in from the second opening of the first tube in the direction of the solid arrow in Figure 28, and the first liquid flows out from the first opening 112 in the direction of the solid arrow in Figure 28. However, the direction in which the first liquid flows through the first tube 110 may be the opposite.

[0156] In the catheter shown in Figure 28, the second tube 111 comprises a first opening 113 and a second opening 114. The second liquid flows in from the first opening 113 of the second tube in the direction of the dotted arrow in Figure 28, and flows out from the second opening 114 of the second tube in the same direction. However, the direction in which the second liquid flows through the second tube 111 may be the opposite.

[0157] The first liquid preferably contains a drug.

[0158] The second liquid preferably does not contain all or part of the drugs contained in the first liquid. However, when using ECMO or the like, drugs that improve blood fluidity, such as antiplatelet agents and anticoagulants, may be included.

[0159] In the catheter shown in Figure 28, with reference to the direction in which the first liquid flows through the first pipe 110, the first balloon 115 and the first balloon 116 are located downstream of the second opening of the first tube and upstream of the first opening 112 of the first tube. In the catheter shown in Figure 28, with reference to the direction in which the first liquid flows through the first pipe 110, the first opening 112 of the first tube is located upstream of the second balloon 117 and the second balloon 118. In the catheter shown in Figure 28, unlike the catheter shown in Figure 25, with reference to the direction in which the first liquid flows through the first pipe 110, the side wall of the first pipe 110 is in contact with the second balloon 118 downstream of the first opening 112 of the first tube.

[0160] In the catheter shown in Figure 28, the first balloon 115 and the first balloon 116 are located downstream of the second opening 114 of the second tube, with reference to the direction in which the first liquid flows through the first pipe 110. In the catheter shown in Figure 28, the second balloon 117 and the second balloon 118 are located downstream of the first balloon 115 and the first balloon 116, with reference to the direction in which the first liquid flows through the first pipe 110. In the catheter shown in Figure 28, the first opening 113 of the second tube is located downstream of the second balloon 117 and the second balloon 118, with reference to the direction in which the first liquid flows through the first pipe 110.

[0161] The catheter shown in Figure 28 can be applied to the human body in general as shown in Figures 8 to 10, but more specifically, it is placed in a branched blood vessel. Although not shown in Figure 28, the first opening 113 of the second tube is placed in the blood vessel before branching, the second opening 114 of the second tube is placed in one of the blood vessels after branching, and the first opening 112 of the first tube is placed in the other blood vessel after branching. As a result, the second fluid, such as blood, which was flowing from the blood vessel before branching to one of the blood vessels after branching and the other blood vessel after branching, will now flow only to one of the blood vessels after branching, while the first fluid will flow to the other blood vessel after branching. The catheter shown in Figure 28 is useful because it can be applied even when the blood vessel to the organ is short and the balloon cannot be expanded. Although not shown in Figure 28, the second opening of the first tube may be connected to a first pump for circulating the first fluid. The first pump may be connected to equipment such as ECMO, which introduces oxygen and other substances into the bloodstream to keep the isolated organs alive. The first pump may also include a sensor to monitor drug concentration. Furthermore, the first pump may include an injection system for administering drugs. It is preferable that the first pump has these configurations.

[0162] Figure 29 shows the catheter shown in Figure 28 when used in combination with the guidewire 120. As shown in Figure 29, the catheter shown in Figure 28 can be supported as a whole by the guidewire 120, making it easier to position at the required site.

[0163] When applying a catheter according to an embodiment of the present invention to the human body, the pressure conditions are preferably 66.6 kPa (500 mmHg) or less, the temperature conditions are preferably in the range of 4 to 45°C, the oxygen conditions are preferably blood oxygen saturation of 20% to 100%, and the pH conditions are preferably in the range of 6.8 to 7.8.

[0164] Regarding pressure conditions, examples of pressures below 500 mmHg include 450 mmHg or less, 400 mmHg or less, 350 mmHg or less, 300 mmHg or less, 250 mmHg or less, and 200 mmHg or less. Regarding pressure conditions below 500 mmHg, examples of pressures above 200 mmHg, 250 mmHg or more, 300 mmHg or more, 350 mmHg or more, 400 mmHg or more, and 450 mmHg or more.

[0165] Regarding temperature conditions, 4 to 45°C can be defined as, for example, 4°C or higher, 5°C or higher, 6°C or higher, 7°C or higher, 8°C or higher, 9°C or higher, 10°C or higher, 11°C or higher, 12°C or higher, 13°C or higher, 14°C or higher, 15°C or higher, 16°C or higher, 17°C or higher, 18°C ​​or higher, 19°C or higher, 20°C or higher, 21°C or higher, 22°C or higher, 23°C or higher, 24°C or higher, 25°C or higher, 26°C or higher, 27°C or higher, 28°C or higher, 29°C or higher, 30°C or higher, 31°C or higher, 32°C or higher, 33°C or higher, 34°C or higher, 35°C or higher, 36°C or higher, 37°C or higher, 38°C or higher, 39°C or higher, 40°C or higher, 41°C or higher, 42°C or higher, 43°C or higher, 44°C or higher, 45°C or higher, and so on. Regarding temperature conditions, 4 to 45°C can include, for example, 45°C or below, 44°C or below, 43°C or below, 42°C or below, 41°C or below, 40°C or below, 39°C or below, 38°C or below, 37°C or below, 36°C or below, 35°C or below, 34°C or below, 33°C or below, 32°C or below, 31°C or below, 30°C or below, 29°C or below, 28°C or below, 27°C or below, 26°C or below, 25°C or below, 24°C or below, 23°C or below, 22°C or below, 21°C or below, 20°C or below, 19°C or below, 18°C ​​or below, 17°C or below, 16°C or below, 15°C or below, 14°C or below, 13°C or below, 12°C or below, 11°C or below, 10°C or below, 9°C or below, 8°C or below, 7°C or below, 6°C or below, 5°C or below, and 4°C or above.

[0166] Regarding blood oxygen saturation, the range of 20% to 100% includes, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, and 100%. Regarding blood oxygen saturation, the range of 20% to 100% includes, for example, 100% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, and 20% or less.

[0167] Regarding pH conditions, examples of values ​​between 6.8 and 7.8 include 6.8 or higher, 6.9 or higher, 7.0 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, 7.5 or higher, 7.6 or higher, 7.7 or higher, and 7.8 or higher. Regarding pH conditions between 6.8 and 7.8, examples of values ​​between 7.8 or lower include 7.8 or lower, 7.7 or lower, 7.6 or lower, 7.5 or lower, 7.4 or lower, 7.3 or lower, 7.2 or lower, 7.1 or lower, 7.0 or lower, 6.9 or lower, and 6.8 or lower.

[0168] The present invention allows for the circulation of a secondary fluid within a single internal body part by confining it to a region enclosed by shielding, with the upstream end representing the arterial side and the downstream end representing the venous side, if the pipes represent the blood vessels of the human body. In this case, the internal body part is separated from the body, so it is necessary to replace the role that the internal body part played by a predetermined process. For example, if the lungs are separated, oxygen is taken into the blood by connecting an ECMO machine. The present invention can be applied to a method of treating only a specific internal body part using a fluid to which a pharmaceutical drug has been added as a secondary fluid. Furthermore, the present invention can be applied to more effective treatment by monitoring the secondary fluid with a sensor and maintaining the concentration of the pharmaceutical drug at the highest possible concentration. In treatments that always use the highest concentration of pharmaceutical drugs approved for use in the human body, the amount of pharmaceutical drug introduced into the human body can be minimized by using sufficient secondary fluid.

[0169] Although Figures 25 to 29 above show examples of catheters, the instruments of the present invention are not limited to catheters and may be used, for example, for cleaning or painting pipes. Therefore, among the methods of the present invention, a second liquid different from the first liquid is circulated in a part of the system in which the first liquid circulates, and the first liquid is circulated in the part of the system excluding that part, can be said to be acts performed as medical treatment on humans, as well as acts that are not performed as medical treatment on humans.

[0170] <Second Invention> The present invention provides a site-independent perfusion animal in which a specific internal body part of the animal is isolated from the systemic circulation of the animal, and in which a perfusion fluid circulating only to the specific internal body part is supplied and collected by an external perfusion circuit via an introduction device and an discharge device connected to the specific internal body part.

[0171] The animal is preferably a mammal, more preferably a rodent, and even more preferably a rat. Examples of animals include small laboratory animals. Examples of small laboratory animals include small primates such as marmosets.

[0172] The animal is preferably a non-human animal.

[0173] The animal is preferably a model animal. Examples of animals include living animals as well as non-living animals. Preferably, living humans are excluded from the animals. The site-independent perfusion material is preferably a site-independent perfusion animal model. The site-independent perfusion material is preferably a site-independent perfusion animal model system.

[0174] The aforementioned device is preferably a catheter.

[0175] The aforementioned specific internal organ is preferably an organ, and more preferably a kidney. Furthermore, the aforementioned specific internal organ is preferably an organ called an endoorgan. An endoorgan is preferably an organ or tissue having a vascular structure in which there is basically one afferent artery, which is the source of the perfusion fluid, and basically one efferent vein, which is the destination of the perfusion fluid, thereby preventing leakage of the perfusion fluid into the systemic circulation.

[0176] Blocking from the systemic circulation is preferably performed by ligation of internal arteries and internal veins.

[0177] In the present invention, the internal site-independent perfusion fluid preferably involves ligating internal site arteries and internal site veins, including the blood vessels and catheter, with silk thread.

[0178] Preferably, the instrument is inserted under X-ray fluoroscopy.

[0179] The internal site-independent perfusion material of the present invention is preferably prepared by a method that includes the step of using a contrast agent as the perfusion fluid and taking a perfusion image within the specific internal site.

[0180] In the internal site independent perfusion animal of the present invention, preferably, the introduction device is inserted into the internal site artery, and the discharge device is inserted into the internal site vein.

[0181] In the internal site-independent perfusion animal of the present invention, preferably, the external perfusion circuit is equipped with a pump for circulating the perfusion fluid and is configured as a circuit that prevents the perfusion fluid from leaking into the systemic circulation. Here, the pump for circulating the perfusion fluid can be an automatic mechanical pump, a manual pump, or a manual perfusion means operated by a syringe. Furthermore, as a circuit that prevents the perfusion fluid from leaking into the systemic circulation, for example, a closed circuit that prevents the perfusion fluid from leaking into the systemic circulation can be used.

[0182] The present invention provides a method for evaluating the site-specific efficacy, toxicity, or pharmacokinetics of a drug contained in a perfusion fluid using the aforementioned site-independent perfusion animals. The present invention also provides a drug for use in said method. The method preferably excludes methods for treating and diagnosing human conditions.

[0183] The present invention provides a method for evaluating the site-specific accumulation or distribution of a substance using the aforementioned site-independent perfusion animals. The present invention also provides a substance for use in said method. The substance is preferably a contrast agent. The said method preferably excludes human treatment and diagnostic methods.

[0184] The present invention provides a method for administering a drug to a specific body site while reducing systemic toxicity, using the aforementioned body site-independent perfusion animals, and measuring the drug response at that specific body site. The present invention also provides a drug for use in the above method. The method preferably excludes methods for treating and diagnosing humans.

[0185] The present invention provides a method for treating a specific internal site in an animal with independently-controlled internal site perfusion, by perfusing the site with a substance while keeping it isolated from the systemic circulation, as a pretreatment for internal site transplantation. The present invention provides a substance for use in the above method. The substance is preferably a therapeutic agent, a gene transfer agent, a protective agent, or a washing solution. The method preferably excludes therapeutic and diagnostic methods for humans.

[0186] <Third Invention> The present invention provides a method for producing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, and includes a step of administering the drug only to a specific body part of the target, independent of the blood flow within the target body.

[0187] The method is preferably a method for producing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, and is administered only to a target body site independent of the blood flow within the target body, and includes a step of administering the drug only to a target body site independent of the blood flow within the target body.

[0188] The method of the present invention preferably does not involve therapeutic procedures on humans.

[0189] In the method of the present invention, the internal body part is preferably an organ. Examples of internal body parts include the liver, heart, lungs, pancreas, spleen, kidneys, brain, spinal cord, small intestine, lower limbs, upper arms, bladder, and pelvic cavity.

[0190] In the method of the present invention, the internal body part of the target, which has been isolated from the blood flow within the target, is intended to be reconnected to the blood flow within that target.

[0191] The administered drug is not limited to drugs that have already received manufacturing and marketing approval, but may also be drugs that have not yet received manufacturing and marketing approval. Preferably, the drug has been confirmed to exhibit toxicity at a site other than the affected area for treating the specific disease mentioned above. Preferably, the drug has been confirmed to exhibit toxicity systemically.

[0192] Preferably, the drug is one whose use in a pharmaceutical composition for treating the aforementioned specific disease is avoided due to its high unit cost. Examples of drugs whose use in a pharmaceutical composition for treating the aforementioned specific disease is avoided due to its high unit cost include new drugs. The unit cost of the drug is, for example, 10,000 yen or more, 100,000 yen or more, 1,000,000 yen or more, 10,000,000 yen or more, or 100,000,000 yen or more per dose. The unit cost of the drug is, for example, 100,000,000 yen or less, 10,000,000 yen or less, 1,000,000 yen or less, or 10,000,000 yen or less per dose.

[0193] Preferably, in the step of administering the drug, a site-independent perfusion animal is used, in which a specific body part of the animal is isolated from the systemic circulation of the animal, and in which a perfusion fluid circulating only to that specific body part is supplied by an external perfusion circuit via an introduction device connected to that specific body part.

[0194] Preferably, in the step of administering the drug, a site-independent perfusion animal is used, in which a specific body part of the animal is isolated from the systemic circulation of the animal, and a perfusion fluid circulating only through that specific body part is supplied and collected by an external perfusion circuit via an introduction device and an discharge device connected to that specific body part.

[0195] Preferably, in the step of administering the drug, a device is used to administer the drug only to an internal body part that is independent of the blood flow in the target body. Preferably, the device for administering the drug only to an internal body part that is independent of the blood flow in the target body is a device connected to the internal body part.

[0196] Preferably, in the step of administering the drug, a device is used to circulate blood flow that is independent of the body part, bypassing the body part.

[0197] The method of the present invention preferably includes a step of reconnecting an internal body part, which has been isolated from the blood flow within the body of the subject, to the blood flow within the subject, and as a step prior to the step of reconnecting to the blood flow, the method includes a step of washing the internal body part with a secondary fluid that does not contain the drug, a step of detoxifying the drug in the internal body part, or a step of neutralizing the drug in the internal body part. Examples of the steps of detoxifying the drug in the internal body part or neutralizing the drug in the internal body part include a step of removing the drug in the internal body part and a step of decomposing the drug in the internal body part. Examples of the step of removing the drug in the internal body part include a step of removing the drug in the internal body part by dialysis. More specifically, the step of washing the internal body part with a secondary fluid that does not contain the drug may include delivering a liquid that does not contain the drug, or a liquid with a low content of the drug, to the internal body part, and then recovering the liquid from the internal body part to reduce the amount of the drug in the internal body part.

[0198] Preferably, in the step of administering the drug, a device is used to recover the administered drug only from an internal body site that is independent of the blood flow in the target body. Preferably, the device for recovering the administered drug only from an internal body site that is independent of the blood flow in the target body is a device connected to the internal body site.

[0199] The method of the present invention preferably includes a step of recovering the administered drug only to a body part that is independent of the blood flow within the target body. In the method of the present invention, preferably, no device is used for filtering the recovered drug.

[0200] The method of the present invention may be a clinical trial or a non-clinical trial. That is, an example of the method of the present invention is conducting a clinical trial or a non-clinical trial. The method of the present invention includes a process of administering a drug only to a specific body part of the target, independent of the blood flow in the target body, for the purpose of producing a pharmaceutical composition for treating a specific disease that is subject to manufacturing and marketing approval, and it is not essential that the pharmaceutical composition for treating a specific disease that is subject to manufacturing and marketing approval is actually being manufactured. That is, the production method of the present invention includes, as an example, a method for developing a pharmaceutical composition for treating a specific disease that is subject to manufacturing and marketing approval, or a method for testing a pharmaceutical composition for treating a specific disease that is subject to manufacturing and marketing approval.

[0201] The present invention provides a method for screening pharmaceutical compositions for treating specific diseases that are subject to manufacturing and marketing approval, the method comprising the step of administering the drug only to a specific body part of the target, independent of the blood flow within the target body. More specifically, the method is a method for obtaining manufacturing and marketing approval.

[0202] The method is preferably a screening method for pharmaceutical compositions for treating specific diseases that are subject to manufacturing and marketing approval, in which the drug is administered only to a target body site independent of the blood flow within the target body, and the method includes the step of administering the drug only to a target body site independent of the blood flow within the target body. More specifically, the method is a method for obtaining manufacturing and marketing approval, in which the drug is administered only to a target body site independent of the blood flow within the target body.

[0203] More specifically, the present invention provides a method for developing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, and which includes a step of administering the drug only to a specific body part, independent of the blood flow within the body. More specifically, the method is a method for obtaining manufacturing and marketing approval.

[0204] The method is preferably a method for developing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, and is administered only to a target body site, independent of the blood flow within the target body, and includes the step of administering the drug only to a target body site, independent of the blood flow within the target body. More specifically, the method is a method for obtaining manufacturing and marketing approval, which is administered only to a target body site, independent of the blood flow within the target body.

[0205] More specifically, the present invention provides a method for testing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, and which includes the step of administering the drug only to a specific body part, independent of the blood flow within the body of the subject. More specifically, the method is a method for obtaining manufacturing and marketing approval.

[0206] The method is preferably a method of testing a pharmaceutical composition for treating a specific disease that is subject to manufacturing and marketing approval, in which the drug is administered only to a target body site, independent of the blood flow within the target body, and the method includes the step of administering the drug only to a target body site, independent of the blood flow within the target body. More specifically, the method is a method for obtaining manufacturing and marketing approval, in which the drug is administered only to a target body site, independent of the blood flow within the target body.

[0207] Furthermore, pharmaceutical compositions for treating specific diseases that are subject to manufacturing and marketing approval include not only pharmaceutical compositions for treating specific diseases that have received manufacturing and marketing approval, but also pharmaceutical compositions for treating specific diseases that are subject to manufacturing and marketing approval, and pharmaceutical compositions for treating specific diseases that are subject to manufacturing and marketing approval.

[0208] The present invention will be described in more detail below. The method of the present invention can eliminate the following economic disadvantages. In a closed circulation, when 1) a drug is used systemically, and 2) it is used in advanced medical treatment, pharmaceutical companies see a reduction in drug usage and a significant decrease in drug sales; doctors cannot reliably profit from advanced medical treatment; and patients face high treatment costs because medical insurance does not cover advanced medical treatment.

[0209] This invention allows 1) new drugs to be administered under health insurance, which offers numerous economic benefits to pharmaceutical companies: A) they can reduce the number of clinical trials required for new drugs, B) they can introduce (even highly toxic or excessively expensive new drugs) to the market, and C) they can provide affordable medical care, thus expanding the market. For doctors, it provides insurance points, allowing them to earn profits with peace of mind, and they can also earn additional points for surgical procedures. For patients, it provides insurance coverage, highly effective medical care with fewer side effects, and for society, it represents a drastic reduction in medical costs compared to systemic administration of new drugs (while still providing greater profit margins to pharmaceutical companies and doctors). Furthermore, since side effects are reduced even in a normal closed circulatory system, it is thought that clinical trials can be reduced. It is also thought that the number of cases can be reduced. If the trial is completed with only microdose toxicity testing, the cost of clinical trials will be further reduced.

[0210] In one embodiment, the present invention contributes to the research and development of novel pharmaceuticals in perfusion systems created using vascular balloon catheters, and to the market introduction of novel pharmaceuticals specifically for perfusion systems. The present invention contributes to the true social implementation of closed circulatory system medicine, which has extremely high medical efficacy, while increasing its economic rationality.

[0211] The present invention will now be described in more detail. The problems that this invention aims to solve (the reasons why closed-circuit therapy has not become widespread) were that, for pharmaceutical companies, there were economic disadvantages due to the decrease in sales volume resulting from the reduction in drug usage; for doctors, it was not possible to obtain stable profits from advanced medical treatment; and for patients, it was expensive as it was not covered by insurance.

[0212] In contrast, in one embodiment of the present invention, the solution involves creating an internal site perfusion (closed circulation) system within the patient's body using a vascular balloon catheter, researching and developing a novel drug specifically for that perfusion system, and bringing it to market, which may include clinical trials.

[0213] The benefits for pharmaceutical companies in this invention are the development of new drugs, the revival and approval of failed drugs, and market expansion. Specifically, this invention reduces the risk of systemic toxicity, allows for the revival of drugs whose development was discontinued due to toxicity during systemic administration, significantly reduces dosages, lowers medical costs, expands the market, and enables the introduction of new drugs to the market with reduced clinical trials (including new drugs with high toxicity and high cost). Furthermore, the benefits for doctors, patients, and society in this invention are insured medical treatment and reduction of medical costs. Specifically, this invention allows doctors to achieve stable revenue through insurance points and additional points for surgical procedures, patients to receive insurance coverage and highly effective medical treatment with fewer side effects, and society to achieve medical cost reductions compared to systemic administration.

[0214] In one embodiment, the implementing body and division of roles of the present invention are as follows: the patient is the subject of the perfusion system construction, the medical professional constructs the perfusion system, administers and collects the drugs, and the pharmaceutical company selects the target drug, conducts clinical trials, approval, and market launch.

[0215] In one embodiment, the business process of the present invention is as follows: 1) Identify drugs that are about to proceed to clinical trials or drugs that have been discontinued due to toxicity after systemic administration (e.g., hepatotoxicity) as target drugs. 2) Create a perfusion system using a vascular balloon catheter and construct a closed circulation (internal site perfusion system) within the patient's body. 3) Administer the drug only to the target site within the body and then retrieve it. 4) Research and develop the drug as a novel drug specifically for perfusion systems. 5) Launch the drug into the market with a view to approval and inclusion in health insurance coverage. Here, we consider the direction of introducing the novel drug into health insurance coverage.

[0216] In one embodiment, the components of the present invention are as follows: A) A configuration for creating a closed circulation (internal site perfusion system) within a patient's body using a vascular balloon catheter. B) A process and function for researching and developing a novel pharmaceutical product (specifically designed for) the perfusion system. C) A process and function for bringing the novel pharmaceutical product to market. D) A process for a pharmaceutical company to utilize the product from the clinical trial stage. E) A process for limiting administration to a target site within the body and then recovering the drug (internal site selective administration and recovery). F) The invention may also target drugs that have been discontinued due to systemic toxicity or high drug cost.

[0217] In one embodiment, the technical field of the present invention is DDS using intracellular site perfusion (closed circulation) and the development and commercialization of pharmaceuticals using the same. In one embodiment, prior to the present invention, there was a situation where closed circulation therapy was highly effective but not widely adopted for economic reasons. In one embodiment, the problem that the present invention aims to solve is to eliminate the above-mentioned economic disadvantages. In one embodiment, the means of solving the problem of the present invention are the construction of a perfusion system, R&D of a dedicated novel drug, and market launch. The means of solving the problem of the present invention may also include clinical trials. In one embodiment, the effects of the present invention are, as described above, benefits for pharmaceutical companies, physicians, patients, and society.

[0218] In the above, the inventions have been explained separately as the first, second, and third inventions. However, these inventions are not independent but rather complement each other in their understanding. Therefore, for example, the explanation for the first invention can be appropriately used as an explanation for the third invention.

[0219] Example 1 Autoimmune hepatitis model (target organ: liver): The groups used were: (1) a group that underwent perfusion surgery only (sham operation), (2) a group that underwent perfusion surgery while also receiving systemic steroid administration (posicon), and (3) a group that underwent perfusion surgery and received steroid perfusion only in the liver (perfusion group). The protocol was as follows: First, autoimmune hepatitis was induced using the S100 protein. Subsequently, mice underwent perfusion surgery (groups (1) and (2) underwent perfusion surgery only, while group (3) received steroid administration to the liver via perfusion). Group (2) received systemic steroid administration. After drug administration, the therapeutic effect on autoimmune hepatitis in the liver was evaluated. After drug administration, renal function, a systemic side effect of steroids, was evaluated.

[0220] Example 2 Normal mice (target organ: heart): The groups consisted of (1) a negative control (untreated), (2) a group that received systemic administration of p53 ASO, and (3) a group that perfused only the heart with p53 ASO. The protocol was as follows: Group (1) was untreated, Group (2) received only systemic administration of p53 ASO, and Group (3) perfused only the heart with p53 ASO. The hearts of each group were collected, total RNA was extracted, and the amount of p53 mRNA was quantitatively measured and compared. Note that ASO does not accumulate easily in the heart when administered systemically, so it may be easier to confirm the effect with perfusion.

[0221] Example 3: Bleomycin-Induced Pulmonary Fibrosis Model (Target Organ: Lungs): It has been reported that bleomycin-induced pulmonary fibrosis is partly caused by the activation of p53 and the resulting autocrineization of downstream signals (Enomoto Y., et al, 2023, Nat. commn.). Suppression of p53 expression during bleomycin administration may suppress the induction of pulmonary fibrosis. 8-10 week old C57BL / 6 mice were randomly divided into three groups. The group composition was as follows: (1) Negacon (untreated), (2) Group administered p53 ASO systemically, and (3) Group perfused only the lungs with p53 ASO. The protocol was as follows: the day before or immediately after bleomycin administration, group (1) was untreated, group (2) received only p53 ASO systemically, and group (3) perfused only the lungs with p53 ASO. Pulmonary fibrosis can be induced with bleomycin as follows: C57BL / 6 mice aged 8-10 weeks are anesthetized by intraperitoneal administration of 10% pentobarbital 100 μL / g weight, and bleomycin (3 μg (2.88 U / g weight)) is administered intratracheally via tracheostomy. Lungs are collected from each group, total RNA is extracted, and the amount of p53 mRNA is quantitatively measured and compared. In addition, the efficacy of p53 is evaluated using fibrosis markers. For example, the concentration of surfactant protein D in the lavage fluid obtained by bronchoalveolar lavage is measured. Note that ASO does not easily accumulate in the lungs when administered systemically, so it may be easier to confirm its effect through perfusion.

[0222] Perfusion procedure: Perfusion is performed, for example, using a Mera cardiopulmonary bypass machine or ECMO. For example, when using ECMO, blood cannulas (blood withdrawal: 19-25 Fr, blood return: 17-23 Fr) are inserted through the femoral vein (blood withdrawal side) and the internal jugular vein (blood return side) to access the right atrium. After cannula insertion, the pump is connected and rotation is started. The pump flow rate should be maintained at 50-80 mL / kg / min for humans, and the goal should be to manage an SpO2 of 85% or higher. The sweep gas volume should be approximately 30-40 mmHg. In addition, platelet counts should be controlled to 20,000-50,000 / μl or higher, PT-INR (prothrombin time-international normalized ratio) to 2.0 or lower, fibrinogen to 100-200 mg / dl or higher, hemoglobin (Hb) > 7-10 g / dl, and AT III > 50%. By mixing nucleic acid drugs with the perfusion blood and returning it to the right atrium, the nucleic acid drugs can be efficiently delivered to the heart and lungs.

[0223] Example 4: Rats were kept in a supine position under general anesthesia and kept sufficiently warm. Subsequently, intravenous infusion needles were inserted into the tail artery and tail vein (Figure 11). Catheters and wires were inserted into each and guided to the origin of the renal artery and the root of the renal vein using an X-ray fluoroscopy device. The wires were removed, and contrast agent was injected through the catheter to perform abdominal angiography (Figure 12). Based on the angiographic information, the renal artery and renal vein were cannulated (Figure 13). After that, the renal artery and vein were exposed by a midline abdominal incision and taped (Figure 14). By ligating the blood vessels and catheters with the silk thread used for taping, the kidneys were isolated from the systemic circulation. This established an independent circulatory system in which the target substance was injected through the catheter cannulated into the renal artery and retrieved through the catheter cannulated into the renal vein (Figure 15).

[0224] Figures 16 to 24 show still images taken from an 8-second video of the kidney and surrounding areas when a contrast agent was perfused in an established independent circulation system, with each image being taken at a 1-second interval.

[0225] As shown in Figures 16 to 24, by isolating a specific body part from the body's blood flow and administering a drug to that body part, it became clear that even drugs that are highly water-soluble and excreted by the kidneys can be localized only to that body part, preventing them from localizing to other areas and thus suppressing drug-induced side effects.

[0226] 10 First tube 11 Second tube 12 First opening of the first tube 13 Second opening of the second tube 14 Balloon 15 Balloon 16 Gas 17 Gas 20 First tube 21 Second tube 22 Second opening of the first tube 23 First opening of the second tube 24 End 30 First tube 31 Second tube 32 First opening of the first tube 33 Second opening of the second tube 34 Balloon 35 Balloon 36 Gas 37 Gas 40 First tube 41 Second tube 42 Second opening of the first tube 43 First opening of the second tube 44 End 50 First tube 51 Second tube 52 Third tube 53 Balloon support of the second tube 54 Balloon support of the third tube 55 First opening of the first tube 56 Second opening of the second tube 57 Second opening of the third tube 58 Balloon 59 Balloon 501 Gas 502 Gas 503 Fixing part 504 Fixing part 60 First tube 61 Second tube 62 Third tube 63 Balloon support part of second tube 64 Balloon support part of 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 Fixing part 604 Fixing part 70 First tube 71 Second tube 72 Second opening of first tube 73 First opening of second tube 81 Second pump 82 First pump 80 First tube 81 Second tube 82 First opening of first tube 83 First opening of second tube 84 Second opening of second tube 85 First balloon 86 First balloon 87 Second balloon 88 Second balloon 90 Second tube 91 First tube 92 Third tube 93 First opening of second tube 94 First opening of first tube95 First opening of the third tube 96 First balloon 97 First balloon 98 Second balloon 99 Second balloon 100 Guidewire 110 First tube 111 Second tube 112 First opening of the first tube 113 First opening of the second tube 114 Second opening of the second tube 115 First balloon 116 First balloon 117 Second balloon 118 Second balloon 120 Guidewire

Claims

1. A method for producing a pharmaceutical composition for treating a specific disease, which is subject to manufacturing and marketing approval, comprising the step of administering the drug only to a body part of the target, independent of the blood flow within the target body.

2. The method according to claim 1, wherein it does not involve a medical treatment to a human being.

3. The method according to claim 1, wherein the target body part is an organ.

4. The method according to claim 1, wherein a part of the body of the target, which has been isolated from the blood flow within the target, is used to reconnect to the blood flow in the target.

5. The method according to claim 1, wherein the drug has been confirmed to exhibit toxicity at a site other than the site of the treatment of the specific disease described above.

6. The method according to claim 1, wherein the drug has been confirmed to exhibit systemic toxicity.

7. The method according to claim 1, wherein the drug is avoided in use in pharmaceutical compositions for treating the aforementioned specific disease due to its high unit cost.

8. The method according to claim 1, wherein in the step of administering the drug, a site-independent perfusion animal is used, wherein a site-independent perfusion animal is used in which a specific internal part of the animal is isolated from the systemic circulation of the animal, and a perfusion fluid circulating only to the specific internal part is supplied by an external perfusion circuit via an introduction device connected to the specific internal part.

9. The method according to claim 1, wherein, in the step of administering the drug, a site-independent perfusion animal is used, wherein a site-independent perfusion animal is used in which a specific internal part of the animal is isolated from the systemic circulation of the animal, and a perfusion fluid circulating only through the specific internal part is supplied and collected by an external perfusion circuit via an introduction device and an discharge device connected to the specific internal part.

10. The method according to claim 1, wherein, in the step of administering the drug, a device is used to administer the drug only to a part of the body that is independent of the blood flow in the target body.

11. The method according to claim 10, wherein the device for administering a drug to a specific body part, independent of the blood flow within the target body, is a device connected to the body part.

12. The method according to claim 1, wherein, in the step of administering the drug, a device is used to circulate blood flow that is independent of the body part, bypassing the body part.

13. The method according to claim 1, comprising the step of reconnecting an internal body part, which has been separated from the blood flow within the body of the subject, to the blood flow within the subject, wherein, as a step prior to the step of reconnecting to the blood flow, the method comprises the step of washing the internal body part with a secondary fluid that does not contain the drug, the step of detoxifying the drug in the internal body part, or the step of neutralizing the drug in the internal body part.

14. The method according to claim 1, wherein, in the step of administering the drug, a device is used to recover the administered drug only from a part of the body that is independent of the blood flow in the target body.

15. The method according to claim 14, wherein the device for recovering a drug administered to a specific body part, independent of the blood flow within the target body, is a device connected to the body part.

16. The method according to claim 1, further comprising the step of recovering the administered drug only to a specific body part, independent of the blood flow within the target body.

17. The method according to claim 16, wherein no device is used to filter the recovered drug.

18. A method for screening pharmaceutical compositions for treating specific diseases that are subject to manufacturing and marketing approval, comprising the step of administering the drug only to a body part of the target, independent of the blood flow within the target body.

19. A site-independent perfusion animal in which a specific internal body part of the animal is isolated from the systemic circulation of the animal, wherein a perfusion fluid circulating only through the specific internal body part is supplied and collected by an external perfusion circuit via an introduction device and an discharge device connected to the specific internal body part.

20. The internal site-independent perfusion animal according to claim 19, wherein the instrument is a catheter.

21. The body site-independent perfusion animal according to claim 19, wherein the specific body site is the kidney.

22. The organ-independent perfusion animal according to claim 19, wherein isolation from the systemic circulation is performed by ligation of internal arteries and internal veins.

23. The internal site independent perfusion animal according to claim 22, wherein the internal site arteries and internal site veins are ligated with silk thread, including the blood vessels and catheters.

24. The internal site-independent perfusion animal according to claim 19, wherein the instrument is inserted under X-ray fluoroscopy.

25. The internal site-independent perfusion animal according to claim 19, prepared by a method comprising the step of using a contrast agent as the perfusion fluid and taking a perfusion image within the specific internal site.

26. The internal site independent perfusion animal according to claim 19, wherein the introduction device is inserted into an internal site artery and the discharge device is inserted into an internal site vein.

27. The internal site-independent perfusion animal according to claim 19, wherein the external perfusion circuit is equipped with a pump for circulating the perfusion fluid and is configured as a circuit that prevents the perfusion fluid from leaking into the systemic circulation.

28. A method for evaluating the site-specific efficacy, toxicity, or pharmacokinetics of a drug contained in a perfusion fluid using an animal with site-independent perfusion according to any one of claims 19 to 27.

29. A method for evaluating the site-specific accumulation or distribution of a substance using a site-independent perfusion animal according to any one of claims 19 to 27.

30. The method according to claim 29, wherein the substance is a contrast agent.

31. A method for administering a drug to a specific body site while reducing systemic toxicity, using an animal with independently perfused body sites as described in any one of claims 19 to 27, and measuring the drug response at the specific body site.

32. A method for treating a specific internal body part as a pretreatment for transplantation, in which a substance is perfused to the internal body part in an internal body part-independent perfusion animal according to any one of claims 19 to 27, while the internal body part is isolated from the systemic circulation.

33. The method according to claim 32, wherein the substance is a therapeutic agent, a gene transfer agent, a protective agent, or a washing solution.

34. A drug for use in the method described in claim 28.

35. A substance for use in the method described in claim 29.

36. A drug for use in the method according to claim 31.

37. A substance for use in the method described in claim 32.

38. An apparatus for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising: a first shielding part for shielding the part from the second liquid; a second shielding part for shielding the part from the second liquid; a first pipe for circulating the first liquid; and a second pipe for circulating the second liquid.

39. The apparatus according to claim 38, wherein the first pipe and the second pipe extend along the railway line, the first shielding portion is located along the railway line, and the second shielding portion is located along the railway line.

40. The apparatus according to claim 38, wherein in the second pipe for circulating the second liquid, the direction in which the second liquid circulates is reversed with respect to the direction in which the first liquid circulates in the first pipe for circulating the first liquid.

41. The apparatus according to claim 38, wherein in the second pipe for circulating the second liquid, the direction in which the second liquid is circulated is the same as the direction in which the first liquid is circulated in the first pipe for circulating the first liquid.

42. The apparatus according to claim 38, wherein the first pipe comprises an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing a second liquid and an opening for discharging the second liquid, the opening in the first pipe for introducing the first liquid is located upstream of the first shielding portion with respect to the direction in which the first liquid flows in the first pipe, the first shielding portion is located upstream of the opening in the first pipe for discharging the first liquid with respect to the direction in which the first liquid flows in the first pipe, and the opening in the first pipe for discharging the first liquid is located upstream of the second shielding portion with respect to the direction in which the first liquid flows in the first pipe.

43. The apparatus according to claim 38, wherein the first pipe comprises an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing a second liquid and an opening for discharging the second liquid, the opening for discharging the first liquid in the first pipe is located downstream of the first shielding portion with respect to the direction in which the first liquid flows in the first pipe, the first shielding portion is located downstream of the opening for introducing the first liquid in the first pipe with respect to the direction in which the first liquid flows in the first pipe, and the opening for introducing the first liquid in the first pipe is located downstream of the second shielding portion with respect to the direction in which the first liquid flows in the first pipe.

44. The apparatus according to claim 38, wherein the first pipe comprises an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing a second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is located upstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe, the first shielding portion is located upstream of the second shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located upstream of the opening for introducing the second liquid in the second pipe with reference to the direction in which the first liquid flows in the first pipe.

45. The apparatus according to claim 38, wherein the first pipe comprises an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing a second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is located downstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe, the first shielding portion is located downstream of the second shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located downstream of the opening for introducing the second liquid in the second pipe with reference to the direction in which the first liquid flows in the first pipe.

46. ​​The apparatus according to claim 38, wherein the first pipe comprises an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing a second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is located upstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe, the first shielding portion is located upstream of the second shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located upstream of the opening in the second pipe for discharging the second liquid with reference to the direction in which the first liquid flows in the first pipe.

47. The apparatus according to claim 38, wherein the first pipe comprises an opening for introducing a first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing a second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is located downstream of the first shielding portion with reference to the direction in which the first liquid flows in the first pipe, the first shielding portion is located downstream of the second shielding portion with reference to the direction in which the first liquid flows in the first pipe, and the second shielding portion is located downstream of the opening in the second pipe for discharging the second liquid with reference to the direction in which the first liquid flows in the first pipe.

48. The apparatus according to claim 38, further comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is connected to the opening for introducing the second liquid in the third pipe, and the opening for discharging the second liquid in the third pipe is located upstream of the first shielding portion with reference to the direction in which the first liquid flows through the first pipe.

49. The apparatus according to claim 38, comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening for discharging the second liquid in the second pipe is connected to the opening for introducing the second liquid in the third pipe, and the opening for discharging the second liquid in the third pipe is located downstream of the first shielding portion with reference to the direction in which the first liquid flows through the first pipe.

50. The apparatus according to claim 38, comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is connected to the opening in the third pipe for discharging the second liquid, and the opening in the third pipe for introducing the second liquid is located upstream of the first shielding portion with reference to the direction in which the first liquid flows through the first pipe.

51. The apparatus according to claim 38, comprising a third pipe for circulating a second liquid, wherein the first pipe comprises an opening for introducing the first liquid and an opening for discharging the first liquid, the second pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the third pipe comprises an opening for introducing the second liquid and an opening for discharging the second liquid, the opening in the second pipe for introducing the second liquid is connected to the opening in the third pipe for discharging the second liquid, and the opening in the third pipe for introducing the second liquid is located downstream of the first shielding portion with reference to the direction in which the first liquid flows through the first pipe.

52. The apparatus according to claim 38, wherein the first pipe comprises a first side wall, the second pipe comprises a second side wall, and all or part of the first side wall surrounds part of the second side wall.

53. The apparatus according to any one of claims 48 to 51, wherein the third pipe comprises a third side wall, and all or part of the third side wall surrounds a part of the first side wall.

54. The apparatus according to claim 38, wherein the first pipe has a first side wall, and the second pipe has a second side wall, and a portion of the second side wall is in contact with the second shielding portion.

55. The apparatus according to claim 38, wherein a first pipe for circulating a first liquid is connected to a first pump for circulating the first liquid.

56. The apparatus according to claim 38, wherein a second pipe for circulating a second liquid is connected to a second pump for circulating the second liquid.

57. An apparatus comprising the apparatus described in claim 38 and a first pump for circulating a first liquid.

58. The device according to claim 38, wherein the device is a catheter.

59. A method for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, wherein the second liquid circulates in the system in which the second liquid circulates, the method using the apparatus described in claim 38.

60. The method according to claim 59, which is not performed as a medical treatment for a human being.

61. An apparatus for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, the apparatus being equipped with a pipe for circulating the first liquid.

62. The apparatus according to claim 61, wherein the pipe for circulating the first liquid is for connecting to the part thereof.

63. The apparatus according to claim 61, further comprising a shielding portion for shielding the portion thereof from the second liquid.

64. The apparatus according to claim 61, further comprising a pipe for circulating a second liquid.

65. An apparatus for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, and for circulating the second liquid in the system in which the second liquid circulates, comprising a pipe for introducing the first liquid and a pipe for discharging the first liquid.

66. The apparatus according to claim 65, wherein the pipe for introducing the first liquid is for connecting to the part thereof.

67. The apparatus according to claim 65, wherein a pipe for discharging the first liquid is for connecting to the part thereof.

68. The apparatus according to claim 65, further comprising a shielding portion for shielding the portion thereof from the second liquid.

69. The apparatus according to claim 65, wherein the portion is a portion created by damming a system through which the second liquid circulates, and the portion is provided with a shielding part for shielding from the second liquid the portion into which the second liquid flowed before the damming.

70. The apparatus according to claim 65, wherein the portion is a portion created by damming a system through which the second liquid circulates, and the portion is provided with a shielding part for shielding from the second liquid the portion through which the second liquid flowed before the damming.

71. The apparatus according to claim 65, wherein the part is a part created by damming a system through which the second liquid circulates, and the part comprises a shielding portion for shielding from the second liquid the part into which the second liquid flowed before the damming, and the part comprises a shielding portion for shielding from the second liquid the part into which the second liquid flowed out before the damming.

72. The apparatus according to claim 65, further comprising a pipe for circulating a second liquid.

73. A method for circulating a first liquid, different from the second liquid, in a part of the system in which the second liquid circulates, wherein the second liquid circulates in the system in which the second liquid circulates, the method using the apparatus described in claim 61 or claim 65.

74. The method according to claim 73, which is not performed as a medical treatment for a human being.

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