Novel cerium oxide nanocomposite with enhanced biological stability and application thereof

Abstract

The present invention relates to a cerium oxide nanocomposite, a method for preparing the same, and a composition for preventing or treating inflammatory or autoimmune diseases comprising the cerium oxide nanocomposite as an active ingredient. The present invention can be used as an excellent therapeutic composition in which the surface of cerium oxide nanoparticles is modified with an optimal content of a pyrrolidone-derived polymer to maximize both biological stability and in vivo reactive oxygen scavenging efficiency at the same time. Furthermore, the nanocomposite preparation method of the present invention can prepare uniform particles having an optimal diameter while thoroughly removing reaction residues and nitrate-derived toxicity by a simple process in which washing is performed using a sodium chloride solution of a specified concentration. The nano-composite disclosed by the invention can be used for remarkably inhibiting inflammatory reactions in various tissues. The composition is especially suitable for being used as an excellent treatment composition, and neuronal damage caused by excessive inflammatory reaction in hematoma surrounding areas after cerebral hemorrhage can be reduced to the maximum extent, so that the neurological function is recovered, and the survival rate of patients is remarkably increased.

Description

Technical Field

[0001] This invention relates to a cerium oxide nanocomposite whose production process is simplified but whose biological stability is significantly improved, and to a composition containing the cerium oxide nanocomposite as an active ingredient for the prevention or treatment of various inflammatory diseases. Background Technology

[0002] Recently, nanoparticle-based therapies have been extensively researched as drugs for treating various intractable diseases. Leveraging the unique optical, electromagnetic, and chemical properties imparted by their nanoscale diameter, nanoparticles are being applied in diverse medical fields such as diagnostic imaging, drug delivery systems, and therapeutics. In particular, based on their inherent properties, such as magnetothermal generation and antioxidant activity, nanoparticles themselves can serve as active pharmacological components. Furthermore, by customizing the composition, shape, size, and surface properties of particles to meet specific application needs, researchers are working to develop nanoparticles with optimized performance to satisfy the demands of a wide range of medical applications.

[0003] Reactive oxygen species (ROS) are naturally occurring byproducts of oxygen metabolism and are essential for life due to their functions in cell signaling and immune responses. However, excessive ROS production can cause oxidative damage to biomolecules and cells, leading to various forms of oxidative stress. Cerium oxide nanoparticles, also known as cerium dioxide nanoparticles, exhibit thermal stability at high temperatures. Their lattice structure allows Ce... 4+ and Ce 3+ They can undergo redox reactions depending on the surrounding oxygen concentration. Therefore, they can be used as electrolytes in solid electrolyte batteries, ultraviolet filter materials, oxygen sensors, and optical devices.

[0004] In the medical field, cerium oxide nanoparticles are increasingly attracting attention as a potential pharmaceutical composition for treating various inflammatory diseases. Cerium oxide nanoparticles can reversibly bind with oxygen, and the Ce on the particle surface... 3+ and Ce 4+ The changes in oxidative state between particles enable them to efficiently scavenge free radicals. This can not only effectively control secondary brain damage caused by neuroinflammation from various etiologies, but also serve as a pharmacological treatment for various diseases caused by excessive inflammatory responses in tissues such as the skin, intestines, lungs, and liver, including dermatitis, inflammatory bowel disease, Crohn's disease, acute respiratory distress syndrome, and inflammatory liver disease. However, due to the small diameter of nanoparticles, inhibiting aggregation in large-scale production while maintaining uniform particle size, excellent dispersibility, and low surface charge (Zeta potential) is a significant challenge. Therefore, it is necessary to develop cerium oxide nanoparticles with novel structures that can exhibit superior antioxidant effects and optimized particle properties while ensuring effective therapeutic doses in industrial-scale production.

[0005] This specification references and cites several documents and patent documents. To more clearly describe the current state of the technology involved in this invention and the content of this invention, the entire contents of the cited documents and patent documents are incorporated herein by reference.

[0006] Public content Technical issues The inventors conducted in-depth research to develop a nanoparticle therapeutic composition capable of effectively treating various inflammatory diseases caused by tissue damage induced by oxidative stress. The results showed that when the pyrrolidone polymer shown in Formula 1 was incorporated into the surface of cerium oxide nanoparticles at a specific concentration to form an outer layer, the dispersibility of the nanoparticles was significantly improved, and their surface charge tended to 0 mV. This allows for the preparation of an ideal therapeutic composition that combines excellent biocompatibility with high efficiency in scavenging reactive oxygen species in vivo.

[0007] Therefore, one object of the present invention is to provide a novel cerium oxide nanocomposite and a method for preparing the same.

[0008] Another object of the present invention is to provide a composition for the prevention or treatment of inflammatory or autoimmune diseases comprising the nanocomposite of the present invention.

[0009] In a first aspect of the present invention, a cerium oxide nanocomposite is provided, comprising: (a) The core layer of cerium oxide nanoparticles; (b) Contains an outer layer of polymer represented by the following formula 1: [Formula 1] In this case, R1 and R2 are each independently hydrogen or oxygen. Indicates a single or double bond, l is 1 or 2, and m is an integer from 100 to 1000.

[0010] The inventors conducted in-depth research to develop a nanoparticle-based therapeutic composition that can effectively treat various inflammatory diseases caused by tissue damage due to oxidative stress. The results showed that when the pyrrolidone polymer shown in Formula 1 was incorporated into the surface of cerium oxide nanoparticles at a specific concentration to form an outer layer, the dispersibility of the nanoparticles was significantly improved, and the surface charge approached 0 mV. Therefore, it can be used as a therapeutic composition with maximized biocompatibility and reactive oxygen species scavenging efficiency.

[0011] As used herein, the term "core layer" refers to the innermost layer in a multilayer composite where only one surface is in contact with the other layers.

[0012] As used herein, the term "multilayer complex" refers to a complex consisting of multiple layers of different components, including but not limited to laminated multilayer structures, core-shell multilayer structures, and combinations thereof. Specifically, the multilayer complex according to this disclosure has a core-shell multilayer structure in which nanoparticles are located at the center, while the polymer of Formula 1 and a biocompatible dispersion stabilizer surround the nanoparticles in a shell.

[0013] As used in this article, the term "outer layer" refers to the core layer that surrounds the core-shell structure and is further from the center than the core layer. The outer layer is not necessarily the layer that directly contacts the core layer; there may be additional layers (e.g., inner layers) that are closer to the core layer than the outer layer. Furthermore, the outer layer is not necessarily the outermost layer; there may be additional outermost layers that are further away from the core than the outermost layer.

[0014] According to this disclosure, the boundary between the core layer and the outer layer can be clear or unclear. If the boundary between the core layer and the outer layer is unclear, the components of the core layer and the outer layer may mix near the interface or throughout the entire cross-sectional region.

[0015] As used herein, the term "polymer" refers to a synthetic or natural polymer compound formed by the continuous linkage of monomers of the same or different types. Therefore, such polymers include homopolymers (polymers formed from a single monomer) and interpolymers formed from at least two different monomers, wherein the interpolymers include both copolymers prepared from two different monomers and polymers prepared from more than two different monomers. Specifically, the polymer of Formula 1 used in this disclosure is a homopolymer.

[0016] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, such as methyl, ethyl, propyl, isopropyl, etc. C1-C3 alkyl refers to an alkyl unit having 1 to 3 carbon atoms, and when C1-C3 alkyl is substituted, the number of carbon atoms in the substituent is not included.

[0017] As used herein, the term "biocompatibility" refers to the property of not causing short-term or long-term side effects when applied in vivo and in contact with the cells, tissues, or body fluids of an organ. Specifically, it refers not only to tissue compatibility and blood compatibility, which do not cause tissue necrosis or blood clotting when in contact with biological tissues or blood, but also includes biodegradability (i.e., the property of a material to disappear spontaneously after a certain period of time after application in vivo) and excretivity (i.e., the property of a material to not accumulate in vivo and to be excreted from the body after application). Therefore, the term "biocompatible dispersion stabilizer" refers to a component that possesses the above-mentioned biocompatibility while improving particle dispersion.

[0018] As used in this article, the term "biodegradability" refers to the property of a material to decompose naturally when exposed to physiological solutions with a pH of 6 to 8. More specifically, it refers to the property of a material to be broken down over time in the body by bodily fluids, enzymes, or microorganisms.

[0019] According to specific embodiments of the present invention, the cerium oxide nanoparticles used in the present invention may be selected from the following group: cerium oxide (IV) nanoparticles, cerium oxide (III) nanoparticles, and mixtures thereof.

[0020] According to a specific embodiment of the present invention, in Formula 1, R1 is hydrogen, R2 is oxygen, and l is 1. According to the octet rule, when R1 is hydrogen, It is clearly a single bond; when R2 is oxygen, It is a double bond. When R1 is hydrogen, R2 is oxygen, and l is 1, the compound of formula 1 is polyvinylpyrrolidone.

[0021] According to a specific embodiment of the present invention, the content ratio of the polymer to cerium oxide nanoparticles represented by Formula 1 is 7:1 to 11:1.

[0022] The inventors have discovered that when the ratio of the polymer of Formula 1 to cerium oxide nanoparticles in the nanocomposites of this invention is 7:1 to 11:1, they exhibit optimal biostability, dispersibility, and maximized anti-inflammatory effects, thus possessing the most outstanding particle characteristics. This confirms that, compared to traditional cerium oxide nanocomposites that require an additional outer coating of dispersing stabilizers (such as polyglutamic acid), this invention significantly enhances biocompatibility and therapeutic efficacy while greatly improving the efficiency and economic benefits of large-scale production through structural simplification.

[0023] More specifically, the ratio of the polymer to cerium oxide nanoparticles represented by Formula 1 is from 7.5:1 to 10.9:1, more specifically from 8:1 to 9.5:1, even more specifically from 8.5:1 to 9:1, and most specifically, the ratio is about 8.7:1.

[0024] According to specific embodiments, the nanocomposite of the present invention further comprises a multifunctional ligand represented by the following formula 2: [Equation 2] Where n is an integer from 3 to 7.

[0025] As used herein, the term "multifunctional ligand" refers to a molecule having two or more active functional groups and capable of binding to two or more molecules, thereby acting as an intermolecular linker. The multifunctional ligand of Formula 2 disclosed in this invention has a carboxyl group capable of binding to cerium oxide nanoparticles and an amino group capable of binding to the outer layer compound of Formula 1 (such as polyvinylpyrrolidone PVP), which enables the nanocomposites of this invention to form more efficiently and stably. Therefore, the multifunctional ligand of Formula 2 can exist inside the outer layer or between the core layer and the outer layer. In this case, the carboxyl group of the multifunctional ligand can be oriented towards the core, while the amino group can be oriented towards the compound of Formula 1, exhibiting a directional arrangement. Figure 1a ).

[0026] According to a specific embodiment, in Formula 2 above, n is 5. The compound of Formula 2 with n = 5 is 6-aminohexanoic acid.

[0027] According to specific embodiments, the average particle size of the nanocomposite disclosed in this invention is from 5 nm to 80 nm. More specifically, the average particle size of the nanocomposite is from 10 nm to 50 nm, more specifically from 15 nm to 30 nm, and most specifically, about 20 nm.

[0028] According to specific embodiments of the present invention, the disclosed nanocomposite has a surface charge of -1.0 to 1.0 mV. More specifically, the nanocomposite has a surface charge of -0.5 to 0.5 mV. According to the present invention, the nanocomposite exhibits an extremely low surface charge approaching 0 mV, thereby minimizing interaction with the in vivo aquatic environment during human injection and exhibiting excellent biocompatibility.

[0029] In another aspect of the invention, a composition for the prevention or treatment of inflammatory or autoimmune diseases is provided, comprising the aforementioned nanocomposite of the invention as an active ingredient.

[0030] In another aspect of the invention, a method for preventing or treating inflammatory or autoimmune diseases is provided, comprising administering the aforementioned nanocomposite of the invention to a subject in need.

[0031] The cerium oxide nanocomposite used in this invention has been described in detail above, and its description is omitted here to avoid excessive repetition.

[0032] As used in this article, the term "prevention" refers to the suppression of the development of a disease or condition in subjects who have not yet been diagnosed with it but are likely to develop it.

[0033] As used herein, the term "treatment" means: (a) inhibiting the progression of a disease, condition, or symptom; (b) alleviating a disease, condition, or symptom; or (c) eliminating a disease, condition, or symptom. The compositions according to this disclosure inhibit, eliminate, or alleviate the development of symptoms caused by excessive or unnecessary immune responses or inflammation by reducing reactive oxygen species. Specifically, as shown in the examples below, the compositions of the present invention significantly improve the survival rate of subjects with severe cerebral infarction and substantially reduce the volume of infarct lesions. Therefore, the compositions according to this disclosure can be used alone as compositions for treating inflammatory or autoimmune diseases (particularly cerebral infarction), or can be used in combination with other pharmacologically active ingredients with anti-inflammatory effects as adjuvants to the treatment of such diseases. Therefore, as used herein, the terms "treatment" or "therapeutic agent" include the meaning of "therapeutic adjuvant" or "therapeutic adjuvant."

[0034] As used herein, the term “application” means the direct administration of a therapeutically effective amount of the composition of this disclosure to a subject, thereby forming the same amount in the subject’s body, and has the same meaning as “transplantation” or “injection”.

[0035] As used herein, the term "therapeutic effective amount" means that the amount of the composition contained herein is sufficient to provide a therapeutic or preventive effect to an individual who wishes to administer the compositions of this disclosure, and is therefore intended to include "preventive effective amount".

[0036] As used herein, the term "subject" includes, but is not limited to, humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, monkeys, chimpanzees, baboons, or rhesus monkeys. Specifically, the subject of this invention is a human.

[0037] According to a specific embodiment of the present invention, the inflammatory or autoimmune disease is one or more diseases selected from the group consisting of: intracerebral hemorrhage (ICH), cerebral infarction, dermatitis, traumatic brain injury, inflammatory bowel disease (IBD), subarachnoid hemorrhage (SAH), cerebral edema, hypoxic-ischemic encephalopathy, stroke, traumatic spinal cord injury, gunshot wound, acute respiratory distress syndrome, cytokine storm syndrome, sepsis, systemic inflammatory response syndrome, peritonitis, multiple sclerosis, rheumatoid arthritis, reactive arthritis, type 1 diabetes, systemic lupus erythematosus, idiopathic pulmonary fibrosis, polymyositis, dermatomyositis, localized scleroderma, systemic scleroderma, Sjögren's syndrome, Raynaud's phenomenon, Behçet's disease, Kawasaki disease, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, myasthenia gravis, autoimmune vasculitis, primary vasculitis of the central nervous system, and inflammatory liver disease.

[0038] According to a specific implementation, the inflammatory or autoimmune disease is cerebral hemorrhage.

[0039] As used in this article, the term "cerebral hemorrhage," also known as "intracranial hemorrhage," refers to a condition in which brain tissue is contaminated and damaged by blood leaking from damaged cerebral blood vessels. Physical damage to brain tissue is primarily caused by the hematoma volume formed by the leakage of blood from cerebral blood vessels. Subsequently, cytotoxic substances such as reactive oxygen species, heme, and thrombin trigger an inflammatory response, leading to edema around the hematoma. Therefore, the key to suppressing the symptoms of cerebral hemorrhage is to rapidly suppress the edema and inflammatory response around the hematoma in the early stages to prevent neuronal damage.

[0040] According to a specific implementation, the inflammatory or autoimmune disease is cerebral infarction.

[0041] As used herein, the term "cerebral infarction" refers to ischemic injury caused by occlusion of cerebral blood vessels, leading to neurological dysfunction. Ischemic brain injury caused by cerebral infarction, similar to hematoma formation caused by cerebral hemorrhage, leads to an excessive inflammatory response and ultimately becomes one of the main causes of cerebral edema. Therefore, "cerebral edema" can also be included within the scope of inflammatory or autoimmune diseases that can be prevented or treated by the compositions of this invention.

[0042] As used in this article, the term "cerebral edema" refers to a condition in which fluid enters cells or tissues due to any brain tissue damage, such as trauma, tumors, or inflammation, causing an increase in the volume of brain tissue. Cerebral edema originates from an inflammatory response within the brain tissue. When large-area cerebral edema occurs within the limited space of the cranial cavity, it exerts physical pressure on surrounding tissues. In severe cases, it can lead to brain herniation, brainstem compression, and hydrocephalus, and may cause additional neurological damage or even death.

[0043] According to specific embodiments of the present invention, the cerebral edema to be prevented or treated includes cerebral edema caused by stroke, cerebral infarction, intracranial hemorrhage, brain tumor, traumatic brain injury, encephalitis, inflammatory encephalopathy, demyelinating encephalopathy, or intracranial vasculitis. More specifically, the cerebral edema is caused by cerebral infarction.

[0044] According to a specific implementation, the inflammatory or autoimmune disease is dermatitis.

[0045] As used herein, the term "dermatitis" refers to any disease resulting from or caused by an excessive or unnecessary immune response or inflammation, leading to damage to skin tissue, including the epidermis, dermis, and subcutaneous tissue, and impairing the inherent biological functions of the skin tissue, including its barrier function. Dermatitis that can be prevented or treated by the compositions of the present invention is selected from the group consisting of atopic dermatitis, eczema, erythema multiforme, erythema nodosum, and pyoderma gangrenosa, with atopic dermatitis being particularly prominent.

[0046] As used in this article, the term "atopic dermatitis" is a chronic allergic inflammatory skin condition that commonly affects children and can persist into adulthood. Atopic dermatitis is influenced by a family history of allergic diseases and is triggered by allergens such as food or house dust mites. Most medications currently in use, including steroids, are largely symptomatic treatments and do not address the underlying cause, making it a typical intractable skin condition.

[0047] According to a specific implementation, the inflammatory or autoimmune disease is traumatic brain injury.

[0048] As used herein, the term "traumatic brain injury" refers to a condition in which brain tissue is damaged by external physical forces, resulting in impaired brain function, including cognitive abilities. Oxidative stress caused by excessive production of reactive oxygen species (ROS) after trauma is a major secondary injury mechanism in traumatic brain injury. Reducing the immediate post-traumatic burst of ROS production is crucial for preventing further tissue damage. Furthermore, similar to hematoma formation caused by cerebral hemorrhage and ischemic brain injury caused by cerebral infarction, traumatic brain injury is also one of the main causes ultimately leading to cerebral edema. Therefore, using the compositions of this invention to prevent or treat traumatic brain injury can simultaneously provide prevention or treatment of "cerebral edema."

[0049] According to a specific implementation, the inflammatory or autoimmune disease is a gunshot wound.

[0050] As used herein, the term "gunshot wound" refers to injury caused by a projectile (e.g., a bullet fired from a firearm) entering or penetrating body tissue. In this disclosure, it is synonymous with "inflammation caused by gunshot" or "sepsis caused by gunshot." Injuries caused by gunshot wounds include bleeding, fractures, organ damage, wound infection, inflammation, and death. Long-term complications include intestinal obstruction, growth retardation, neurogenic bladder and paralysis, recurrent respiratory distress and pneumothorax, and early dementia due to hypoxic-ischemic brain injury. In particular, penetrating bullets create perforations in tissues, leading to bleeding and the entry of foreign bodies, thereby causing inflammation and sepsis. Therefore, controlling the inflammatory response and rapid escalation of reactive oxygen species after a gunshot wound, while simultaneously performing surgical suturing, is a critical factor in determining patient survival.

[0051] According to a specific implementation, the inflammatory or autoimmune disease is acute respiratory distress syndrome.

[0052] As used in this article, the term "acute respiratory distress syndrome (ARDS)," also known as "acute lung injury (ALI)," refers to a pathological state characterized by a sudden decline in lung function, leading to a decrease in arterial blood oxygen partial pressure and carbon dioxide buildup, thereby inducing respiratory failure. Representative causes of a sudden decline in lung function include sepsis due to systemic infection, trauma, massive blood transfusions, and pancreatitis. Bacterial infection or trauma can lead to a large influx of foreign bodies, causing severe inflammation in the lungs and resulting in a sudden loss of lung function. Acute respiratory distress syndrome is classified into acute, proliferative, and fibrotic phases based on its course. Since the acute phase is primarily driven by an excessive inflammatory response, controlling inflammation is crucial to preventing disease progression.

[0053] According to a specific implementation, the inflammatory or autoimmune disease is inflammatory bowel disease (IBD).

[0054] As used herein, the term "inflammatory bowel disease" encompasses inflammatory conditions occurring in the gastrointestinal tract, including but not limited to the two most common forms: ulcerative colitis and Crohn's disease. Inflammatory bowel disease is a chronic and intractable condition characterized by symptoms such as abdominal pain, diarrhea, rectal bleeding, and weight loss that persist for months or longer. Fundamental treatment requires controlling the inflammation occurring throughout the digestive tract and the resulting multiple oxidative stresses.

[0055] According to a specific implementation, the inflammatory or autoimmune disease is subarachnoid hemorrhage (SAH).

[0056] As used in this article, the term "subarachnoid hemorrhage (SAH)" refers to a condition in which blood leaks from a cerebral blood vessel into the subarachnoid space, causing various inflammatory responses and brain cell damage in the brain tissue located near the brain parenchyma. As a hemorrhage occurring within the extensively swathed subarachnoid space, SAH can cause widespread damage to the entire brain. Therefore, it often results in immediate death or severe, permanent brain damage upon occurrence. Brain damage caused by SAH is triggered by a series of inflammatory cascades in the brain tissue, initiated by blood-derived components such as hemoglobin and thrombin, subsequently inducing oxidative damage through reactive oxygen species (ROS). Therefore, rapid control of ROS and swift suppression of the inflammatory response are crucial for minimizing neurological damage.

[0057] According to a specific implementation, the inflammatory or autoimmune disease is sepsis.

[0058] As used herein, the term "sepsis" encompasses a harmful systemic inflammatory response to external infectious agents, such as viruses or bacteria, and the resulting pathological conditions, including complications such as "severe sepsis" and "septic shock." Sepsis is characterized by fever, respiratory distress, and rapid changes in white blood cell count, leading to multiple organ failure and ultimately high mortality. Treatment typically involves multiple interventions simultaneously, such as the use of antibiotics and antifungals to clear the source of infection, fluid resuscitation, maintaining blood pressure, blood transfusions, and correction of acidosis to alleviate septic shock. However, fundamental treatment requires eliminating the excessive reactive oxygen species generated by the inflammatory response.

[0059] According to a specific implementation, the inflammatory or autoimmune disease is inflammatory liver disease.

[0060] As used in this article, the term "inflammatory liver disease" refers to a range of diseases caused by various etiologies that directly or indirectly lead to excessive or unnecessary immune or inflammatory responses, resulting in liver tissue damage.

[0061] More specifically, the inflammatory liver disease is selected from the group consisting of: viral hepatitis, toxoplasmosis hepatitis, alcoholic liver disease, toxic liver disease, acute and subacute liver failure, liver abscess, nonspecific reactive hepatitis, hepatic infarction, hepatic venous occlusive disease, liver or gallbladder injury, and hepatitis related to liver transplantation.

[0062] When the compositions according to this disclosure are formulated into pharmaceutical compositions, the pharmaceutical compositions of this disclosure contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers contained in the pharmaceutical compositions of this disclosure are commonly used in formulations, and examples include, but are not limited to: lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil, etc. In addition to the above-mentioned components, the pharmaceutical compositions of this disclosure may further contain: lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington Pharmaceutical Science (19th edition, 1995).

[0063] The pharmaceutical compositions disclosed herein can be administered via a variety of routes of administration, specifically parenteral administration, and more specifically intravenous, intra-arterial, subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, intrathecal, intrathecal, inhalation, nasal, intra-articular, or local administration.

[0064] The appropriate dosage of the pharmaceutical composition disclosed herein may vary depending on factors such as preparation method, route of administration, patient age, weight, sex, pathological condition, food, time of administration, route of administration, excretion rate, and responsiveness. The preferred dosage of the pharmaceutical composition disclosed herein for adults is in the range of 0.0001 to 1000 mg / kg.

[0065] The pharmaceutical compositions disclosed herein can be formulated using pharmaceutically acceptable carriers and / or excipients according to methods readily practiced by those skilled in the art, to be in unit dose form or packaged in multi-dose containers. The dosage form can be a solution, suspension, syrup, or emulsion in an oily or aqueous medium, or it can be in the form of an extract, powder, granules, tablet, or capsule, and may additionally contain dispersants or stabilizers.

[0066] In another aspect of the invention, a method for preventing or treating inflammatory or autoimmune diseases is provided, comprising administering to a subject in need a cerium oxide nanocomposite according to the present disclosure or a pharmaceutical composition containing thereas as an active ingredient. The cerium oxide nanocomposite used in this disclosure and the inflammatory or autoimmune diseases that can be prevented or treated by the cerium oxide nanocomposite have been described in detail above, and their description is omitted here to avoid excessive repetition.

[0067] In another aspect of the present invention, a method for preparing cerium oxide nanocomposites is provided, the method comprising: (a) A mixed solution is prepared by adding a cerium precursor, a polymer represented by Formula 1, and a crosslinking compound represented by Formula 2 into a C1-C3 alcohol solvent; [Formula 1] In this case, R1 and R2 are each independently hydrogen or oxygen. Indicates a single or double bond, where l is 1 or 2, and m is an integer from 100 to 1000; [Equation 2] Where n is an integer from 3 to 7.

[0068] (b) The mixed solution was sequentially heated and cooled to obtain cerium oxide nanoparticles; and (c) Wash the cerium oxide nanoparticles with an inorganic salt solution.

[0069] According to the present invention, step (a) can form a core-shell structure, wherein the compound of formula 1 is bonded to the core of cerium oxide nanoparticles through a crosslinking compound of formula 2, thereby forming a coating outer layer.

[0070] As used herein, the term "coating" refers to applying a specific material to a target surface to form a new layer of a certain thickness. The target surface and the coating material can be bonded by ionic or non-covalent bonds. The term "non-covalent bond" includes physical bonds such as adsorption, cohesion, entanglement, and embedding, as well as bonds arising from interactions, such as hydrogen bonds and van der Waals bonds, which can act alone or in combination with the aforementioned physical bonds. When the compound of Formula 1 is coated onto the surface of cerium oxide nanoparticles, it can form a completely or partially sealed layer encapsulating the coated surface.

[0071] According to a specific embodiment of the present invention, the C1-C3 alcohol solvent is ethanol.

[0072] According to a specific embodiment of the present invention, the cerium precursor is one or more precursors selected from the group consisting of: cerium(III) acetate hydrate, cerium(III) acetylacetone hydrate, cerium(III) carbonate hydrate, cerium(III) fluoride, cerium(III) chloride, cerium(III) chloride heptahydrate, cerium(III) bromide, cerium(III) iodide, cerium(III) nitrate hexahydrate, cerium(III) oxalate hydrate, cerium(III) sulfate, and cerium(III) sulfate hydrate. More specifically, the cerium precursor is cerium(III) nitrate hexahydrate.

[0073] According to a specific embodiment of the invention, the heating is performed at 60 to 80°C. More specifically, it is performed at 65 to 75°C, and most specifically, at approximately 70°C.

[0074] According to a specific embodiment of the invention, the cooling is performed by reducing the temperature to 35 to 50°C. More specifically, it is performed by cooling to 40 to 50°C, and most specifically, by cooling to approximately 45°C.

[0075] As used herein, the term "washing" refers to the process of physically and chemically removing impurities bound to reaction products using washing solutions or buffers. Washing is performed during the separation and purification of reaction products to reduce the amount of undesirable impurities and improve the purity of the desired final product.

[0076] As used herein, the term "inorganic salt" refers to a salt derived from inorganic materials that does not contain CH bonds, wherein its cations and anions are bonded by ionic bonds in aqueous solution. According to specific embodiments, the inorganic salt is selected from the group consisting of NaCl, CaCl2, KCl, MgCl2, or combinations thereof.

[0077] More specifically, the inorganic salt solution is a sodium chloride solution.

[0078] According to a specific embodiment, the concentration of the inorganic salt solution is 0.15 to 0.35 M.

[0079] The inventors have discovered that by adding a washing step using a 0.15 to 0.35 M sodium chloride solution after the reaction is complete, particles with optimal uniform particle size can be efficiently obtained while completely eliminating unreacted residues and nitrate toxicity. More specifically, the sodium chloride solution concentration of the present invention is 0.20 to 0.30 M, and most specifically, the concentration is about 0.25 M.

[0080] Beneficial effects The features and advantages of this invention are summarized as follows: (a) The present invention provides a cerium oxide nanocomposite, a method for preparing the same, and a composition comprising the cerium oxide nanocomposite as an active ingredient for the prevention or treatment of inflammatory or autoimmune diseases.

[0081] (b) The present invention can serve as an excellent therapeutic composition in which the surface of cerium oxide nanoparticles is modified with an optimal amount of pyrrolidone-derived polymer to simultaneously maximize biostability and in vivo reactive oxygen species scavenging efficiency.

[0082] (c) The method for preparing nanocomposites of the present invention, which can be achieved by washing with a sodium chloride solution of a specified concentration, produces uniform particles with optimal diameter while completely removing reaction residues and nitrate-derived toxicity.

[0083] (d) The nanocomposite of the present invention significantly inhibits inflammatory responses in various tissues. It is particularly effective as a therapeutic composition, effectively suppressing neuronal damage caused by excessive inflammation in the peri-hematoma area after cerebral hemorrhage, thereby restoring neurological function and significantly improving patient survival.

[0084] Brief description of the attached figures Figure 1 shows a schematic diagram of the cerium oxide nanocomposite of the present invention. Figure 1a ) and images observed by transmission electron microscopy ( Figure 1b ).

[0085] Figure 2 shows the particle size, dispersion stability in a biomimetic environment, and surface charge changes of the synthesized cerium oxide nanocomposite of the present invention as a function of the content of its outer surface-modified polymer PVP (polyvinylpyrrolidone). Figure 2a ), and the content of PVP in the dry cerium oxide nanocomposite of the present invention, expressed in units of cerium content ( Figure 2b ).

[0086] Figure 3 The particle size of the cerium oxide nanocomposite of the present invention as it is exposed to a biomimetic environment over time is shown, and this data was measured by a dynamic light scattering device.

[0087] Figure 4The surface charge comparison between the conventionally developed cerium oxide nanocomposite (CX213) and the cerium oxide nanocomposite of the present invention is shown.

[0088] Figure 5 shows the different reaction residues ( ) during the purification of the cerium oxide nanocomposite of the present invention, depending on the concentration of the sodium chloride aqueous solution used. Figure 5a ) and particle size variation ( Figure 5b ).

[0089] Figure 6 The results show a comparative analysis of the therapeutic effects of conventionally developed cerium oxide nanocomposite (CX213) and the cerium oxide nanocomposite (CX301) of the present invention on severe cerebral infarction in a rat model of severe cerebral infarction, based on survival rate assessment after intravenous injection.

[0090] Figure 7 The results show a comparative analysis of the therapeutic effects of a conventionally developed cerium oxide nanocomposite (CX213) and the cerium oxide nanocomposite (CX301) of the present invention on severe cerebral infarction based on infarct volume.

[0091] Figure 8 The results show the efficacy of the cerium oxide nanocomposite of the present invention in treating cerebral hemorrhage by comparing and analyzing changes in brain water content caused by cerebral edema.

[0092] Figure 9 The cylinder symmetry score is shown in a traumatic brain injury model, used to evaluate the therapeutic effect of the cerium oxide nanocomposite of the present invention on traumatic brain injury.

[0093] Figure 10 shows the results of evaluating the therapeutic effect of the cerium oxide nanocomposite of the present invention in a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis model, showing the degree of transepidermal water loss (…). Figure 10a ) and the degree of epidermal thickening and inflammatory mast cell infiltration ( Figure 10b ).

[0094] Figure 11 The results show the changes in body weight and disease activity score (DAI) measured in a dextran sulfate sodium (DSS)-induced inflammatory bowel disease animal model to evaluate the therapeutic effect of the cerium oxide nanocomposite of the present invention on inflammatory bowel disease.

[0095] Figure 12 The results show the changes in post-treatment survival rate measured in a CLP-induced sepsis animal model to evaluate the therapeutic effect of the cerium oxide nanocomposite of the present invention on sepsis.

[0096] Figure 13The results show the cell viability of hepatocytes (hepa-1c1c7) induced by pyrogallol toxicity after treatment with the cerium oxide nanocomposite of the present invention to confirm the therapeutic effect on inflammatory liver disease.

[0097] Figure 14 shows the changes in post-treatment survival rate in an animal model of induced subarachnoid hemorrhage, measured to evaluate the therapeutic effect of the cerium oxide nanocomposite of the present invention on subarachnoid hemorrhage.

[0098] The present invention will be described in more detail below by way of embodiments. These embodiments are only used to illustrate the present invention in more detail, and those skilled in the art will not find the scope of the present invention as defined by the subject matter to be limited by these embodiments.

[0099] Example Example 1: Synthesis of cerium oxide nanocomposites A first solution was prepared by dissolving 6-aminohexanoic acid (37.75 g, Sigma-Aldrich, St. Louis, MO) in deionized water (1.7 L). Ethanol (1.4 L) was added to the first solution with stirring, followed by 132.83 g of polyvinylpyrrolidone (PVP, Ashland). The mixture was then heated in air to 70 °C to prepare a second solution. Simultaneously, a third solution was prepared by dissolving cerium nitrate hexahydrate (Ce(NO3)3·6H2O, 31.05 g, Alfa Aesar, Ward Hill, MA) in ethanol (2.9 L) at room temperature (approximately 20 °C). The third solution was then added to the second solution to prepare a fourth solution. The temperature of the fourth solution was maintained at 70 °C for 2 hours, then gradually decreased to 45 °C. Through this process, cerium oxide nanoparticles with 6-aminohexanoic acid and polyvinylpyrrolidone bound to their surface were obtained. Figure 1a and 1b Subsequently, the nanoparticles were washed five times with a mixture of acetone and sodium chloride aqueous solution to remove unreacted material.

[0100] Example 2: Study on the optimal content of polyvinylpyrrolidone as the outer polymer To determine the optimal content of polyvinylpyrrolidone (PVP) dispersant stabilizer for forming the outer layer of cerium oxide nanoparticles, the particle formation tendency and dispersion stability in a biomimetic environment were analyzed as a function of PVP content. During the synthesis of the cerium oxide nanocomposite in Example 1, the PVP content ratio was adjusted to 15–30 mg PVP / total batch mL. The particle size of the synthesized product and its dispersion stability (Z-mean, nm) and surface charge (Zeta potential, mV) in a biomimetic environment containing protein and sodium bicarbonate were measured. The results showed that the particle properties were optimal when PVP was applied at a content ratio of 20–25 mg PVP / total batch mL. Figure 2a ).

[0101] Furthermore, to more clearly measure the derived optimal PVP content range based on the final product (i.e., the nanocomposite), the entire synthesized nanocomposite was freeze-dried, and the PVP content in the dried nanocomposite was then quantitatively determined and converted into the content per unit of cerium. The results showed that when the PVP to cerium oxide nanoparticle ratio was between 7.5 and 10.9 (7.5–10.9 mg PVP / mg Ce), the final nanocomposite exhibited the most favorable particle characteristics, and the optimal ratio was determined to be 8.7. Figure 2b The composition ratio explored in this invention can be considered as the result of determining the optimal conditions after taking into account the influence of nanocomposite size on dispersibility, functionality, and biostability.

[0102] Experimental Example 1: Comparison of biostability and dispersibility of conventionally developed particles and particles of the present invention in a biomimetic environment. In a biomimetic environment, the biostability (dispersibility) of CX213 (a previously developed cerium oxide nanocomposite in which polyglutamic acid is introduced as an additional dispersing stabilizing outermost layer) and CX301 (cerium oxide nanoparticles of the present invention, without this additional polymer layer) were compared. For this purpose, the particle size change over time in 0.05 M PBS (phosphate-buffered saline) was analyzed. Samples were taken at 0, 20, 40, and 60 minutes, and the particle size was analyzed using dynamic light scattering. The results showed that the CX213 nanocomposite exhibited particle aggregation reaching hundreds of nanometers over time, while the CX301 of the present invention maintained a constant particle size over time. Figure 3 ).

[0103] Experimental Example 2: Comparison of surface charge between conventionally developed particles and particles of the present invention The inventors measured the surface charge of conventionally developed CX213 and the CX301 of this invention to evaluate the differences in biostability and dispersibility with or without PVP-based optimization. Each synthesized cerium oxide nanocomposite was dispersed in deionized water, and the surface properties of the cerium nanocomposite were analyzed using dynamic light scattering. The results showed that the surface charge of CX213 was -17.5 mV, while that of CX301 was 0 mV, demonstrating a significant difference between the two particles. Figure 4 This indicates that the present invention has a surface charge tending to 0 mV, which minimizes interactions in the in vivo environment compared to CX213, which has a strong negative charge due to the terminal PGA polymer.

[0104] Experiment Example 3: Evaluating the effect of sodium chloride solution on the concentration and particle size of reaction residues during purification. To measure the particle size of the reaction residues and final products of cerium oxide nanocomposites obtained by adding sodium chloride solution of different concentrations during purification, the concentration of the sodium chloride aqueous solution was adjusted to 0, 0.25, 0.5, 1.0, 2.5, and 5 M during the preparation of the cerium oxide nanocomposites in Example 1. The resulting reaction residues, particularly the residual nitrate content, were measured using nitrate indicator paper (PP paper, Johnson). Furthermore, the particle size was confirmed using a dynamic light scattering device. Figure 5a As shown, using 0.25 M sodium chloride solution during purification is most effective for removing reaction residues (especially nitrates). This demonstrates that the manufacturing process of this invention is efficient in reducing drug residues and eliminating the toxicity caused by nitrates. Furthermore, the particle size was also optimized (20 nm) when using 0.25 M sodium chloride solution, confirming that the addition of sodium chloride significantly affects the stability of particle formation. Figure 5b ).

[0105] Experiment Example 4: Evaluating the therapeutic effect on non-infectious inflammatory diseases through survival rate To compare and evaluate the therapeutic effects of the conventionally developed cerium oxide nanocomposite CX213 and the CX301 of this invention prepared in Example 1 on non-infectious inflammatory diseases, SD (Sprague-Dawley) rats (Coatech Co., Ltd.) were anesthetized with isoflurane. Severe cerebral infarction, a representative non-infectious inflammatory disease, was induced by ligating the left middle cerebral artery with a 4-0 proline suture. One hour after induction of severe cerebral infarction, both types of cerium oxide nanocomposite were intravenously injected at a dose of 0.5 mg Ce / kg for more than 5 minutes. As a control group, an equal volume of physiological saline was injected. Survival rate was measured by periodically checking the mortality status of SD rats starting 7 days after induction of MIS. The experimental group consisted of 18 SD rats, and the control group consisted of 15 SD rats; the average value is expressed as the survival rate. Figure 6As shown, the survival rate of the CX213 nanocomposite was increased by 2.25 times compared with the control group (control group: 28.57%, CX213 treatment group: 64.28%), while the group injected with the CX301 of the present invention showed a survival rate increased by up to 6 times (control group: 13.33%, CX301 administration group: 80.00%).

[0106] This confirms that the novel cerium oxide nanocomposite CX301 of the present invention can be effectively used as a therapeutic composition for non-infectious inflammatory diseases, as its therapeutic effect was observed to be 2.6 times that of CX213 previously developed by the inventors.

[0107] Experimental Example 5: Evaluating the therapeutic effect of infarct volume on non-infectious inflammatory diseases Brain tissue was obtained from SD rats in Experiment 4 to obtain coronal sections, which were then stained with Nissl stain to confirm the degree of infarction. After staining, the volume was calculated based on the area of ​​each section. Compared with the control group, the infarct volume was reduced by 18.58% in the CX213 treatment group and by 51.22% in the CX301 group. Therefore, when assessed based on infarct volume, the cerium oxide nanocomposite of the present invention exhibits a therapeutic effect 2.76 times higher than that of previously developed nanocomposites. Figure 7 This indicates that the CX301 nanocomposite of the present invention not only significantly improves the survival rate, but also greatly reduces the infarct volume in actual brain tissue, confirming its significant and superior therapeutic effect from multiple perspectives.

[0108] Experimental Example 6: Evaluation of the therapeutic effect on other non-infectious inflammatory diseases Intracerebral hemorrhage Intracerebral hemorrhage is a disease characterized by persistent neuronal damage caused by excessive inflammation around the hematoma. The inventors sought to confirm whether the anti-inflammatory effect of the cerium oxide nanocomposite of this invention could alleviate the symptoms of intracerebral hemorrhage. First, randomly assigned SD rats were anesthetized with 2.5% isoflurane. The rats' heads were fixed in a stereotaxic apparatus, and holes were drilled at the following coordinates relative to the anterior fontanelle: 0.02 mm posterior to the coronal plane and 0.30 mm lateral to the midline. To induce intracerebral hemorrhage, 1 μl of collagenase VII (0.5 units) was injected to a depth of 0.66 mm. Subsequently, at 1 hour and 24 hours after model induction, cerium oxide nanocomposite (0.5 mg / kg) or saline was administered intravenously twice. To assess disease severity, cerebral edema was assessed by measuring brain water content on day 3. Brain water content measurements showed that the cerium oxide nanocomposite treatment group showed a 22.72% improvement compared to the saline-treated control group. Figure 8 These results confirm that the cerium oxide nanocomposite of the present invention also exhibits excellent therapeutic effects on intracerebral hemorrhage.

[0109] Traumatic brain injury Traumatic brain injury (TBI) is a disease characterized by secondary neuronal damage caused by an inflammatory response resulting from excessive reactive oxygen species (ROS). The inventors aimed to verify whether the cerium oxide nanocomposite of this invention has a therapeutic effect on TBI. To induce TBI, SD rats were anesthetized with 2.5% isoflurane. The rats' heads were fixed in a stereotaxic apparatus, and a hole was drilled 3.5 mm posterior to the anterior fontanelle and 3.5 mm lateral to the midline in the coronal plane. To induce brain injury at the designated site, a 5 mm diameter impactor was mounted on a precision impactor (PCI3000, Hatteras), with an impact depth of 6 mm and an impact speed of 4 m / s. One hour after induction, a single intravenous injection of 0.1 mg / kg of the cerium oxide nanocomposite of this invention was administered, and the degree of motor dysfunction was assessed using a cylinder test. To ensure measurement accuracy, a mirror was placed opposite the behavioral recording area to eliminate blind spots. The animals were then placed in the cylinder, and their movement was observed for 10 minutes. Measurements were recorded after confirming the use of wall support, balance, and foot placement for landing. Scores were calculated using the formula [(ipsilateral + 1 / 2 bilateral) / (ipsilateral + contralateral + bilateral)] × 100, where I represents the ipsilateral (affected side), C represents the contralateral (unaffected side), and B represents bilateral (both sides). Test results showed that, compared to the saline group, the cerium oxide nanocomposite group exhibited a 47.02% improvement in motor function on day 3. Figure 9 These results confirm that the cerium oxide nanocomposite of the present invention can be effectively used as a therapeutic composition for treating traumatic brain injury, a refractory disease.

[0110] dermatitis In inflammatory skin diseases caused by various factors, excessive inflammatory responses induced by reactive oxygen species can exacerbate the severity of dermatitis. To determine whether the cerium oxide nanocomposite of the present invention can alleviate the severity of inflammatory skin diseases, a dermatitis model was established using hairless SKH-1 mice. To induce atopic dermatitis, 0.2 ml of 1% 2,4-dinitrochlorobenzene (DNCB) was applied to the back of the mice daily for 35 days. Starting from day 17 of application, 0.2 ml of the nanocomposite of the present invention at doses of 0.5 mg / kg or 1 mg / kg was applied to the same site. To observe the improvement of dermatitis, the degree of skin moisture loss was measured every 3 days using a moisture measurement device (GP skin barrier, GP skin). On the last day, skin tissue was harvested, and changes in epidermal thickness and the degree of inflammatory cell infiltration were confirmed by staining. The results showed that by the last day, the moisture loss in the 0.5 mg / kg cerium oxide nanocomposite treatment group improved by 12.13%, while that in the 1 mg / kg treatment group improved by 19.19%. Figure 10aRegarding epidermal thickness, the hypertrophy was reduced by 38.78% and 47.09% in the 0.5 mg / kg and 1 mg / kg cerium oxide nanocomposite treatment groups, respectively. Figure 10b (Left). In the dermatitis model, the degree of inflammatory mast cell infiltration characteristically observed was reduced by 27.21% and 33.05%, respectively. Figure 10b ,right).

[0111] colitis In inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, oxidative stress plays a crucial role in pathogenesis and progression. The inventors sought to verify whether the antioxidant and anti-inflammatory activities of the cerium oxide nanocomposite of this invention could also inhibit the symptoms and progression of inflammatory bowel disease. To establish a disease model, C57BL / 6 mice were given either regular drinking water or 2% DSS (sodium dextran sulfate, an agent that induces epithelial cell damage) daily for 10 days. The cerium oxide nanocomposite was dissolved in 0.2 ml at a dose of 1 mg / kg and administered rectally daily from 7 days before the start of DSS-induced inflammatory bowel disease until the end of the test period. To assess disease severity, body weight, stool consistency, and rectal bleeding were recorded daily. The scoring criteria were as follows: 0 points for normal condition; 1 point for weight loss ≤10%; 2 points for weight loss ≤15% with loose stools; 3 points for weight loss within 20%; and 4 points for weight loss exceeding 20% ​​with diarrhea or bloody stools. This score was used to calculate the disease activity index to assess severity. Results showed that, compared to the saline-treated control group, the group treated with cerium oxide nanocomposite experienced an 8.05% reduction in body weight loss. Figure 11 (Left), the severity of the disease decreased by 24.21% ( Figure 11 (Right). This indicates that even under direct intestinal administration conditions, the cerium oxide nanocomposite of the present invention exhibits significant antioxidant and anti-inflammatory effects, demonstrating its potential as an effective therapeutic composition for inflammatory bowel disease.

[0112] sepsis Sepsis is a disease caused by an overreaction of the body to various infections, leading to tissue damage and organ failure. The inventors aimed to verify the therapeutic effect of the cerium oxide nanocomposite of this invention on sepsis. Sepsis was induced using the cecal ligation and perforation method. Specifically, SD rats were anesthetized with 2.5% isoflurane, followed by ligation and puncture of their cecum to induce intraperitoneal infection. One hour after disease induction, the cerium oxide nanocomposite of this invention was administered via a single intravenous injection at a cerium concentration of 0.5 mg / kg. Survival rate was measured over 6 days. Nineteen SD rats were used in each of the experimental and control groups, with survival rate as the outcome measure. The results showed that, compared with the saline-treated control group, the survival rate of the cerium oxide nanocomposite-treated group was approximately three times higher by day 6 (control group: 5.3%, experimental group: 15.8%). Figure 12 This confirms that the cerium oxide nanocomposite of the present invention also exhibits excellent therapeutic effects on sepsis.

[0113] Inflammatory liver disease Inflammatory liver disease (IBD) is a condition caused by liver damage, metabolic disorders, and the accumulation of toxic substances, leading to the liver's inability to perform its normal functions. The inventors aimed to verify the therapeutic effect of the cerium oxide nanocomposite of this invention on IBD. To induce the disease, Hepa-1C1C7 hepatocytes were treated with the cytotoxic substance 500 μM pyrogallol to induce acute IBD. Simultaneously, the cells were treated with the cerium oxide nanocomposite of this invention at concentrations ranging from 0.01 to 5 μM. After three hours of treatment, the viability of Hepa-1C1C7 cells was measured using the NRU assay, a biochemical analysis method that measures cell viability by allowing neutral red dye to be absorbed by living cells. The results showed that the viability of cells treated with pyrogallol was approximately 50.43% compared to the control group not treated with pyrogallol. When treated with the cerium oxide nanocomposite of this invention, a viability rate of 74.55% was observed at the minimum concentration of 0.01 μM, and approximately 93.19% at the maximum concentration of 5 μM. Compared to cells treated with pyrogallol alone, this represented an increase in survival rate of at least 47.81% and up to 84.78%. Figure 13 These results indicate that the cerium oxide nanocomposite of the present invention can also be used as an effective therapeutic composition for inflammatory liver diseases.

[0114] Subarachnoid hemorrhage Subarachnoid hemorrhage is a condition in which blood leaks into the subarachnoid space of the brain, primarily caused by the rupture of a cerebral aneurysm. The inventors aimed to verify the therapeutic effect of the cerium oxide nanocomposite of this invention on subarachnoid hemorrhage. SD rats were anesthetized with 2.5% isoflurane, their heads were fixed, and an incision was made below the neck to locate the common carotid artery, internal carotid artery, and external carotid artery. A thin wire was inserted into the external carotid artery and advanced to the middle cerebral artery. The middle cerebral artery was then punctured to induce bleeding, resulting in subarachnoid hemorrhage. One hour after induction, the cerium oxide nanocomposite of this invention was administered to the rats via a single intravenous injection at a cerium concentration of 0.5 mg / kg. Survival rates were measured over 10 days, and the survival of 5 rats in each of the control and experimental groups was recorded. The results showed that, compared with the saline-treated control group, the survival rate of the cerium oxide nanocomposite-treated group was increased by 2 times by day 10 (control group: 40%, experimental group: 80%). Figure 14a Furthermore, measurements of brain water content on day 3 showed that although the difference in the contralateral side of the lesion between the control group (79.5%) and the experimental group (79.8%) was less than 0.3%, the water content of the ipsilateral side of the lesion in the experimental group (80.8%) was 0.7% lower than that in the control group (80.1%). Figure 14b This confirms that the cerium oxide nanocomposite of the present invention also exhibits excellent therapeutic effects on subarachnoid hemorrhage.

[0115] The specific embodiments of the present invention have been described in detail above. It should be understood that variations and modifications falling within the spirit and scope of the present invention may be apparent to those skilled in the art, and the scope of the present invention should be determined by the appended claims and their equivalents.

Claims

1. A cerium oxide nanocomposite comprising: (a) The core layer of cerium oxide nanoparticles; (b) Contains an outer layer of polymer represented by the following formula 1: [Formula 1] in, R1 and R2 are each independently hydrogen or oxygen. Indicates a single or double bond, l is 1 or 2, and m is an integer from 100 to 1000.

2. The nanocomposite of claim 1, wherein the cerium oxide nanoparticles are selected from the group consisting of cerium oxide (III) nanoparticles, cerium oxide (IV) nanoparticles, and mixtures thereof.

3. The nanocomposite of claim 1, wherein in formula 1, R1 is hydrogen, R2 is oxygen, and l is 1.

4. The nanocomposite of claim 3, wherein the ratio of the polymer represented by Formula 1 to the cerium oxide nanoparticles is 7:1 to 11:

1.

5. The nanocomposite of claim 1, further comprising a multifunctional ligand represented by formula 2: [Equation 2] in, n is an integer from 3 to 7.

6. The nanocomposite of claim 5, wherein in formula 2, n is 5.

7. The nanocomposite of claim 1, wherein the average particle size of the nanocomposite is from 5 nm to 80 nm.

8. The nanocomposite of claim 1, wherein the surface charge of the nanocomposite is -1.0 to 1.0 mV.

9. A composition for the prevention or treatment of inflammatory or autoimmune diseases, comprising the nanocomposite of any one of claims 1 to 8 as an active ingredient.

10. The composition of claim 9, wherein the inflammatory or autoimmune disease is one or more diseases selected from the group consisting of: intracerebral hemorrhage (ICH), cerebral infarction, dermatitis, traumatic brain injury, inflammatory bowel disease (IBD), subarachnoid hemorrhage (SAH), cerebral edema, hypoxic-ischemic encephalopathy, stroke, traumatic spinal cord injury, gunshot wound, acute respiratory distress syndrome, cytokine storm syndrome, sepsis, systemic inflammatory response syndrome, peritonitis, multiple sclerosis, rheumatoid arthritis, reactive arthritis, type 1 diabetes, systemic lupus erythematosus, idiopathic pulmonary fibrosis, polymyositis, dermatomyositis, localized scleroderma, systemic scleroderma, Sjögren's syndrome, Raynaud's phenomenon, Behçet's disease, Kawasaki disease, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, myasthenia gravis, autoimmune vasculitis, primary vasculitis of the central nervous system, and inflammatory liver disease.

11. The composition of claim 10, wherein the inflammatory or autoimmune disease is intracerebral hemorrhage (ICH).

12. The composition of claim 10, wherein the inflammatory or autoimmune disease is cerebral infarction.

13. The composition of claim 10, wherein the inflammatory or autoimmune disease is dermatitis.

14. The composition of claim 10, wherein the inflammatory or autoimmune disease is traumatic brain injury.

15. The composition of claim 10, wherein the inflammatory or autoimmune disease is inflammatory bowel disease (IBD).

16. The composition of claim 10, wherein the inflammatory or autoimmune disease is subarachnoid hemorrhage (SAH).

17. The composition of claim 10, wherein the inflammatory or autoimmune disease is sepsis.

18. The composition of claim 10, wherein the inflammatory or autoimmune disease is inflammatory liver disease.

19. A method for preparing cerium oxide nanocomposites, comprising: (a) A mixed solution is prepared by adding a cerium precursor, a polymer represented by Formula 1, and a crosslinking compound represented by Formula 2 into a C1-C3 alcohol solvent; [Formula 1] In this case, R1 and R2 are each independently hydrogen or oxygen. Indicates a single or double bond, where l is 1 or 2, and m is an integer from 100 to 1000; [Equation 2] Where n is an integer from 3 to 7; (b) The mixed solution was sequentially heated and cooled to obtain cerium oxide nanoparticles; and (c) Wash the cerium oxide nanoparticles with an inorganic salt solution.

20. The method of claim 19, wherein the C1-C3 alcohol solvent is ethanol.

21. The method of claim 19, wherein the cerium precursor is one or more precursors selected from the group consisting of: cerium acetate hydrate (III), cerium acetylacetone hydrate (III), cerium carbonate hydrate (III), cerium fluoride (III), cerium chloride (III), cerium chloride heptahydrate (III), cerium bromide (III), cerium iodide (III), cerium nitrate hexahydrate (III), cerium oxalate hydrate (III), cerium sulfate (III), and cerium sulfate hydrate (III).

22. The method of claim 19, wherein the heating is performed at 60 to 80°C.

23. The method of claim 19, wherein the cooling is performed by reducing the temperature to 35 to 50°C.

24. The method of claim 19, wherein the inorganic salt is selected from the group consisting of NaCl, CaCl2, KCl, MgCl2, and combinations thereof.

25. The method of claim 19, wherein the inorganic salt solution is a NaCl solution.

26. The method of claim 25, wherein the concentration of the inorganic salt solution is 0.15 to 0.35 M.

Images