Pharmaceutical composition, organ preserving fluid and application thereof

Abstract

The invention discloses a pharmaceutical composition, an organ preserving fluid and application of the organ preserving fluid. The pharmaceutical composition comprises Ceridutinib and edaravone. The mass ratio of the tidutinib to the edaravone is 1: (0.0001-10000). The pharmaceutical composition disclosed by the invention has a good cell protection effect, and the cedutinib and the edaravone show a synergistic effect, so that an excellent curative effect can be obtained, the dosage of the medicine can be reduced, and the clinical medication safety can be improved.

Description

A pharmaceutical composition, organ preservation solution and use thereof Technical Field

[0001] The present invention relates to a pharmaceutical composition for protecting cells, an organ preservation solution and applications thereof. The composition can be used to protect individuals (especially at-risk individuals), organs, tissues or cells from damage, and belongs to the field of biomedicine. Background Art

[0002] When organs, tissues or cells are in the process of decline or pathological conditions, especially those that may lead to cell death, such as various diseases, trauma or exposure to various physical and / or chemical damage factors, embolism / infarction, bleeding, surgery or organ transplantation, various pathological processes such as oxidative stress, calcium overload, energy metabolism disorders, and inflammatory response will occur, leading to various death modes such as apoptosis and necrosis of organs, tissues or cells, and ultimately leading to cell death.

[0003] Cellular necrosis involves various pathways, including necroptosis, ferroptosis, and pyroptosis. Studies have shown that RIPK1 / RIPK3 / MLKL-dependent necroptosis is involved in a variety of injury-related diseases, such as ischemic stroke, myocardial infarction, liver and kidney ischemia / reperfusion injury, autoimmune diseases, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy, Huntington's disease, and Parkinson's plus syndrome. Inhibiting RIPK1 / RIPK3-dependent necroptosis, ferroptosis, or pyroptosis, such as with the RIPK1 inhibitor necrostatin-1 (Nec-1), can reduce the extent of tissue, organ, and cell damage and alleviate cell death. In mice undergoing cerebral ischemia / reperfusion injury, the RIPK1 inhibitor necrostatin-1 can reduce ischemic damage and improve neurological function.

[0004] Oxidative stress (OS) refers to a state of imbalance between oxidative and antioxidant functions in the body, with a tendency toward oxidation, leading to inflammatory infiltration of neutrophils, increased secretion of proteases, and the production of large amounts of oxidative intermediates. Oxidative stress is a negative effect produced by free radicals in the body and is considered a major factor in aging and disease. Elevated oxidative stress levels are seen in a variety of injury-related diseases, including ischemic stroke, myocardial infarction, liver and kidney ischemia / reperfusion injury, autoimmune diseases, and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy, Huntington's disease, and Parkinson's plus syndrome. Inhibiting oxidative stress can reduce the extent of tissue, organ, and cell damage and reduce cell death.

[0005] If, in various pathological conditions, such as cardiac or cerebral ischemia / reperfusion injury, apoptosis, necroptosis, ferroptosis, or pyroptosis pathways are simultaneously inhibited, a synergistic inhibition of cell death can be achieved, significantly reducing the extent of tissue, organ, and cell damage, reducing cell death, and simultaneously reducing the dosage of individual drugs and alleviating their adverse reactions. However, existing compounds that inhibit these pathways can only serve as tool drugs and cannot meet clinical needs.

[0006] Therefore, it is very necessary to find new pharmaceutical compositions (cytoprotectants) for protecting cells with better clinical application prospects.

[0007] Cerdulatinib is an oral multi-target tyrosine kinase inhibitor that inhibits spleen tyrosine kinase (SYK) and Janus kinase (JAK), significantly reduces the cell activity of some non-Hodgkin's lymphoma (NHL) cell lines, and induces apoptosis of NHL cell lines with BCR signals. It can be used to treat peripheral T-cell lymphoma. However, whether Cerdulatinib has cytoprotective and anti-cell damage effects, as well as its anti-neurological effects, has not been reported. The chemical formula of Edaravone is C 10 H 10 Nitrogen dioxide (N2O) is primarily used as a free radical scavenger to improve neurological symptoms and functional impairment. However, whether the combination of these two drugs has a synergistic effect is unclear. Summary of the Invention

[0008] According to the present invention, the term "cytoprotective" refers to any agent or compound (whether natural or non-natural) that has the effect of protecting and / or preventing and / or treating cells against the consequences of pathological conditions (in particular conditions that may lead to cell death) or degenerative processes at the cellular level.

[0009] As used herein, unless otherwise indicated, "pathological condition" refers to, for example, a symptom or disease or trauma or exposure to various factors (particularly factors that trigger cell death processes), and also includes events such as hemorrhage, accidental occlusion (infarction) and / or medical procedures (particularly surgical procedures, such as organ transplantation).

[0010] According to the present invention, "protection" means preventing the occurrence of, inhibiting, reducing or treating the consequences of pathological conditions or degenerative processes at the cellular level that may lead to cell death, in particular in individuals at risk.

[0011] According to the present invention, "treatment" refers to preventive (advantageously for individuals at risk) and / or palliative and / or curative treatment. It includes the following: a) inhibiting and / or eliminating the occurrence and / or development of the degenerative process or pathological condition; b) or reducing the severity of the degenerative process or pathological condition, such as reducing the frequency or severity of symptoms associated with the degenerative process or pathological condition, improving the quality of life of the individual suffering from the degenerative process or pathological condition, reducing the amount of other drugs required to treat the degenerative process or pathological condition, enhancing the effect of another treatment taken to treat the degenerative process or pathological condition, or prolonging the life of the individual suffering from the degenerative process or pathological condition.

[0012] "Prevent" or "preventing" means reducing the likelihood of developing or arresting or delaying the onset of a degenerative process or pathological condition in an individual who has not yet developed but is at risk of developing the degenerative process or pathological condition.

[0013] "At risk" means that an individual has one or more risk factors for a degenerative process or pathological condition, which are measurable parameters that can be associated with the development of a degenerative process or pathological condition and are known to those skilled in the art. An individual who exhibits one or more of these risk factors has a higher likelihood of developing a degenerative process or pathological condition than an individual who does not exhibit these risk factors. For example, an individual who is scheduled for surgery may be considered an individual at risk. As another example, an individual with the following risk factors may be considered an individual with risk factors for stroke and cerebral ischemia: hypertension, carotid artery stenosis, transient ischemic attack, coronary artery disease, history of myocardial infarction, lack of physical exercise, atrial fibrillation, left ventricular dysfunction or mitral valve stenosis, heart failure, hyperlipidemia, smoking, diabetes.

[0014] The terms "organ," "tissue," or "cell" refer to one or more cells, a portion of an organ, an entire organ, a tissue, or a group of tissues (limbs, etc.) of human or animal origin. The present invention may be directed to all organs, tissues, or cells. Examples include: solid organs, such as the heart, liver, brain, lungs, kidneys, or pancreas, intestines, and eyes; cells, such as cells or stem cells of the aforementioned organs; and tissues, such as skin, cornea, and vascularized composite tissue (VCA). Preferably, the present invention is directed to solid organs; even more preferably, the brain, heart, intestines, lungs, liver, and kidneys are the targets of the present invention.

[0015] In the present invention, unless otherwise indicated, seletinib refers to seletinib compound (drug) or its pharmaceutically acceptable salt, or cocrystal, any stereoisomer, tautomer, hydrate, or solvate. Edaravone refers to edaravone compound (drug) or its pharmaceutically acceptable salt or ester or their isomer or one of their semi-synthetic derivatives or one of their salts (salts of compounds or salts of semi-synthetic derivatives) or one of their esters or one of their ester salts (salts of esters of compounds or salts of esters of semi-synthetic derivatives) or its deuterated compound (deuterated edaravone) or isotope-labeled compound. Alternatively, seletinib is a seletinib compound. Alternatively, edaravone is an edaravone compound.

[0016] Optionally, the pharmaceutically acceptable salt is a salt commonly used in pharmacy. Further, the salt is selected from one or more of acetate, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzoate, fumarate, maleate, succinic acid, tartaric acid, citrate, oxalic acid, glyoxylic acid, aspartic acid, tartrate, 2,5-dihydroxybenzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, benzoylsulfonate, hydroquinonesulfonate and p-toluenesulfonate, or salts formed with carboxylic acids (such as formic acid, acetic acid or propionic acid).

[0017] Generally, the structural formula of the seletinib compound is shown in Formula I, and the molecular formula is C 20 H 27 N7O3S.

[0018] The structural formula of the edaravone compound is shown in Formula II, and the molecular formula is C 10 H 10 N2O.

[0019] In view of the deficiencies in the prior art, one of the objects of the present invention is to provide a pharmaceutical composition that can protect, prevent and / or treat cells from resisting cell death or processes that cause cell death, such as drugs against pathological apoptosis and / or necrosis and / or necroptosis and / or ferroptosis and / or pyroptosis and / or disulfide death and / or autophagy, or a pharmaceutical composition that resists surgical operations that may cause cell death processes; a second object of the present invention is to provide a pharmaceutical composition for use in the preparation of a drug that protects, prevents and / or treats cells from resisting cell death or processes that cause cell death.

[0020] More specifically, in response to the deficiencies of the prior art, the present invention aims to provide a pharmaceutical composition for protecting cells with better efficacy; a second purpose of the present invention is to provide the use of the above-mentioned pharmaceutical composition in the preparation of cell protection drugs; a third purpose of the present invention is to provide the use of the above-mentioned pharmaceutical composition in the preparation of organ preservation fluid; and a fourth purpose of the present invention is to provide an organ preservation fluid.

[0021] In order to solve the above technical problems, the technical solutions of the present invention are as follows:

[0022] A pharmaceutical composition for protecting cells, comprising seletinib and edaravone.

[0023] Furthermore, the mass ratio of celutinib to edaravone is 1:0.0001-10000, preferably 1:0.001-1000, more preferably 1:0.01-100, even more preferably 1:0.05-25, further preferably 1:0.1-10, even more preferably 1:0.15-1, and even more preferably 1:0.2-0.8.

[0024] Optionally, the mass ratio of celutinib to edaravone is 1:0.5-20, further 1:1-10, further 1:1.5-9, further 1:2-8.5, and further 1:2.5-8.

[0025] Furthermore, the mass ratio of cilutinib to edaravone is 5-40:1-10, preferably 10-35:2-8, more preferably 15-30:3-6, further 18-25:4-5, further 19:4-5, 20:4-5, 21:4-5, 22:4-5, 23:4-5 or 24:4-5. Furthermore, the mass ratio of cilutinib to edaravone is 3-30:1-10, preferably 5-25:2-8, more preferably 7.5-15:3-6.

[0026] Optionally, in the pharmaceutical composition, the mass ratio of celutinib to edaravone is 20:7, 19:7, 18:7, 17:7, 16:7, 15:7, 14:7, 12:7, 11:7, 10:7, 9:7, 8:7, 7:7, 6:7, 5:7, 20:6, 19:6, 18:6, 17:6, 16:6, 15:6, 14:7 :6, 12:6, 11:6, 10:6, 9:6, 8:6, 7:6, 6:6, 5:6, 20:5, 19:5, 18:5, 17:5, 16:5, 15:5, 14:5, 12:5, 11:5, 10:5, 9:5, 8:5, 7:5, 6:5, 5:5, 20:4, 19:4, 18:4, 17:4, 1 6:4, 15:4, 14:4, 12:4, 11:4, 10:4, 9:4, 8:4, 7:4, 6:4, 5:4, 20:3, 19:3, 18:3, 17:3, 16:3, 15:3, 14:3, 12:3, 11:3, 10:3, 9:3, 8:3, 7:3, 6:3, 5:3, 20:2, 19:2, 18:2, 17:2, 16:2, 15:2, 14:2, 12:2, 11:2, 10:2, 9:2, 8:2, 7:2, 6:2, 5:2, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1 or 5:1.

[0027] Furthermore, the molar ratio of celutinib to edaravone is 5-75:3-65, preferably 6-70:4-60, and more preferably 7-68:5-58.

[0028] Furthermore, the active ingredients of the pharmaceutical composition include or are celutinib and edaravone.

[0029] Furthermore, the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form according to known techniques. The pharmaceutical composition of the present invention can be prepared into the following forms: a suspension or a ready-to-use injection solution or a temporary injection solution, a gel, an oil, a tablet, a suppository, a powder, a capsule, a granule, a suspension, an emulsion, a polymer, nanoparticles, microspheres, a rectal capsule, an enema, a paste, an ointment, a cream, a plaster, a potion, an implant, a spray, an aerosol, etc., and can optionally be controlled and / or sustained-released by a dosage form or device. The preferred dosage form is an injection, a capsule, a tablet, a granule, a powder, a spray, a liposome, an oral solution, or a dripping pill.

[0030] The pharmaceutical combination of Celutinib and Edaravone can be used for the prevention and / or protection and / or treatment of humans and / or animals (particularly mammals, preferably humans), advantageously in individuals at risk.

[0031] Based on the same inventive concept, the present invention also provides use of the above-mentioned pharmaceutical composition in the preparation of cell protection drugs.

[0032] Furthermore, the cell protection drug is a drug used to prevent, protect and / or treat cells from damage caused by pathological conditions and / or decline processes; the pathological conditions and / or decline processes include conditions that may lead to cell death, preferably, the pathological conditions and / or decline processes include pathological apoptosis and / or pathological necrosis and / or necroptosis and / or pyroptosis and / or ferroptosis and / or dependent cell death and / or disulfide death and / or autophagy (anti-apoptotic drugs and / or anti-necrosis drugs and / or anti-necroptosis drugs and / or anti-pyroptosis drugs and / or anti-ferroptosis drugs and / or anti-dependent cell death drugs and / or disulfide death drugs and / or anti-autophagy drugs) and / or diseases or conditions; preferably, the diseases or conditions include but are not limited to: nervous system diseases, cardiovascular system diseases , bleeding and thrombotic diseases, diffuse connective tissue diseases, organ-specific inflammatory or systemic inflammatory or autoimmune diseases, autoimmune diseases, bone diseases, joint diseases and cartilage diseases, ischemic diseases or attacks of the limbs, ophthalmic diseases, skin diseases, kidney diseases, blood diseases and vascular diseases, lung diseases, gastrointestinal diseases, liver diseases, metabolic diseases, muscle diseases, pancreatic diseases, severe poisoning by chemicals, infectious agents, toxins or drugs, diseases related to aging, dental diseases, auditory conduction pathway diseases, mitochondrial-related diseases, and / or trauma and / or exposure to factors of biological and / or chemical and / or physical origin and / or and / or medical and / or surgical procedures, such as accidental infarction and hemorrhage, and / or medical and / or surgical procedures, such as cell, tissue or organ transplantation.

[0033] Furthermore, the cytoprotective drug refers to a drug that has the effect of preventing, inhibiting or treating damage, degeneration or dysfunction of tissues, organs and cells caused by hypoxia / reoxygenation;

[0034] Alternatively, the cytoprotective drug refers to a drug that has the function of preventing, inhibiting or treating damage, degeneration or dysfunction of tissues, organs and cells caused by necroptosis.

[0035] Furthermore, the neurological diseases include stroke, transient ischemic attack, ischemia, intracranial hemorrhage, prenatal cerebral hypoxia, adult or childhood cerebral hypoxia, neurodegenerative diseases, muscle diseases, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, progressive bulbar palsy, primary lateral sclerosis (PLS), pseudobulbar palsy, invertebrate disc syndrome, cervical spondylosis, plexus disorder, thoracic outlet destruction syndrome, porphyria, peripheral neuropathy, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, Lewy body dementia, demyelinating disease, frontotemporal dementia, Guillain-Barré syndrome, multiple sclerosis, Creutzfeldt-Jakob disease, progressive Charcot-Marie-Tooth disease, prion disease, fatal Familial insomnia, Gerstmann-Strauss-Scheinker syndrome, bovine spongiform encephalopathy, epilepsy, hereditary ataxia, Friedreich-type ataxia, spinocerebellar ataxia, hereditary spastic paraplegia, dystonia, multiple system atrophy, lysosomal storage disease, Niemann-Pick disease, Gaucher disease, AIDS dementia syndrome, nerve damage caused by exposure to toxic compounds in the group consisting of industrial solvents, heavy metals, drugs and chemotherapeutic agents, nerve damage caused by mechanical, physical or chemical trauma or several thereof; preferably, stroke includes one or several of ischemic stroke and hemorrhagic stroke; preferably, the neurodegenerative disease includes Alzheimer's disease (Alzheimer's disease), Parkinson's disease, amyotrophic lateral sclerosis (ALS) and infantile spinal muscular atrophy, Huntington's disease, Parkinson's plus syndrome; preferably, the muscle disease includes one or more of muscular dystrophy, Duchenne muscular dystrophy, myotonic muscular dystrophy, myopathy and myasthenia gravis, progressive muscular dystrophy, spinal muscular atrophy, hereditary muscular atrophy;

[0036] Preferably, the cardiovascular system disease includes one or more of cardiac ischemia and / or vascular ischemia, ischemic heart disease, angina pectoris, unstable angina pectoris, refractory angina pectoris, myocardial infarction (occlusion), myocardial ischemia / reperfusion injury, anoxia, hypoxia, chronic or acute heart failure, systolic heart failure and diastolic heart failure, left ventricular dysfunction, left ventricular dysfunction after myocardial infarction, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, myocardial hypertrophy, hypertrophic cardiomyopathy, myocarditis, valvular heart disease, arrhythmia, paroxysmal tachycardia, atrial fibrillation, ventricular fibrillation, arteriosclerosis, atherosclerosis, peripheral vascular disease, aneurysm, peripheral vascular obstructive disease (preferably brain obstruction, lung obstruction or intestinal obstruction), chronic venous insufficiency or varicose veins, hypertension, systemic hypertension, pulmonary hypertension, portal hypertension, and cardiovascular toxic side effects caused by drug (preferably anticancer drug) treatment;

[0037] Preferably, the stroke includes ischemic stroke;

[0038] Preferably, the diffuse connective tissue disease comprises one or more of rheumatoid arthritis, juvenile idiopathic arthritis, lupus erythematosus, systemic lupus, scleroderma, idiopathic inflammatory myopathy, polymyositis, dermatomyositis, vasculitis, necrotizing vasculitis, polyarteritis nodosa, granulomatosis with polyangiitis, giant cell arteritis, Sjögren's syndrome, systemic sclerosis, allergic cutaneous vasculitis, and Behcet's disease;

[0039] Preferably, the organ-specific inflammation or systemic inflammation or autoimmune disease includes one or more of chronic inflammatory bowel disease, bronchial asthma, chronic obstructive pulmonary disease, eosinophilic sinusitis, and systemic lupus;

[0040] Preferably, the ophthalmic disease or condition comprises one or more of diabetic retinopathy, glaucoma, retinal degeneration, retinitis pigmentosa corneal reticular dystrophy, optic neuropathy and optic neuritis, optic nerve drusen, ptosis, chronic progressive external ophthalmoplegia, macular degeneration, retinal hole or retinal tear, retinal ischemia, retinal ischemia / reperfusion injury, retinal detachment, acute retinopathy associated with trauma, inflammatory degeneration, postoperative complications, drug-induced retinopathy or cataract, wet or dry AMD-related photoreceptor degeneration;

[0041] Preferably, the skin disease comprises one or more of dermatitis, psoriasis, scar formation, aging or altered healing process, eczema, and collagen disease;

[0042] Preferably, the trauma and / or exposure to factors such as biological sources and / or chemical sources and / or physical sources and / or and / or medical operations and / or surgical operations include severe poisoning caused by infectious agents, toxins, chemicals or drugs. More preferably, the symptoms of severe poisoning include one or more of sepsis, septic shock and its consequences or iatrogenic diseases.

[0043] Furthermore, the cytoprotective drug is a drug used to prevent and / or protect and / or treat cell death of transplanted organs and / or organ donors and / or organ recipients, prevent acute transplant rejection of organs and / or increase long-term survival rate, limit primary organ dysfunction and / or limit delayed recovery of transplanted organ function and / or improve transplanted organ function recovery, and mainly prevents or treats cell death of transplanted organs.

[0044] Advantageously, the pharmaceutical composition containing selegiline and edaravone can be used for living or clinically dead organ donors, tissue donors, cell donors, organ recipients, tissue recipients, cell recipients before, during or after transplantation; and / or more specifically, the organs, tissues or cells are not only in situ organs, tissues or cells (for example, in medicine, surgery or in pathological processes), but also ex vivo organs, tissues or cells (for example, in certain specific operations that require temporary removal of organs, tissues or cells from the body, especially those for modification or purification, or during the transportation and storage of organs, tissues or cells, during transplantation or during their reperfusion after reimplantation of organs, tissues or cells).

[0045] Thus, this prevention and protection can be carried out in a general manner on an individual, donor or recipient, or on an organ, tissue or cell in situ or ex vivo, for example during certain surgeries, or during their transport or during their storage for reimplantation.

[0046] Ischemia primarily occurs when blood supply to an organ is reduced or interrupted, leading to decreased blood, oxygen, and energy supply to organs, tissues, and cells, resulting in functional impairment and death. This condition is associated with, but is not limited to, atherosclerotic plaques, thrombosis, arterial compression (e.g., through limb crush, tourniquet application, tumors, hematomas, or fluid extravasation), artificial circulatory arrest (such as during surgery), bleeding, or hypoperfusion. Ischemia or hypoperfusion can affect or damage the function of all organs, particularly the brain, heart, liver, lungs, kidneys, intestines, or limbs. When blood circulation is restored to an organ after a period of ischemia, reperfusion can also cause damage to organs, tissues, and cells, a condition known as ischemia / reperfusion injury (I / R injury). This can limit functional recovery and may even jeopardize survival. I / R injury involves multiple types of cell death.

[0047] Unexpectedly, the inventors discovered that a pharmaceutical composition containing selegiline and edaravone can reduce damage and increase the survival rate of animals undergoing organ ischemia / reperfusion and human or animal cells from different types of organs subjected to hypoxia / reoxygenation (oxygen glucose deprivation / reoxygenation) and necroptosis induction.

[0048] Preferably, the cytoprotective drug is a drug for preventing and / or protecting and / or treating pathological conditions or degenerative processes associated with ischemia / reperfusion symptoms (especially those conditions leading to cell death). More preferably, the pathological conditions or degenerative processes associated with ischemia / reperfusion symptoms include one or more of actual cold ischemia, warm ischemia, actual reperfusion, and ischemia / reperfusion phenomena.

[0049] Preferably, the cytoprotective drug is a drug used to prevent and / or protect and / or treat organs, tissues or cells against ischemia / reperfusion injury. Optionally, the ischemia / reperfusion injury is caused by cold ischemia or warm ischemia and / or reperfusion and / or during ischemia / reperfusion; further, the ischemia / reperfusion injury includes one or more of cerebral ischemia / reperfusion injury, myocardial ischemia / reperfusion injury, liver ischemia / reperfusion injury, renal ischemia / reperfusion injury, lung ischemia / reperfusion injury, intestinal ischemia / reperfusion injury and limb ischemia / reperfusion injury.

[0050] In a preferred form, the pharmaceutical composition containing selegiline and edaravone can be used as a medicament for the prevention and / or protection and / or treatment of: neurological sequelae due to stroke or trauma, heart failure due to infarction, tissue damage affecting the heart, liver, intestine, lung or kidney after transplantation or surgery, or damage caused by surgical procedures.

[0051] In a more preferred form, the pharmaceutical composition containing seletinib and edaravone can be used as a medicament for preventing and / or protecting and / or treating ischemic stroke caused by actual warm ischemia or cold ischemia and / or actual reperfusion and / or ischemia / reperfusion.

[0052] In a more preferred form, the pharmaceutical composition comprising seletinib and edaravone can be used as a medicament for preventing and / or protecting and / or treating myocardial infarction caused by actual warm ischemia or cold ischemia and / or actual reperfusion and / or ischemia / reperfusion.

[0053] According to the present invention, the pharmaceutical composition containing cerutinib and edaravone is used in a physiologically effective amount.

[0054] As a drug, the pharmaceutical composition containing cilutinib and edaravone can be formulated for administration to the digestive tract or the parenteral tract.

[0055] Furthermore, the cytoprotective drug is a drug for preventing and / or protecting and / or treating one or more of: heart failure caused by infarction, neurological sequelae caused by stroke or trauma, tissue damage affecting the liver, intestine, heart, lung or kidney after transplantation or surgery or the consequences of surgical procedures;

[0056] Alternatively, the cell protective drug is a drug used to prevent and / or protect and / or treat one or more of nerve cells (brain protective drugs), heart cells (heart protective drugs), liver cells (liver protective drugs), kidney cells (kidney protective drugs), intestinal cells or lung cells. Preferably, the cell protective drug is a drug used to protect nerve cells, vascular endothelial cells, brain endothelial cells and / or myocardial cells.

[0057] Alternatively, the factor triggering the cell death process may be of biological and / or chemical and / or physical origin.

[0058] Use of the pharmaceutical composition as described above in the preparation of drugs for preventing, protecting and / or treating ischemia / reperfusion injury and / or neurodegenerative diseases.

[0059] Optionally, the ischemia / reperfusion injury includes one or more of cerebral ischemia / reperfusion injury, myocardial ischemia / reperfusion injury, liver ischemia / reperfusion injury, renal ischemia / reperfusion injury, lung ischemia / reperfusion injury, intestinal ischemia / reperfusion injury and limb ischemia / reperfusion injury; preferably, cerebral ischemia / reperfusion injury includes ischemic stroke;

[0060] The neurodegenerative diseases include one or more of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, infantile spinal muscular atrophy, Huntington's disease, and Parkinson's plus syndrome.

[0061] Use of the above-mentioned pharmaceutical composition in preparing organ preservation solution.

[0062] Alternatively, biological sources include, for example, asphyxia, ischemia / reperfusion, hypoxia or oxygen deprivation, nutritional deprivation, in situ generated free radicals or poisoning caused by reactive oxygen species, growth factor deficiency, massive release of cytotoxins or cytokines. They may also originate from certain events, such as hemorrhage, accidental occlusion (infarction), and certain medical procedures (e.g., use of air bag inflation, artificial respirators, sutures), as well as biological or chemical agents used as therapeutic agents in medical treatment (e.g., immunosuppressants, cytostatic or cytotoxic agents, anti-inflammatory drugs).

[0063] Alternatively, chemical sources include, for example, poisoning by toxicants, waste, pH changes, free radicals, reactive oxygen species, environmental toxins.

[0064] Optionally, physical sources include, for example, impact, cuts, exposure to radiation (X-radiation, gamma radiation, UV radiation, etc.), hyperthermia, hypothermia, or the presence of foreign matter or crystals in the organism.

[0065] Alternatively, surgical procedures that may lead to cell death processes may be, for example, procedures requiring a brief interruption of blood circulation leading to systemic or local ischemia or hypoperfusion (e.g., the use of tourniquets, hemostats, etc.), for example during surgery, in particular during procedures such as angioplasty of an organ or the heart or major or peripheral blood vessels or thoracic surgery that sometimes requires (bypassing) the cardiopulmonary system or arresting the heart, cardiac surgery or vascular surgery, as well as any surgery requiring the voluntary occlusion of an organ or part of an artery or the reduction of blood flow through an organ.

[0066] Alternatively, very important diseases or symptoms that may lead to cell death processes include (but are not limited to) the following diseases or symptoms (these diseases or symptoms are often accompanied by apoptosis and / or necrosis and / or necroptosis and / or ferroptosis and / or pyroptosis and / or autophagy):

[0067] Neurological diseases include stroke, transient ischemic attack, ischemia, intracranial hemorrhage, prenatal cerebral hypoxia, adult or childhood cerebral hypoxia, neurodegenerative diseases, muscle diseases, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, progressive bulbar palsy, primary lateral sclerosis (PLS), pseudobulbar palsy, invertebrate disc syndrome, cervical spondylosis, plexus disorders, thoracic outlet disruption syndrome, porphyria, peripheral neuropathy, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, dementia with Lewy bodies, demyelinating diseases, frontotemporal dementia, Guillain-Barré syndrome, multiple sclerosis, Creutzfeldt-Jakob disease, Charcot-Marie-Tooth disease, prion diseases, and fatal familial insomnia. Preferably, the stroke includes one or more of ischemic stroke and hemorrhagic stroke; preferably, the neurodegenerative disease includes Alzheimer's disease (Alzheimer's) disease), Parkinson's disease, amyotrophic lateral sclerosis (ALS) and infantile spinal muscular atrophy, Huntington's disease, Parkinson's plus syndrome; preferably, the muscle disease includes one or more of muscular dystrophy, Duchenne muscular dystrophy, myotonic muscular dystrophy, myopathy and myasthenia gravis, progressive muscular dystrophy, spinal muscular atrophy, hereditary muscular atrophy;

[0068] Pain, such as neuropathic pain, inflammatory pain, and diabetic pain;

[0069] Cardiovascular diseases, such as cardiac ischemia and / or vascular ischemia, ischemic heart disease, angina pectoris, unstable angina pectoris, refractory angina pectoris, myocardial infarction (MI), myocardial ischemia / reperfusion injury, anoxia, hypoxia, chronic or acute heart failure, systolic heart failure and diastolic heart failure, left ventricular dysfunction, left ventricular dysfunction after myocardial infarction, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, myocardial hypertrophy, hypertrophic cardiomyopathy, myocarditis, valvular heart disease, arrhythmias, paroxysmal tachycardia, atrial fibrillation, ventricular fibrillation, arteriosclerosis, atherosclerosis, peripheral vascular disease, aneurysm, peripheral vascular obstructive disease (especially cerebral, pulmonary or intestinal obstruction), chronic venous insufficiency or varicose veins, hypertension, systemic hypertension, pulmonary hypertension, portal hypertension, cardiovascular side effects due to drug therapy (especially anticancer drugs);

[0070] Myocardial remodeling includes myocardial remodeling after myocardial ischemia / hypoxia (such as myocardial infarction), myocardial remodeling after cardiac surgery, myocardial remodeling after aortic valve disease, vascular hypertrophy (smooth muscle cell hypertrophy), and vascular remodeling;

[0071] Bleeding and thrombotic diseases, thromboembolic diseases and venous thrombosis, vascular permeability disorders, restenosis, acute coronary syndrome, thrombolytic therapy or coronary angioplasty, venous embolism, venous thrombosis and pulmonary embolism, thrombosis leading to cerebrovascular syndromes such as embolic stroke, transient ischemic attack, occlusive coronary thrombosis. Coagulopathy, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, occlusive thromboangiitis and heparin-induced thrombocytopenia-related thromboangiitis. Thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with devices such as cardiac or other intravascular catheterization, intra-aortic balloon surgery, coronary stents or heart valves, conditions requiring the installation of assistive devices and similar conditions;

[0072] Diffuse connective tissue diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, lupus erythematosus, systemic lupus, scleroderma, idiopathic inflammatory myopathy, polymyositis, dermatomyositis, vasculitis, necrotizing vasculitis, polyarteritis nodosa, granulomatosis with polyangiitis, giant cell arteritis, Sjögren's syndrome, systemic sclerosis, allergic cutaneous vasculitis, Behçet's disease, etc.

[0073] Organ-specific inflammatory or systemic inflammatory or autoimmune diseases, such as chronic inflammatory bowel disease, bronchial asthma, chronic obstructive pulmonary disease, eosinophilic sinusitis, or systemic lupus;

[0074] Autoimmune diseases or conditions, including but not limited to Hashimoto's thyroiditis, autoimmune atrophic gastritis, autoimmune orchitis, autoimmune encephalomyelitis, autoimmune thrombocytopenia, autoimmune alopecia, ulcerative colitis, hemolytic anemia, pernicious anemia, sympathetic ophthalmia, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, conjunctival quadrangularis, systemic lupus erythematosus;

[0075] Bone, joint, and cartilage diseases, such as osteoporosis, osteomyelitis, avascular necrosis, arthritis (including, for example, osteoarthritis and psoriatic arthritis), spondyloarthropathies, ankylosing spondylitis, rickets, fibrodysplasia ossificans progressiva, and Cushing's syndrome;

[0076] limb ischemic disease or attack;

[0077] ophthalmic diseases or conditions, such as diabetic retinopathy, glaucoma, retinal degeneration, retinitis pigmentosa corneal dystrophy, optic neuropathy and optic neuritis, optic nerve drusen, ptosis, chronic progressive external ophthalmoplegia, macular degeneration, retinal hole or tear, retinal ischemia, retinal ischemia / reperfusion injury, retinal detachment, acute retinopathy associated with trauma, inflammatory degeneration, post-surgical complications, drug-induced retinopathy or cataracts, photoreceptor degeneration associated with wet or dry AMD;

[0078] Skin disorders such as dermatitis, psoriasis, scarring, aging or altered healing processes, eczema, collagen disorders;

[0079] Renal disease, such as renal fibrosis, acute renal disease, renal ischemia, renal capillary infarction, acute kidney injury, acute or chronic interstitial nephropathy, glomerulonephritis, diabetic nephropathy, renal arteriosclerosis, renal insufficiency, acute or chronic renal failure or side effects of dialysis, renal failure after myocardial ischemia / reperfusion;

[0080] Blood disorders, such as anemia, bleeding, angioamyloidosis, sickle cell disease, neutropenia, red cell fragmentation syndrome, pancytopenia, leukopenia, bone marrow aplasia, thrombocytopenia, and hemophilia;

[0081] Lung diseases such as pulmonary hypertension, acute respiratory distress syndrome, respiratory infections, chronic obstructive pulmonary disease such as chronic bronchitis and emphysema, asthma, cystic fibrosis, cystic lung disease.

[0082] Gastrointestinal diseases, such as chronic inflammatory bowel disease, ulcer or mesenteric infarction, portal hypertension;

[0083] Liver diseases, such as autoimmune hepatitis, viral hepatitis or hepatitis caused by other infectious agents, liver fibrosis, alcoholic liver disease (ALD), alcoholic hepatitis, fulminant hepatitis, cirrhosis, liver disease caused by toxins or drugs;

[0084] Steatosis, such as hepatic ischemia or associated with exogenous intoxication by drugs, alcohol, or nonalcoholic steatohepatitis (NASH);

[0085] Metabolic diseases, such as diabetes, diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic foot disease, thyroiditis, Hashimoto's thyroiditis, glucose intolerance syndrome, obesity, abetalipoproteinemia, hyperlipidemia, hypothalamic-pituitary axis dysfunction, diabetes insipidus, galactosemia, glycogenopathies, gout, Wilson's disease, or Weber-Christian disease;

[0086] pancreatic disease, such as chronic pancreatitis or acute pancreatitis;

[0087] Severe poisoning caused by infectious agents, toxins, chemicals or drugs, such as sepsis, septic shock and its consequences or iatrogenic diseases;

[0088] Aging-related diseases, such as accelerated aging syndrome;

[0089] dental diseases, such as those that cause tissue damage, such as periodontitis;

[0090] Auditory pathway disorders, such as antibiotic-induced deafness and otosclerosis;

[0091] Mitochondrial-related diseases (mitochondrial pathology), such as congenital muscular dystrophy with structural mitochondrial abnormalities and Friedrich's ataxia;

[0092] and / or trauma and / or exposure to factors of biological and / or chemical and / or physical origin and / or events, such as unexpected bleeding and infarction, and / or medical and / or surgical procedures, such as cell, tissue or organ transplantation.

[0093] Advantageously, the above-mentioned pharmaceutical composition is used, for example, for preventing and / or protecting and / or treating nerve cells (drugs that protect brain cells), myocardial cells (drugs that protect the heart), lungs (drugs that protect the lungs), intestines (drugs that protect the intestines), liver (drugs that protect the liver), kidneys (drugs that protect the kidneys), preferably for protecting nerve cells (drugs that protect the brain), myocardial cells (drugs that protect the heart), intestines (drugs that protect the intestines), and very preferably nerve cells and myocardial cells.

[0094] The pharmaceutical composition of the present invention comprises seletinib and edaravone, for simultaneous use, separate use or spread out use, for use as a medicament, in particular for the prevention and treatment of individuals at risk and / or individuals suffering from at least one pathological condition or at least one of the aforementioned degenerative processes. It should be understood that for simultaneous use, the compounds present in the pharmaceutical composition comprising the compounds may be mixed together or physically separated, whereas for separate use or spread out use, the compounds present must be physically separated.

[0095] The pharmaceutical composition of the present invention comprises seletinib and edaravone, for simultaneous use, separate use or use with time intervals, as a cytoprotective drug or drug for preventing and / or protecting and / or treating the consequences of the above-mentioned pathological conditions or degenerative processes at the cellular level.

[0096] The pharmaceutical composition of the present invention comprises seletinib and edaravone, for simultaneous use, separate use or use at intervals, as a cytoprotective drug or drug for preventing and / or protecting and / or treating the consequences of the above-mentioned pathological conditions or degenerative processes at the cellular level and / or treating a subject suffering from one of the above-mentioned pathological conditions or degenerative processes.

[0097] In a very preferred form, the present invention relates to a pharmaceutical composition which may comprise seletinib, edaravone or a pharmaceutically acceptable salt or ester thereof or one of their isomers or one of their semisynthetic derivatives or one of their salts or one of their esters or one of their ester salts or a deuterated compound or an isotope-labeled compound thereof, for use as a cytoprotective drug or drug for preventing and / or protecting and / or treating the consequences of the above-mentioned pathological conditions or degenerative processes at the cellular level and / or for treating a subject suffering from one of the above-mentioned pathological conditions or degenerative processes.

[0098] Optionally, with respect to this aspect of the invention relating to the composition, the embodiments and definitions describing the use of cilutinib and edaravone as cytoprotective drugs in the pharmaceutical composition of the invention and relating to administration and dosage should also be considered.

[0099] The pharmaceutical composition of the present invention containing seletinib and edaravone is used for simultaneous use, separate use or use at intervals as a drug for preventing and / or protecting and / or treating cells, tissues, and organs against ischemia / reperfusion injury (which may occur during actual cold ischemia or warm ischemia and / or actual reperfusion phenomena and / or ischemia / reperfusion phenomena).

[0100] In a very preferred form, the present invention relates to a pharmaceutical composition as a medicament for preventing and / or protecting and / or treating cells, tissues, organs against ischemia / reperfusion damage that may occur during actual cold or warm ischemia and / or actual reperfusion phenomena and / or during ischemia / reperfusion phenomena.

[0101] In a very preferred form, the present invention relates to pharmaceutical compositions for use as agents for preventing and / or protecting and / or treating cells, tissues, organs against decline and degeneration, such as neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and infantile spinal muscular atrophy, Huntington's disease, Parkinson's plus syndrome and multiple sclerosis).

[0102] According to one embodiment of the present invention, in the pharmaceutical composition of celutinib and edaravone, the amount of celutinib may be 0.0001 mg to 40,000 mg / mg edaravone, preferably 1 mg to 6,000 mg (celutinib) / mg edaravone. Alternatively, the amount of edaravone may be 0.0001 mg to 40,000 mg / mg celutinib, preferably 0.01 mg to 100 mg edaravone / mg celutinib.

[0103] According to the present invention, the cilutinib and edaravone in the pharmaceutical composition may be in a common dosage form. Also according to the present invention, the cilutinib and edaravone in the composition may be in the same dosage form or in different dosage forms.

[0104] It should therefore be understood that according to the present invention, when selutinib and edaravone of the composition are in a common dosage form, they can be administered simultaneously (ie, at the same time) and using the same route of administration.

[0105] It should also be understood that according to the present invention, when selutinib and edaravone of the composition are in the same dosage form or different dosage forms, they can be administered simultaneously, sequentially or separately using the same or different administration routes.

[0106] Preferably, when administered sequentially, cilutinib and edaravone are administered within an interval of no more than about 1 hour (preferably no more than about 10 minutes, even more preferably no more than about 1 minute).

[0107] According to the present invention, seletinib and edaravone can be mixed with one or more acceptable excipients or inert carriers (i.e., pharmaceutically inactive and non-toxic excipients) for the purpose of imparting a specific consistency or other specific physical or taste properties to the finished product, avoiding any chemical interaction between the two drugs. These include saline solutions, isotonic solutions, physiological solutions, buffer solutions, etc. that are compatible with pharmaceutical uses and known to those skilled in the art. The pharmaceutical composition of the present invention may contain one or more agents or media selected from the group consisting of solubilizers, dispersants, stabilizers, sweeteners, preservatives, flavorings, lubricants, anti-caking agents, disintegrants, adsorbents, etc. In particular, the agents or media (liquids and / or injections and / or solids) that can be used for the formulation are: methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, polysorbate 80, cyclodextrin, gelatin, mannitol, lactose, PEG, animal or vegetable oils, etc. The pharmaceutical composition of the present invention can be prepared in the following forms: suspensions or ready-to-use injectable solutions or temporary injectable solutions, oils, gels, tablets, powders, suppositories, capsules, granules, emulsions, suspensions, polymers, microspheres, nanoparticles, rectal capsules, enemas, pastes, creams, ointments, plasters, implants, potions, sprays, aerosols, etc.; optionally, controlled and / or sustained release can be achieved by a dosage form or device. For this type of preparation, agents such as carbonates, cellulose, or starch are advantageously used.

[0108] In one embodiment, the pharmaceutical composition can be prepared in powder form and reconstituted for intravenous injection.

[0109] Administration can be by any method known to those skilled in the art, preferably oral administration or parenteral administration, for example by intramuscular injection, intravenous administration, subcutaneous injection, intraarterial injection, intraperitoneal injection, intracerebral injection or intrathecal injection, oral administration, sublingual administration, intralesional or intracerebral or implanted delivery, spray administration.Intramuscular injection, intravenous administration, subcutaneous injection or oral administration are preferred.For long-term treatment, preferred route of administration is oral, sublingual or transdermal.

[0110] For injection, the compound can be packaged as a suspension or liquid solution and can be injected using a syringe or infusion set. It should be understood that those skilled in the art can adjust the amount to be administered or the amount and / or rate of injection according to pathology, mode of administration, individual, etc. It should be understood that repeated administration can be performed in combination with other active ingredients and / or any pharmaceutically acceptable carrier (buffer, isotonic solution, saline solution, in the presence of a stabilizer, etc.).

[0111] According to certain aspects, the pharmaceutical compositions of the present invention can be administered before, during, or after a process that may result in cell death, such as before surgery or during surgery requiring bypassing the heart, or when an individual is at risk of potential ischemic injury (e.g., cardiac ischemia or vascular ischemia). According to certain aspects, the pharmaceutical compositions of the present invention can be administered after a process that may result in cell death (e.g., after an infarction, etc.).

[0112] In the case of pathological conditions and / or degenerative processes and / or cell death processes caused at least in part by the ischemia-reperfusion phenomenon, the composition of the invention can be administered before the ischemia and / or during the ischemia and / or after the ischemia and / or before the reperfusion and / or during the reperfusion and / or after the reperfusion.

[0113] Whether the organ is in situ or ex vivo, contact of the organ with the composition of the present invention can be carried out by any known means, such as direct contact with the organ by spraying, perfusion, immersion, dipping, flushing, etc.

[0114] Typically, the daily dose of the compound will be the minimum dose that achieves the desired therapeutic effect. Alternatively, for humans, the dose of selutinib may typically be 0.01 mg / kg / day to 150 mg / kg / day, preferably 0.1 mg / kg / day to 60 mg / kg / day, and even more preferably 0.5 mg / kg / day to 10 mg / kg / day.

[0115] Alternatively, for humans, the dosage of edaravone may generally be 0.001 mg / kg / day to 150 mg / kg / day, preferably 0.01 mg / kg / day to 60 mg / kg / day, and even more preferably 0.1 mg / kg / day to 1 mg / kg / day.

[0116] Alternatively, the daily administered amount may be administered as one, two, three, four, five, six or more doses taken daily, or as multiple sub-doses taken at appropriate intervals throughout the day, as desired.

[0117] Alternatively, the amount chosen may depend on a variety of factors, in particular the route of administration, the duration of administration, the time over which the administration is carried out, the rate of elimination of the compound, the different products with which the composition is used in combination, the age, weight and physical condition of the individual, as well as the individual's medical history, the nature of the pathological condition or degenerative process he or she is facing, and any other information known to medicine.

[0118] Alternatively, the doctor's prescription may start with doses lower than those usually used and then gradually increase these doses to better control possible side effects. Preferably, the composition of the present invention may be administered for a period of 1 day to 20 years, even more preferably for a period of 1 day to 3 years.

[0119] The present invention also relates to a method of treatment, which may include administering a therapeutically effective amount of a pharmaceutical composition comprising seletinib and edaravone to a human or animal in need thereof.

[0120] The present invention also relates to a method for preparing a pharmaceutical composition comprising seletinib and edaravone, wherein the compounds of the composition of the present invention are mixed with an acceptable excipient (particularly a pharmaceutically acceptable excipient) according to a method known per se.

[0121] The present invention also relates to the use of a pharmaceutical composition containing cilutinib and edaravone in preparing an organ preservation solution. For example, the organ preservation solution containing the pharmaceutical composition of cilutinib and edaravone can be prepared from any existing organ preservation solution (e.g., any solution used for infusion, storage, transport, and / or flushing of organs). For example, such a solution can be Belzer's refrigeration solution, a preservation solution, or a mixture thereof.

[0122] Based on the same inventive concept, the present invention further provides: an organ preservation solution comprising the pharmaceutical composition described above.

[0123] Furthermore, in the organ preservation solution, the concentration of cilutinib is 0.01 mg / L to 1000 mg / L, preferably 0.1 mg / L to 100 mg / L, and more preferably 1 mg / L to 10 mg / L; the concentration of edaravone is 0.1 mg / L to 150 mg / L, preferably 1 mg / L to 50 mg / L, and more preferably 1 mg / L to 10 mg / L.

[0124] The present invention also relates to a solution, a pharmaceutical composition comprising seletinib and edaravone, intended for organ preservation (preservation solution). For example, the preservation solution of the present invention can be used to in situ infuse the organ before removal from the donor, optionally cooling it, and / or after removal for, for example, static flushing and / or storage and / or transport of the organ, or by, for example, infusion using an infusion machine (with or without oxygen supply) at temperatures ranging from hypothermia to normal body temperature.

[0125] According to the present invention, the preservation solution may contain the pharmaceutical composition of the present invention, seletinib and edaravone, in an amount sufficient to prevent / mitigate / limit pathological changes caused by processes that can lead to cell death (particularly pathological changes caused by ischemia-reperfusion). For example, the concentration of seletinib used in the pharmaceutical composition comprising seletinib and edaravone in the preservation solution may be 0.01 mg / L to 1000 mg / L, preferably 0.1 mg / L to 100 mg / L, and even more preferably 1 mg / L to 10 mg / L of preservation solution. The concentration of edaravone in the preservation solution may be 0.1 mg / L to 150 mg / L, preferably 1 mg / L to 50 mg / L, and even more preferably 1 mg / L to 10 mg / L of preservation solution.

[0126] Advantageously, the organ preservation solution of the present invention can be used for infusion and / or storage and / or transport and / or flushing of organs, such as the liver, lungs, heart, kidneys, or pancreas, preferably the liver. Alternatively, the pharmaceutical composition comprising cilutinib and edaravone of the present invention can be added to the organ preservation solution several hours to minutes before the organ is infused and / or stored and / or transported and / or flushed using the solution.

[0127] Furthermore, the pharmaceutical composition comprising cilutinib and edaravone can be added to the preservation solution while the organ is already in the preservation solution. For example, the pharmaceutical composition comprising cilutinib and edaravone can be added to the preservation solution at any time during warm ischemia, cold ischemia, or reperfusion.

[0128] Alternatively, according to the present invention, when celutinib and edaravone in the pharmaceutical composition are in the same dosage form, they can be added to the preservation solution simultaneously. According to the present invention, when celutinib and edaravone in the pharmaceutical composition are in the same dosage form or different dosage forms, they can be added to the preservation solution simultaneously or sequentially.

[0129] Another object of the present invention relates to a method for temporarily preparing an organ preservation solution comprising cilutinib and edaravone, the method comprising the step of mixing cilutinib and edaravone. According to the present invention, when cilutinib and edaravone are used to prepare a transplant organ preservation solution, the composition can be formulated in a form compatible with such use.

[0130] The present invention also relates to a method for preventing and / or protecting and / or treating an organ, tissue or cell against ischemia-reperfusion injury (which may occur during an actual warm ischemia or cold ischemia phenomenon and / or an actual reperfusion phenomenon and / or an ischemia-reperfusion phenomenon), which method comprises contacting the organ, tissue or cell with an organ preservation solution containing a composition of selegiline and edaravone according to the present invention.

[0131] Another object of the present invention relates to the use of the composition of seletinib and edaravone according to the present invention, the medicament or the preservation solution according to the present invention for preventing and / or protecting and / or treating organs, tissues or cells against ischemia-reperfusion injury (which may occur during actual warm ischemia or cold ischemia and / or actual reperfusion and / or ischemia-reperfusion).

[0132] Another object of the present invention relates to the use of the composition, medicament, composition or preservation solution of seletinib and edaravone according to the present invention for preventing and / or protecting and / or treating organs, tissues or cells against pathological changes that may occur during ischemia-reperfusion phenomena.

[0133] Compared with the prior art, the present invention has the following beneficial effects:

[0134] The pharmaceutical composition of the present invention has an excellent cell protection effect. The combined use of seletinib and edaravone shows a synergistic effect, which helps to achieve excellent therapeutic effects, reduce drug dosage, improve clinical drug safety, and has good clinical application prospects.

[0135] The pharmaceutical composition of the present invention can more effectively prevent and / or treat ischemia / reperfusion injury, especially treat nerve cell damage, and more particularly has an excellent protective effect on ischemic stroke and can significantly reduce cerebral ischemia / reperfusion injury. BRIEF DESCRIPTION OF THE DRAWINGS

[0136] FIG1A shows TTC staining of brain tissue and infarct volume determination of mice in different groups in Example 1.1.

[0137] FIG1B is a graph showing the neurological function scores of mice in different groups in Example 1.1.

[0138] FIG2A is a diagram showing the measurement of brain infarct volume in mice of different groups in Example 1.2.

[0139] FIG2B is a graph showing the neurological function scores of mice in different groups in Example 1.2.

[0140] FIG3A is a diagram showing the brain tissue and infarct volume measurements of mice in different groups in Example 1.3.

[0141] FIG3B is a graph showing the neurological function scores of mice in different groups in Example 1.3.

[0142] FIG4A is a diagram showing the myocardial infarction area of ​​mice in different groups in Example 2. ...

[0143] FIG4B is a graph showing the CK activities of different groups in Example 2. ...

[0144] FIG5A is a diagram showing the escape latency of different groups in Example 3. FIG5A is a diagram showing the escape latency of different groups in Example 3.

[0145] FIG5B is a diagram showing the target quadrant residence time ratios of different groups in Example 3. FIG.

[0146] FIG6A is a diagram showing the incubation period of different groups in Example 4. ...

[0147] FIG6B is a diagram showing the gripping forces of different groups in Example 4. ... DETAILED DESCRIPTION

[0148] The present invention will be described in detail below with reference to the embodiments. It should be noted that the embodiments and features of the embodiments of the present invention can be combined with each other without conflict.

[0149] The present invention will be described in detail below with reference to the embodiments.

[0150] Application of seletinib and edaravone in the preparation of cell protective drugs.

[0151] Materials and methods:

[0152] To demonstrate the role of idarucizumab and edaravone in cell protection, the applicant used a variety of animal models, such as an ischemic stroke mouse model, a myocardial ischemia / reperfusion injury mouse model, and Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease animal models, and administered seletinib and edaravone at different time points. Cell damage and the protective effects of the drugs were detected according to the corresponding detection methods of each disease model.

[0153] Experimental drugs: Cerutinib (compound) and edaravone (compound) were purchased from a reagent company and dissolved and prepared according to the company's reagent instructions.

[0154] Example 1

[0155] To explore the anti-ischemic stroke effect of the combination of seletinib and edaravone

[0156] Animal experiment: An ischemic stroke mouse model was used to investigate the anti-ischemic stroke effect of the combination of selegiline and edaravone.

[0157] Experimental animals: 7-week-old male C57BL / 6J mice. All experimental animals were housed in an SPF-grade breeding room with a temperature of 22°C ± 2°C, a relative humidity of 45% ± 15%, free access to water, and a 12-h light / dark cycle for one week, and then dosed according to the requirements of each experimental group.

[0158] Establishment of an Ischemic Stroke Mouse Model: A mouse cerebral ischemia / reperfusion model was established using middle cerebral artery occlusion (MCAO). The procedure was as follows: 8-week-old male C57BL / 6J mice were anesthetized with an intraperitoneal injection of 0.3% (w / v, same below) sodium pentobarbital (20 mL / kg). The left common carotid artery (CCA) was isolated, and the left external carotid artery (ECA) and internal carotid artery (ICA) were dissected superiorly. The ECA and ICA were temporarily clamped with ophthalmic forceps, and the proximal end of the CCA was ligated. A knotted silk suture was placed distally to the CCA, and a small slit was made at the lower end of the suture. The suture was inserted into the internal carotid artery. The arterial clamps on the ECA and ICA were released, and the suture was advanced into the brain along the ICA. The suture was tightened upon encountering resistance to secure the suture. After 1 hour of ischemia, the suture was removed, the skin was sutured, and the animals were processed after 24 hours of reperfusion.

[0159] The Longa 5-point scale was used to evaluate the neurological deficits in the mouse cerebral ischemia / reperfusion injury model (neurological function score). A score of 0 indicated no neurological deficits; a score of 1 indicated inability to fully extend the right forelimb; a score of 2 indicated rightward rotation; a score of 3 indicated a rightward tilt; and a score of 4 indicated inability to walk spontaneously and loss of consciousness. Scores of 1 to 4 were considered effective models.

[0160] TTC staining of mouse brain and determination of infarct volume. After the mouse is anesthetized, the brain is quickly removed, the olfactory bulb and hindbrain are removed, and 3 to 5 coronal brain slices are cut starting from the frontal pole. They are immediately placed in 1% (w / v, the same below) TTC solution and incubated at 37°C in the dark for 30 minutes. Then, the slices are fixed by immersion in 10% (w / v) paraformaldehyde solution. The infarcted area appears white, and the non-infarcted area appears red. Each group of brain slices is neatly arranged and scanned. ImageJ is then used to measure the infarct area of ​​each brain slice, and the corresponding volume is calculated according to the formula: infarct volume (%) = (brain tissue volume on the opposite side of the infarct - brain tissue volume of the non-infarcted area on the infarcted side) / brain tissue volume on the opposite side of the infarct × 100%.

[0161] According to the different administration methods and dosages, it is divided into three parts, detecting the neurological function score of mice and measuring the cerebral infarction volume to evaluate the drug effect.

[0162] Data Statistics: Statistical analysis was performed using GraphPad Prism 9.0 software. All data are presented as mean ± standard error (±SEM). Differences in multiple groups were analyzed using one-way ANOVA or two-way ANOVA, followed by Tukey's test to compare whether there were significant differences between groups. Neurological function scores were analyzed using Kruskal-Wallis and Wilcoxon tests. A P < 0.05 was considered statistically significant (the same below).

[0163] Example 1.1

[0164] Experimental grouping and drug administration method: The experimental animals were randomly divided into the following 7 groups. The relevant drugs were dissolved in a solvent (10% DMSO + 30% PEG400 + 60% saline), namely:

[0165] Sham group: The internal and external carotid arteries were separated without inserting suture into the artery.

[0166] Cerebral ischemia / reperfusion group (I / R group): cerebral ischemia for 1 hour (hour, h), reperfusion for 24 hours.

[0167] Cerdulatinib + cerebral ischemia / reperfusion group (Cerdulatinib + I / R): During the above reperfusion period, 1 hour after reperfusion, Cerdulatinib (15 mg / kg) was given by intramuscular injection.

[0168] Edaravon+I / R group: During the reperfusion period, edaravon (6 mg / kg) was injected intramuscularly 1 hour after reperfusion.

[0169] Cerdulatinib + edaravon + cerebral ischemia / reperfusion group (Cerdulatinib + Edaravon + I / R): During the above reperfusion period, 1 hour after reperfusion, Cerdulatinib (15 mg / kg) and Edaravon (3 mg / kg) were given intramuscularly.

[0170] Cerdulatinib + edaravon + cerebral ischemia / reperfusion group (Cerdulatinib + Edaravon + I / R): During the above reperfusion period, cerdulatinib (7.5 mg / kg) and edaravon (6 mg / kg) were given intramuscularly 1 hour after reperfusion.

[0171] Vehicle+I / R group: During the above reperfusion period, the vehicle was injected intramuscularly 1 hour after reperfusion.

[0172] The composition of the solvent is 10% DMSO, 30% PEG400, and 60% normal saline (v / v, the same below). After Cerutinib and / or Edaravone are dissolved in the solvent, they are used for injection (the same below).

[0173] The neurological function scores of mice were detected and the cerebral infarction volume was measured to evaluate the drug effects.

[0174] result:

[0175] Effects of cilutinib and edaravone combination on cerebral infarction volume and neurological function in mice

[0176] As shown in Figure 1, the I / R group had obvious white infarcts. However, ceruletinib and edaravone alone and in combination reduced infarct volume (Figure 1A) and improved neurological function (Figure 1B), with the combined effect significantly superior to that of either drug alone. (Data are expressed as mean ± standard error, n = 6, **P < 0.01 vs. sham-operated group; # P < 0.05 vs I / R group; + P < 0.05 vs I / R + single drug group).

[0177] Conclusion: The combined use of seletinib and edaravone is more effective than single drug, showing synergistic effect, significantly reducing neuronal cell death and alleviating cerebral ischemia / reperfusion injury, and has a neuronal cell protective effect. It can be used to prepare drugs for alleviating cerebral ischemia / reperfusion injury and for the treatment of ischemic stroke.

[0178] Example 1.2

[0179] Experimental grouping and drug administration method: The experimental animals were randomly divided into the following 6 groups. The relevant drugs were dissolved in a solvent (10% DMSO + 30% PEG400 + 60% saline), namely:

[0180] Sham operation group: The internal and external carotid arteries were separated without inserting suture into the artery.

[0181] Cerebral ischemia / reperfusion group (I / R group): cerebral ischemia for 1 h and reperfusion for 24 h.

[0182] Cerdulatinib + cerebral ischemia / reperfusion group (Cerdulatinib + I / R): During the above reperfusion period, cerdulatinib (7.5 mg / kg) was given intramuscularly 1 hour after reperfusion.

[0183] Edaravon+I / R group: During the reperfusion period, edaravon (3 mg / kg) was injected intramuscularly 1 hour after reperfusion.

[0184] Cerdulatinib + edaravon + cerebral ischemia / reperfusion group (Cerdulatinib + Edaravon + I / R): During the above reperfusion period, cerdulatinib (7.5 mg / kg) and edaravon (3 mg / kg) were given intramuscularly 1 hour after reperfusion.

[0185] Vehicle+I / R group: During the above reperfusion period, the vehicle was injected intramuscularly 1 hour after reperfusion.

[0186] The composition of the solvent is 10% DMSO, 30% PEG400 and 60% normal saline; after Cerutinib and / or Edaravone are dissolved in the solvent, they are used for injection (the same below).

[0187] The neurological function scores of mice were detected and the cerebral infarction volume was measured to evaluate the drug effects.

[0188] result:

[0189] Effects of cilutinib and edaravone combination on cerebral infarction volume and neurological function in mice

[0190] The I / R group showed distinct white infarcts, as shown in Figure 2. Both ceruletinib and edaravone alone and in combination reduced infarct volume (Figure 2A) and improved neurological function (Figure 2B), with the combined effect significantly superior to that of either drug alone. (Data are presented as mean ± standard error, n = 6, **P < 0.01 vs. sham-operated group; # P < 0.05 vs I / R group; + P < 0.05 vs I / R + single drug group).

[0191] Conclusion: The combined use of seletinib and edaravone is more effective than single drug, showing synergistic effect, significantly reducing neuronal cell death and alleviating cerebral ischemia / reperfusion injury, and has a neuronal cell protective effect. It can be used to prepare drugs for alleviating cerebral ischemia / reperfusion injury and for the treatment of ischemic stroke.

[0192] Example 1.3

[0193] Experimental grouping and drug administration method: The experimental animals were randomly divided into the following 6 groups. The relevant drugs were dissolved in a solvent (10% DMSO + 30% PEG400 + 60% saline), namely:

[0194] Sham operation group: The internal and external carotid arteries were separated without inserting suture into the artery.

[0195] Cerebral ischemia / reperfusion group (I / R group): cerebral ischemia for 1 h and reperfusion for 24 h.

[0196] Cerdulatinib + cerebral ischemia / reperfusion group (Cerdulatinib + I / R): During the above reperfusion period, Cerdulatinib (each dose: 1.5 mg / kg) was intraperitoneally injected 1 hour and 5 hours after reperfusion.

[0197] Edaravon+I / R group: During the reperfusion period, edaravon (4 mg / kg each time) was intraperitoneally injected 1 h and 5 h after reperfusion.

[0198] Cerdutinib + Edaravon + I / R Group: During the reperfusion period, 1 hour and 5 hours after reperfusion, 1.5 mg / kg of cerdutinib and 4 mg / kg of edaravon were intraperitoneally injected. Both cerdutinib and edaravon were administered at each dose.

[0199] Vehicle+I / R group: During the reperfusion period, the vehicle was intraperitoneally injected 1 h and 5 h after reperfusion.

[0200] The composition of the solvent is 10% DMSO, 30% PEG400, and 60% normal saline; after dissolving cilutinib and / or edaravone in the solvent, the mixture is used for injection.

[0201] The neurological function scores of mice were detected and the cerebral infarction volume was measured to evaluate the drug effects.

[0202] result:

[0203] Effects of cilutinib and edaravone combination on cerebral infarction volume and neurological function in mice

[0204] The I / R group had distinct white infarcts, as shown in Figure 3. Certutinib and edaravone alone, as well as the combination (i.e., certutinib + edaravone + cerebral ischemia / reperfusion group), reduced infarct volume in mice (Figure 3A) and improved neurological function (Figure 3B), with the combination significantly outperforming the effect of either drug alone. (Data are expressed as mean ± standard error, n = 6, **P < 0.01 vs. sham-operated group; # P<0.05vs I / R group, ## P < 0.01 vs I / R group; ++ P < 0.01 vs I / R + drug alone group).

[0205] Conclusion: The combined use of seletinib and edaravone is more effective than single drug, showing synergistic effect, significantly reducing neuronal cell death and alleviating cerebral ischemia / reperfusion injury, and has a neuronal cell protective effect. It can be used to prepare drugs for alleviating cerebral ischemia / reperfusion injury and for the treatment of ischemic stroke.

[0206] Example 2

[0207] To investigate the effect of seletinib and edaravone combination on myocardial ischemia / reperfusion injury

[0208] Animal experiment: A myocardial ischemia / reperfusion injury mouse model was used to explore the anti-myocardial ischemia / reperfusion injury effect of the combination of seletinib and edaravone.

[0209] Experimental animals: 7-week-old male C57BL / 6J mice. All experimental animals were housed in an SPF-grade breeding room with a temperature of 22°C ± 2°C, a relative humidity of 45% ± 15%, free access to water, and a 12-h light / dark cycle for one week, and then dosed according to the requirements of each experimental group.

[0210] Methods for establishing a mouse myocardial ischemia / reperfusion model: Eight-week-old male C57BL / 6J mice were anesthetized with an intraperitoneal injection of 0.3% sodium pentobarbital (20 mL / kg). The trachea was intubated orally and the tube secured with pressure-sensitive adhesive. Ventilator parameters were set to a tidal volume of 3.2 mL / kg and a rate of 110 breaths per minute. The left anterior descending artery (LAD) was ligated with an 8-0 suture. Myocardial infarction was confirmed by blanching of the cardiac apex, and the ligature remained in place for 1 hour. After 1 hour of ischemia, the LAD suture was removed to restore cardiac perfusion. The thorax was sutured layer by layer, and the ventilator was removed, allowing the mouse to resume spontaneous breathing. After 24 hours of cardiac perfusion, the mouse was anesthetized with 0.3% sodium pentobarbital (20 mL / kg), the thoracotomy was opened, and the LAD was religated in situ. The abdominal cavity was opened, and 0.2 mL of 2% (w / v) Evans Blue solution was injected via the inferior vena cava. When the mouse's lower lip turned blue, blood was collected from the cardiac apex and the heart removed. The heart was frozen at -20°C for 1 hour, then cut into 1-mm-thick slices and incubated with 1% TTC stain (in PBS) at 37°C for 15 minutes. After staining, the stain was removed, the heart washed once with PBS, and fixed with 4% (w / v) paraformaldehyde for 24 hours. The heart was then sliced, the staining observed, and photographed. The area of ​​the ischemic and infarcted regions was determined using ImageJ software.

[0211] The blue area of ​​the heart slice is normal tissue; the area outside the blue area of ​​the heart slice is the ischemic area (also known as the risk area, Area of ​​risk, AOR); the white area of ​​the heart is the infarction area (Area of ​​infarction, AOI). The percentage of infarct area of ​​each slice (Infarct Area, the ratio of the infarct area AOI to the ischemic area AOR) was calculated, and the ratio of the infarct area between the drug group and the model group was compared.

[0212] Serum creatine kinase (CK) activity detection

[0213] After the ischemia / reperfusion surgery, approximately 150 μL of whole blood was collected from the mouse orbital cavity and centrifuged at 3000 rpm at 4°C for 10 minutes. The supernatant was collected and stored at -40°C. Serum CK activity was determined according to the instructions of the commercially available kit as follows: 10 mL of R2 was dissolved in one bottle of R1 to prepare a working solution. 4 μL of serum was added to 200 μL of the CK kit working solution. The solution was incubated at 37°C for 2 minutes. The wavelength of the microplate reader was set to 340 nm. The absorbance values ​​(A0, A1, A2, and A3) were read at 0, 1, 2, and 3 minutes, respectively. The average absorbance change (ΔA) per minute was calculated, and the serum CK concentration (U / L) was calculated.

[0214] Experimental groups: The experimental animals were randomly divided into groups of 6 each. The drug concentration and administration time were set according to the results of the preliminary experiment. The drug groups were treated with different concentrations of cerutinib, edaravone and the combination of the two drugs, namely:

[0215] Sham group: The mice underwent heart surgery but without vascular ligation;

[0216] Model group (myocardial ischemia / reperfusion group): ligation of the left anterior descending coronary artery for 1 hour of ischemia, suture removal, and reperfusion for 24 hours;

[0217] Cerdulatinib + myocardial ischemia / reperfusion group (Cerdulatinib+I / R): Mice were given cerdulatinib (each dose: 1.5 mg / kg) by intraperitoneal injection 30 minutes after ischemia and 5 hours after reperfusion.

[0218] Edaravon + myocardial ischemia / reperfusion group (Edaravon + I / R): Mice were given edaravon (each dose: 4 mg / kg) by intraperitoneal injection 30 minutes after ischemia and 5 hours after reperfusion.

[0219] Cerdutinib + Edaravon + Myocardial Ischemia / Reperfusion Group (Cerdulatinib + Edaravon + I / R): Mice were intraperitoneally injected with 1.5 mg / kg of cerdutinib and 4 mg / kg of edaravon 30 minutes after ischemia and 5 hours after reperfusion. Both cerdutinib and edaravon were administered at each dose.

[0220] Vehicle+I / R group: Mice were treated with vehicle 30 minutes after ischemia.

[0221] The composition of the solvent is 10% DMSO, 30% PEG400, and 60% physiological saline.

[0222] Blood and myocardial tissue were collected and relevant indicators were measured: myocardial infarction area of ​​mice was measured and serum creatine kinase activity (CK activity) was detected.

[0223] result:

[0224] As shown in Figure 4, seletinib and edaravone, alone or in combination, demonstrated protective effects against myocardial ischemia / reperfusion injury in mice, reducing myocardial infarct size (Figure 4A) and serum creatine kinase (creatine kinase) (Figure 4B). The combined effect was significantly superior to that of either drug alone. (Data are presented as mean ± standard error, n = 6, **P < 0.01 vs. sham-operated group; # P < 0.05 vs I / R group; + P<0.05, ++ P < 0.01 vs I / R + drug alone group).

[0225] Conclusion: The combined use of seletinib and edaravone is more effective than that of single drugs, showing a synergistic effect. It can significantly reduce cardiomyocyte death and alleviate myocardial ischemia / reperfusion injury, and has a cardiomyocyte protective effect. It can be used to prepare drugs to alleviate myocardial ischemia / reperfusion injury and to treat myocardial infarction.

[0226] Example 3

[0227] To explore the anti-Alzheimer's disease effect of the combination of seletinib and edaravone

[0228] Animal experiment: The APP / PS1 transgenic mouse Alzheimer's disease animal model was used to explore the anti-Alzheimer's disease effect of the combination of selegiline and edaravone.

[0229] Experimental Animals: APP / PS1 transgenic mice (an Alzheimer's disease animal model, derived from C57BL / 6J mice), male, 5 months old, weighing 24–30 g, and C57BL / 6J mice of the same age (male, 5 months old, weighing 26–30 g) were purchased from Beijing Huafukang Biotechnology Co., Ltd. All experimental animals were housed in an SPF-grade enclosure at 22°C ± 2°C, 45% ± 15% relative humidity, with free access to water, and a 12-h light / dark cycle.

[0230] Experimental groups: 5-month-old APP / PS1 transgenic mice were randomly divided into groups of 6 in each group. The drug concentration and administration time were set according to the preliminary experimental results. The drug groups were treated with different concentrations of seletinib, edaravone and the combination of the two drugs, respectively. The drugs were administered by intraperitoneal injection once a day starting from the age of 5 months for 2 consecutive months; the normal control group and the APP / PS1 mouse control group were given the same volume of solvent.

[0231] Normal control group: APP / PS1 transgenic background mice - C57BL / 6J mice + intraperitoneal injection of solvent.

[0232] APP / PS1(AD)+vehicle group: APP / PS1 transgenic mice+intraperitoneal injection of vehicle.

[0233] APP / PS1(AD)+Cerdulatinib group (+Cerdulatinib): APP / PS1 transgenic mice were treated with intraperitoneal injection of Cerdulatinib (0.75 mg / kg).

[0234] APP / PS1(AD)+Edaravone group (+Edaravone): APP / PS1 transgenic mice were treated with intraperitoneal injection of Edaravone (4 mg / kg).

[0235] APP / PS1(AD)+Cerdulatinib+Edaravone group: APP / PS1 transgenic mice were treated with Cerdulatinib (0.75 mg / kg) and Edaravone (4 mg / kg).

[0236] The composition of the solvent is 10% DMSO, 30% PEG400, and 60% normal saline; after Cerutinib and / or Edaravone are dissolved in the solvent, the mixture is used for injection.

[0237] The learning and memory abilities and cognitive functions of mice were tested using novel object recognition tests and Morris water maze tests.

[0238] Data Statistics: Statistical analysis was performed using GraphPad Prism 9.0 software. All data are presented as mean ± standard error (±SEM). Differences among multiple groups were analyzed using one-way ANOVA or two-way ANOVA, followed by Tukey's test to determine if there were significant differences between groups.

[0239] Testing methods and results:

[0240] (1) Effects of the combination of selegiline and edaravone on the non-spatial learning and memory ability and cognitive function of Alzheimer's disease model mice - novel object recognition experiment.

[0241] The novel object recognition experiment was conducted according to the protocol and consisted of three phases: an acclimation period, a training period, and a testing period. The mice were petted for 2–3 minutes daily for one week before the novel object test to reduce stress. The experiment was conducted in a 40×40 cm open-field chamber. The mice were placed in the experimental room for 20–30 minutes to acclimate to the environment. After acclimation, the novel object training experiment began. Two objects (designated A and B) identical in color, shape, and material were placed in the open-field chamber and trained for 10 minutes. Twenty-four hours after the training period, a novel object test was conducted to assess the mice's short-term nonspatial learning and memory. One of the two objects was replaced with another (designated C) of different shape and color, and the time spent exploring the two different objects within 10 minutes was recorded. The cognitive index was calculated as the novel object exploration time / (new object exploration time + old object exploration time) × 100%.

[0242] Experimental results: Compared with the normal control group mice, the cognitive index of the APP / PS1+solvent group mice was significantly reduced, and the non-spatial learning and memory ability and cognitive function of the APP / PS1 transgenic mice were weakened. After being given selecitinib and edaravone alone or in combination, the cognitive index of the APP / PS1 transgenic mice increased significantly. The effect of the combined use of the two drugs was significantly better than that of single drugs.

[0243] Conclusion: The combination of seletinib and edaravone has a significant effect on improving the non-spatial learning and memory ability and cognitive function of Alzheimer's disease mice.

[0244] (2) Effects of the combination of selegiline and edaravone on spatial learning and memory ability and cognitive function in Alzheimer's disease model mice—Morris water maze test.

[0245] The Morris water maze was conducted according to the experimental requirements. The maze is divided into four quadrants. In one quadrant, a platform (the target quadrant) with a diameter of 12 cm and a height of 35 cm was placed. Water was added to cover the platform by 1–2 cm, and the water was dyed black with carbon ink. After five days of navigation, the platform was removed and a spatial exploration experiment was conducted. The time it took for the mice to reach the original platform position (latency) and the time they spent in the target quadrant (the time they spent in the quadrant where the hidden platform was originally located) were recorded. The percentage of time spent in the target quadrant relative to the total exploration time was analyzed. The movement trajectories and behaviors of the animals were recorded and analyzed using the smart 3.0 small animal analysis software system.

[0246] The experimental results are shown in Figure 5. As can be seen from the figure, compared with the normal control group mice, the time it took for the APP / PS1+solvent group mice to find the original platform position (escape latency) was significantly increased, and the time they stayed in the target quadrant and the time ratio were significantly reduced. The time it took for the APP / PS1 mice to find the original platform (escape latency) was significantly reduced after administration of seletinib, edaravone, or a combination of the two drugs (Figure 5A), and the time they stayed in the target quadrant and the time ratio were significantly increased (Figure 5B). Overall, the effect of the combined use of seletinib and edaravone was significantly better than that of each single drug group. (Data are expressed as mean ± standard error, n = 6, **P < 0.01 vs normal control group, ## P<0.01vs APP / PS1+solvent group, + P < 0.05 vs APP / PS1+ monotherapy). The results showed that the combination of seletinib and edaravone significantly improved learning, memory, and cognitive function in Alzheimer's mice. Conclusion: The combination of seletinib and edaravone significantly improved learning, memory, and cognitive function in Alzheimer's mice, demonstrating a synergistic effect.

[0247] Example 4

[0248] To investigate the effect of seletinib and edaravone combination on amyotrophic lateral sclerosis (ALS)

[0249] 4.1 Animal Experiment: B6SJL.SOD1, an ALS animal model, was used G93A (abbreviated as SOD1 G93A ) mouse model to explore the anti-amyotrophic lateral sclerosis effect of the combination of selegiline and edaravone.

[0250] Experimental animals: ALS model is B6SJL.SOD1 G93A Mouse model, known SOD1 G93A Mice with a mutation in the SOD1 gene remarkably reproduce the pathology of human ALS. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects both upper and lower motor neurons.

[0251] Male SOD1 G93A The transgenic ALS mouse model was purchased from Saiye (Suzhou) Biotechnology Co., Ltd. All experimental animals were housed in an SPF-grade breeding room with a temperature of 22°C ± 2°C, a relative humidity of 45% ± 15%, free access to water, and a 12-h light / dark cycle.

[0252] Experimental groups and drug administration method: SOD1G93A Mice were randomly divided into groups of 6 at 60 days of age according to their motor function. The drug concentration and administration time were set according to the results of the preliminary experiment. The drug groups were treated with different concentrations of seletinib, edaravone or the combination of the two drugs. The drugs were intraperitoneally injected once a day from the 71st day of age (i.e., the 11th week) until death. The normal control group and SOD1 G93A The mice in the control group were given the same volume of vehicle.

[0253] Normal control group: C57BL / 6J mice of corresponding age + intraperitoneal injection of solvent

[0254] ALS+vehicle group (vehicle group): SOD1 G93A Mice + vehicle intraperitoneal injection

[0255] ALS+Cerdulatinib group: SOD1 G93A Mice treated with intraperitoneal injection of seletinib (0.75 mg / kg)

[0256] ALS+Edaravone group (+Edaravon): SOD1 G93A Mice treated with edaravone (6 mg / kg) intraperitoneal injection

[0257] ALS+Cerdulatinib+Edaravone group (+Cerdulatinib+Edaravon): SOD1 G93A Mice were treated with celutinib (0.75 mg / kg) and edaravone (6 mg / kg).

[0258] The composition of the solvent is 10% DMSO, 30% PEG400, and 60% normal saline; after Cerutinib and / or Edaravone are dissolved in the solvent, the mixture is used for injection.

[0259] The motor function and survival rate of mice were detected using indicators such as the rotarod test, limb grasping strength test, and survival period measurement.

[0260] Data Statistics: Statistical analysis was performed using GraphPad Prism 9.0 software. All data are presented as mean ± standard error (±SEM). Differences among multiple groups were analyzed using one-way ANOVA or two-way ANOVA, followed by Tukey's test to determine if there were significant differences between groups.

[0261] (1) Rotarod test

[0262] Before the test (3 days), let the animals adapt to the test environment for 30 minutes, and then place the mice on the YLS-4C rotarod fatigue instrument, starting from 5r (revolutions) / min, and increasing to 30r / min within 180s. Specific steps: First, conduct 5 minutes of adaptation training on the mice, and set the rotation speed to 30r / min, twice a day for three days; when the test starts, perform 3 consecutive tests (180 seconds / time, each interval is 40 minutes); the experiment lasts for 180 seconds, and the time when all animals fall off the platform is recorded as the latency period, or until the end of the experiment. Record the time the mouse spends on the rotarod each time, and take the longest time on the rotarod in the 3 tests as the mouse's motor function. If the time is greater than 180s, terminate the measurement and calculate it as 180s. SOD1 G93A The motor function of mice was measured using the above-mentioned rotarod fatigue instrument starting from day 60 of age, and then observed and measured once a week until the mice died.

[0263] (2) Grip strength test

[0264] The basic method is as follows: a mouse grip strength test is used to directly assess the strength of the mouse's limb muscles. A mouse is gently placed on the central platform of the grip strength tester. The mouse's tail is gently pulled to encourage it to grasp the grip plate. Once the mouse firmly grasps the grip plate, force is applied and the grip is pulled back, causing the mouse to release its claws. At this point, the mouse's maximum grip strength is recorded. Once the mouse completely releases the grip plate, the instrument automatically records the maximum grip strength. This value is recorded. Each mouse's forelimb and hindlimb are measured three times, and the average of the results is used as the forelimb or hindlimb grip strength value.

[0265] (3) Survival measurement: For mice subjected to behavioral evaluation, the survival rate after administration of cerutinib and edaravone was evaluated using Kaplan-Meier curves.

[0266] 4.2 Results:

[0267] 4.2.1. Rotarod test, behavioral test of ALS model mice, as shown in Figure 6A, SOD1 G93A Compared with the normal control group, the mice in the group had significantly weakened muscle strength and significantly shortened the time it took for them to fall from the rotating rod. Treatment with seletinib, edaravone, or both drugs delayed the onset of SOD1 G93A The muscle strength of mice decreased; among them, the combined treatment of seletinib and edaravone decreased SOD1 G93A The mice's time spent on the rotarod (latency) was significantly longer than that of the ALS vehicle control group, celutinib, and edaravone monotherapy groups (P < 0.05 or 0.01), indicating improved motor function in the mice. (Data are expressed as mean ± standard error, n = 6, **P < 0.01 vs. normal control group; ##P < 0.01 vs ALS + vehicle group; + P<0.05 vs ALS+drug alone group)

[0268] 4.2.2. Grip strength test, as shown in Figure 6B, SOD1 G93A Compared with the normal control group, the hind limb grip strength of the mice group was significantly weakened. Compared with ALS model mice, single-drug treatment with seletinib and edaravone and the combination of the two drugs improved SOD1 G93A The hind limb grip strength of mice, and the combined treatment of seletinib and edaravone decreased SOD1 at 91 days of age. G93A The hind limb grip strength of mice was significantly higher than that of the ALS vehicle control group, celecoxib, and edaravone monotherapy groups, with statistically significant differences (P < 0.05 or 0.01). (Data are expressed as mean ± standard error, n = 6, **P < 0.01 vs. normal control group; ## P < 0.01 vs ALS + vehicle group; + P < 0.05 vs ALS + single drug group)

[0269] Compared with the normal control group, the survival time of ALS model mice was significantly shortened. The survival time of mice treated with selecitinib, edaravone alone or in combination with the two drugs was significantly longer than that of the ALS model group, and the survival time of mice in the combination drug group was significantly better than that of mice treated with single drugs.

[0270] Conclusion: Treatment with cilutinib, edaravone or both drugs in combination prolongs the survival time and improves the motor function of ALS mice. The effect of cilutinib and edaravone combination is better than that of single drug, showing a synergistic effect. The combination of cilutinib and edaravone can be used to treat amyotrophic lateral sclerosis.

[0271] Example 5

[0272] To explore the anti-Parkinson's effect of the combination of seletinib and edaravone

[0273] Animal experiment: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to prepare a PD animal model to explore the anti-Parkinson's effect of the combination of seletinib and edaravone.

[0274] Establishment of the MPTP Animal Model: A Parkinson's disease (PD) animal model was established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male C57BL / 6 mice, 10-12 weeks old and weighing 25-30 g, underwent three days of acclimation training beforehand, and mice with motor incoordination were removed. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered intraperitoneally at a dose of 30-40 mg / kg body weight for 5-7 consecutive days. Temporary symptoms of trunk tremor, piloerection, tail hyperextension, decreased movement, and impairment in the pole climbing test occurred after the fifth to seventh injection, indicating successful establishment of a Parkinson's disease (PD) mouse model.

[0275] The scoring criteria for tremor paralysis were as follows: 0 points, similar to normal mice, without any symptoms; 1 point, piloerection, arched back, intermittent fine tremors, but free movement; 2 points, frequent swallowing, frequent tremors, hind limbs spread out, tail shaking, and gradually limited movement; 3 points, drooling, persistent tremors, limb stiffness, and limited movement; 4 points, death due to general paralysis.

[0276] Experimental groups: The experimental animals were randomly divided into groups of 6-10 animals each. The drug concentration and administration time were set according to the results of the preliminary experiment. The drug groups were treated with different concentrations of cerutinib, edaravone and the combination of the two drugs, namely:

[0277] Normal control group (Control group): C57BL / 6 mice

[0278] MPTP model group: MPTP was injected intraperitoneally for 5-7 days.

[0279] Cerdulatinib+MPTP model group: Cerdulatinib was given after model establishment.

[0280] Edaravone + MPTP model group (Edaravon + MPTP): Edaravone was given after modeling.

[0281] Cerdulatinib + Edaravon + MPTP model group: The model was established and treated with Cerdulatinib and Edaravon.

[0282] Detection method: Pole climbing test and rigidity scoring method were used to detect the limb muscle strength and movement balance ability of mice.

[0283] (1) Pole test: The basic method is as follows: a rough wooden ball with a diameter of 9 mm is placed on the top of a wooden stick with a rough surface, a circular cross-section, and a length of 75 cm. The lower end of the stick is placed in a mouse cage. The mouse is placed on the ball and trained one day in advance to crawl to the bottom of the stick with its head facing downwards. On the day of the experiment, a stopwatch is used to record the time it takes the mouse to climb to the top of the stick as A. When it climbs to the bottom of the stick, the time at this moment is recorded as B. The time it takes the mouse to climb the entire stick is C, where C = AB. Each mouse is tested 3 to 5 times, and the average time of 3 to 5 pole climbing times is used as a statistical indicator.

[0284] (2) Rigidity scoring: The basic method is as follows: the mouse is kept in a fixed position during the test, and the mouse's forelimbs are placed on a wooden stick 4 cm high and 1 cm wide from the horizontal plane. A stopwatch is used to record the length of time the animal maintains this posture. The timer is stopped when the two forepaws are removed from the horizontal bar or the animal moves its head in an exploratory manner. The cutoff time is 300 s. Each mouse is tested 3 times, with an interval of 1 minute each time. If the mouse maintains this posture for more than 30 s, it is judged to be rigid and scored according to the time, specifically 0 points for 0 s, 1 point for 1 s to 150 s, and 2 points for 151 s to 300 s.

[0285] Experimental results:

[0286] Compared with the control group, the time required for mice in the MPTP model group to climb the pole was significantly increased, and the rigidity score was significantly increased. Treatment with seletinib and edaravone alone or in combination with the two drugs significantly shortened the time required for mice to climb the pole and reduced the rigidity score. The combined effect of seletinib and edaravone was better than that of single drugs.

[0287] Conclusion: The combined use of seletinib and edaravone is more effective than single drug, showing synergistic effects. It can significantly improve the motor function and spasticity symptoms of Parkinson's mice, reduce nerve cell death, and has a neuroprotective effect. It can be used to prepare anti-Parkinson's drugs.

[0288] Example 6

[0289] To explore the effect of seletinib and edaravone combination on multiple sclerosis

[0290] Animal experiments: The experimental autoimmune encephalomyelitis (EAE) mouse model was used to explore the anti-multiple sclerosis effect of the combination of seletinib and edaravone.

[0291] Experimental animals: 6-8 week old female C57BL / 6J mice weighing 18-25 g. All experimental animals were housed in an SPF-grade breeding room at a temperature of 22°C ± 2°C, a relative humidity of 45% ± 15%, with free access to water, and a 12-h light / dark cycle for one week. Then, the animals were modeled and dosed according to the requirements of each experimental group.

[0292] Establishment of experimental autoimmune encephalomyelitis (EAE) mouse model:

[0293] The basic experimental steps are as follows: first, prepare MOG 35～55 The polypeptide was diluted with PBS to 3 mg / ml (MOG); Mycobacterium tuberculosis was added to Freund's incomplete adjuvant (CFA) to prepare Freund's complete adjuvant at a concentration of 5 mg / ml; MOG and CFA were mixed in a 1:1 ratio to prepare an antigen-adjuvant emulsion. After anesthetizing the mice, the antigen emulsion was injected subcutaneously at the back of the neck at a rate of 0.2 ml / mouse, and injected at four points (4 points were selected at random near the spine), with 50 μl at each point. Subsequently, 0.1 ml (3 μg / ml, i.e. 300 ng) of pertussis toxin was injected intraperitoneally. 48 hours later, 0.1 ml of pertussis toxin was injected intraperitoneally again. After the mice were immunized with MOG, they were housed normally and the general condition of the animals was observed. The first day of mouse immunization was recorded as Day 0, and then two experimenters scored the neurological dysfunction of each group of mice at the same time every day until 28 days after MOG immunization. The modified Kono 5-point scoring system was used for scoring, and the specific scoring rules are as follows:

[0294] 0 points (no clinical symptoms); 0.5 points (decreased tail tension, with visible drooping tip); 1 point (tail dragging on the ground); 1.5 points (partial paralysis of one hind limb); 2 points (complete paralysis of one hind limb, able to turn over on its own); 2.5 points (complete paralysis of one hind limb, accompanied by partial paralysis of the other hind limb); 3 points (complete paralysis of both hind limbs, unable to turn over on its own, but able to move on the ground after stimulation); 3.5 points (complete paralysis of both hind limbs, accompanied by paralysis of one forelimb); 4 points (quadriplegia or accompanied by incontinence); 5 points (moribund or dead).

[0295] The mice's food intake, water intake, activity, weight, and hair were recorded. A score of 0.5 to 5 was used to determine if the mice became ill. The time from model establishment to the onset of disease was recorded as the incubation period, and the time from the onset of disease to the peak of disease (no increase in neurological dysfunction score for three consecutive days) was recorded as the progression period. Mice with disease were killed at the peak of disease, while mice without disease and mice in the normal control group were observed and killed 28 days after model establishment.

[0296] Experimental groups: The experimental animals were randomly divided into groups of 6-10 animals each. The drug concentration and administration time were set according to the results of the preliminary experiment. The drug groups were treated with different concentrations of cerutinib, edaravone and the combination of the two drugs, namely:

[0297] Normal control group (Control group): unmodeled C57BL / 6J mice + solvent

[0298] EAE model group (EAE group): model group + solvent.

[0299] Cerdulatinib+EAE model group: Cerdulatinib was given after model establishment.

[0300] Edaravon+EAE model group: Edaravone was given after modeling.

[0301] Cerdulatinib + Edaravon + EAE model group: Cerdulatinib and Edaravon were given after model establishment.

[0302] Detection method: The modified Kono 5-point score was used to detect the neurological function of mice and the changes in body weight.

[0303] result:

[0304] Effects of seletinib, edaravone, and their combination on neurological function and body weight in mice.

[0305] Compared with the control group, the EAE model group showed clinical symptoms such as decreased tail tension and increased neurological function scores 7-11 days after MOG immunization. Treatment with seletinib and edaravone alone or in combination with the two drugs could reduce the neurological function scores of mice and improve the neurological function of mice. The combined effect of seletinib and edaravone was better than that of single drugs.

[0306] Conclusion: The combined use of seletinib and edaravone is more effective than single drug, showing synergistic effect. It can significantly improve the neurological function of EAE mice, reduce neuronal cell death, and has a neuronal cell protective effect. It can be used to prepare anti-multiple sclerosis drugs for the treatment of multiple sclerosis.

[0307] The above examples found that the pharmaceutical composition containing seletinib and edaravone can be used to treat cerebral ischemia / reperfusion injury (including ischemic stroke), myocardial ischemia / reperfusion injury (myocardial infarction), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease and multiple sclerosis. The combined use is better than that of a single drug, showing a synergistic effect, which helps to ensure the efficacy and reduce the drug dosage, thereby improving the safety of clinical use while ensuring the clinical treatment effect.

[0308] However, the present invention is not limited to the above diseases, and the drug is also applicable to the treatment of other diseases with similar pathogenesis.

[0309] The contents illustrated in the above embodiments should be understood as these embodiments are only used to more clearly illustrate the present invention, and are not used to limit the scope of the present invention. After reading the present invention, various equivalent modifications of the present invention by those skilled in the art shall fall within the scope defined by the claims attached to this application.

Claims

1. A pharmaceutical composition, characterized in that Contains cilutinib and edaravone.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of celutinib to edaravone is 1:0.0001-10000, preferably 1:0.001-1000, more preferably 1:0.01-100, even more preferably 1:0.05-25, further preferably 1:0.1-10, even more preferably 1:0.15-1, and even more preferably 1:0.2-0.

8.

3. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of celutinib to edaravone is 3-30:1-10, preferably 5-25:2-8, and more preferably 7.5-15:3-6.

4. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of cell protection drugs.

5. The use according to claim 4, characterized in that The cell protection drug is a drug used to prevent, protect and / or treat cells from damage caused by pathological conditions and / or decline processes; the pathological conditions and / or decline processes include conditions that may cause cell death, preferably, the pathological conditions and / or decline processes include pathological apoptosis and / or pathological necrosis and / or necroptosis and / or pyroptosis and / or ferroptosis and / or dependent cell death and / or disulfide death and / or autophagy (anti-apoptotic drugs and / or anti-necrosis drugs and / or anti-necroptosis drugs and / or anti-pyroptosis drugs and / or anti-ferroptosis drugs and / or anti-dependent cell death drugs and / or disulfide death drugs and / or anti-autophagy drugs) and / or diseases or conditions; preferably, the diseases or conditions include but are not limited to: nervous system diseases, cardiovascular system diseases, bleeding Factors related to thrombotic diseases, diffuse connective tissue diseases, organ-specific inflammatory or systemic inflammatory or autoimmune diseases, autoimmune diseases, bone diseases, joint diseases and cartilage diseases, ischemic diseases or attacks of the limbs, ophthalmological diseases, skin diseases, kidney diseases, blood diseases and vascular diseases, lung diseases, gastrointestinal diseases, liver diseases, metabolic diseases, muscle diseases, pancreatic diseases, severe poisoning by chemicals, infectious agents, toxins or drugs, diseases related to aging, dental diseases, auditory conduction pathway diseases, mitochondrial-related diseases, and / or trauma and / or exposure to biological and / or chemical and / or physical sources and / or and / or medical and / or surgical procedures, such as accidental infarction and hemorrhage, and / or medical and / or surgical procedures, such as cell, tissue or organ transplantation.

6. The use according to claim 4 or 5, characterized in that The cytoprotective drug refers to a drug that has the effect of preventing, inhibiting or treating damage, degeneration or dysfunction of tissues, organs and cells caused by hypoxia / reoxygenation; Alternatively, the cytoprotective drug refers to a drug that has the function of preventing, inhibiting or treating damage, degeneration or dysfunction of tissues, organs and cells caused by necroptosis.

7. The use according to claim 5, characterized in that The nervous system diseases include stroke, transient ischemic attack, ischemia, intracranial hemorrhage, prenatal brain hypoxia, adult or childhood brain hypoxia, neurodegenerative diseases, muscle diseases, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, progressive bulbar palsy, primary lateral sclerosis, pseudobulbar palsy, invertebrate disc syndrome, cervical spondylosis, plexus disorder, thoracic outlet disruption syndrome, porphyria, peripheral neuropathy, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, Lewy body dementia, demyelinating disease, frontotemporal dementia, Guillain-Barré syndrome, multiple sclerosis, Creutzfeldt-Jakob disease, progressive Charcot-Marie-Tooth disease, prion disease, fatal familial insomnia, Gerstmann-Strauss-Scheinker syndrome, bovine spongiform encephalopathy, epilepsy, hereditary ataxia, Friedreich's ataxia, spinocerebellar ataxia, hereditary One or more of hereditary spastic paraplegia, dystonia, multiple system atrophy, lysosomal storage disease, Niemann-Pick disease, Gaucher disease, AIDS dementia syndrome, nerve damage caused by exposure to toxic compounds selected from the group consisting of industrial solvents, heavy metals, drugs and chemotherapeutic agents, and nervous system damage caused by mechanical, physical or chemical trauma; preferably, the stroke includes one or more of ischemic stroke and hemorrhagic stroke; preferably, the neurodegenerative disease includes one or more of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and infantile spinal muscular atrophy, Huntington's disease, and Parkinson's plus syndrome; the muscle disease includes one or more of muscular dystrophy, Duchenne muscular dystrophy, myopathy and myasthenia, myasthenia gravis, progressive muscular dystrophy, spinal muscular atrophy, and hereditary muscular atrophy; Preferably, the cardiovascular system diseases include cardiac ischemia and / or vascular ischemia, ischemic heart disease, angina pectoris, unstable angina pectoris, refractory angina pectoris, myocardial infarction (occlusion), myocardial ischemia / reperfusion injury, hypoxia, hypoxia, chronic or acute heart failure, systolic heart failure and diastolic heart failure, left ventricular dysfunction, left ventricular dysfunction after myocardial infarction, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, myocardial hypertrophy, hypertrophic cardiomyopathy, myocarditis, valvular heart disease, arrhythmia, paroxysmal arrhythmia, One or more of tachycardia, atrial fibrillation, ventricular fibrillation, arteriosclerosis, atherosclerosis, peripheral vascular disease, aneurysm, peripheral vascular obstructive disease, chronic venous insufficiency or varicose veins, hypertension, systemic hypertension, pulmonary hypertension, portal hypertension, and cardiovascular toxicity caused by drug therapy; preferably, the peripheral vascular obstructive disease is brain obstruction, lung obstruction or intestinal obstruction; preferably, the cardiovascular toxicity caused by drug therapy is a cardiovascular toxicity caused by anticancer drug treatment; Preferably, the stroke includes ischemic stroke; Preferably, the diffuse connective tissue disease comprises one or more of rheumatoid arthritis, juvenile idiopathic arthritis, lupus erythematosus, systemic lupus, scleroderma, idiopathic inflammatory myopathy, polymyositis, dermatomyositis, vasculitis, necrotizing vasculitis, polyarteritis nodosa, granulomatosis with polyangiitis, giant cell arteritis, Sjögren's syndrome, systemic sclerosis, allergic cutaneous vasculitis, and Behcet's disease; Preferably, the organ-specific inflammation or systemic inflammation or autoimmune disease includes one or more of chronic inflammatory bowel disease, bronchial asthma, chronic obstructive pulmonary disease, eosinophilic sinusitis, and systemic lupus; Preferably, the ophthalmic disease or condition comprises one or more of diabetic retinopathy, glaucoma, retinal degeneration, retinitis pigmentosa corneal reticular dystrophy, optic neuropathy and optic neuritis, optic nerve drusen, ptosis, chronic progressive external ophthalmoplegia, macular degeneration, retinal holes or retinal tears, retinal ischemia, retinal ischemia / reperfusion injury, retinal detachment, acute retinopathy associated with trauma, inflammatory degeneration, postoperative complications, drug-induced retinopathy or cataract, wet or dry AMD-related photoreceptor degeneration; Preferably, the skin disease comprises one or more of dermatitis, psoriasis, scar formation, aging or altered healing process, eczema, and collagen disease; Preferably, the trauma and / or exposure to factors such as biological sources and / or chemical sources and / or physical sources and / or and / or medical operations and / or surgical operations include severe poisoning caused by infectious agents, toxins, chemicals or drugs. More preferably, the symptoms of severe poisoning include one or more of sepsis, septic shock and its consequences or iatrogenic diseases.

8. The use according to claim 4 or 5, characterized in that The cytoprotective drug is a drug used to prevent and / or protect and / or treat cell death of a transplanted organ and / or organ donor and / or organ recipient, prevent acute transplant rejection of an organ and / or increase long-term survival rate, limit primary organ dysfunction and / or limit delayed recovery of the function of a transplanted organ and / or improve functional recovery of a transplanted organ, or a combination thereof; Preferably, the cytoprotective drug is a drug for preventing and / or protecting and / or treating a pathological condition or degenerative process associated with ischemia / reperfusion symptoms. More preferably, the pathological condition or degenerative process associated with ischemia / reperfusion symptoms includes one or more of actual cold ischemia, warm ischemia, actual reperfusion, and ischemia / reperfusion phenomena. Preferably, the cytoprotective drug is a drug used to prevent and / or protect and / or treat organs, tissues or cells against ischemia / reperfusion injury. Optionally, the ischemia / reperfusion injury is caused by cold ischemia or warm ischemia and / or reperfusion and / or during ischemia / reperfusion; further, the ischemia / reperfusion injury includes one or more of cerebral ischemia / reperfusion injury, myocardial ischemia / reperfusion injury, liver ischemia / reperfusion injury, renal ischemia / reperfusion injury, lung ischemia / reperfusion injury, intestinal ischemia / reperfusion injury and limb ischemia / reperfusion injury.

9. The use according to claim 4 or 5, characterized in that The cytoprotective drug is a drug for preventing and / or protecting and / or treating one or more of: heart failure caused by infarction, neurological sequelae caused by stroke or trauma, tissue damage affecting them after transplantation or surgery of the liver, intestine, heart, lung or kidney or the consequences of surgical procedures; Alternatively, the cell protective drug is a drug used to prevent and / or protect and / or treat one or more of nerve cells, heart cells, liver cells, kidney cells, intestinal cells or lung cells. Preferably, the cell protective drug is a drug used to protect nerve cells, vascular endothelial cells, brain endothelial cells and / or myocardial cells.

10. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of an organ preservation solution.

11. An organ preservation solution, characterized in that: Comprising the pharmaceutical composition according to any one of claims 1 to 3.

12. The organ preservation solution according to claim 11, characterized in that In the organ preservation solution, the concentration of seletinib is 0.01 mg / L to 1000 mg / L, preferably 0.1 mg / L to 100 mg / L, and more preferably 1 mg / L to 10 mg / L; the concentration of edaravone is 0.1 mg / L to 150 mg / L, preferably 1 mg / L to 50 mg / L, and more preferably 1 mg / L to 10 mg / L.

13. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a medicament for preventing, protecting and / or treating ischemia / reperfusion injury and / or neurodegenerative diseases.

14. The use according to claim 13, characterized in that The ischemia / reperfusion injury includes one or more of cerebral ischemia / reperfusion injury, myocardial ischemia / reperfusion injury, liver ischemia / reperfusion injury, renal ischemia / reperfusion injury, lung ischemia / reperfusion injury, intestinal ischemia / reperfusion injury and limb ischemia / reperfusion injury; preferably, cerebral ischemia / reperfusion injury includes ischemic stroke; The neurodegenerative diseases include one or more of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, infantile spinal muscular atrophy, Huntington's disease, and Parkinson's plus syndrome.

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