Complex pharmaceutical composition for treating cerebral diseases comprising cholinesterase inhibitor and antioxidant

Abstract

The present invention relates to a composite pharmaceutical composition for treating cerebral diseases, comprising a cholinesterase inhibitor and an antioxidant, and more specifically, to a composition for preventing or treating cerebral diseases, the composition comprises a cholinesterase inhibitor and an antioxidant, wherein the cholinesterase inhibitor and the antioxidant have a synergistic effect in the aspects of neuronal protection and neuronal differentiation promotion.

Description

[0001] This application is a divisional application of PCT / KR2021 / 015350, filed on October 28, 2021, entitled "Complex Pharmaceutical Composition for Treating Brain Diseases Containing Cholinesterase Inhibitor and Antioxidant". The application number of the PCT application after entering the Chinese national phase is 202180092279.9. Technical Field

[0002] This application claims priority to Korean Patent Application No. 10-2021-0012659, filed on January 28, 2021, the entire description of which is incorporated herein by reference.

[0003] This invention relates to a compound pharmaceutical composition comprising a cholinesterase inhibitor and an antioxidant for treating brain diseases, and more specifically to a composition for preventing or treating brain diseases, the composition comprising: a cholinesterase inhibitor exhibiting synergistic effects in neuronal protection and neuronal differentiation promotion, and an antioxidant. Background Technology

[0004] According to data released by the Korean Statistical Office in 2010, people aged 65 and over accounted for 11.4% of the total population in 2011, and this figure is projected to reach 37.4% by 2050, making South Korea a super-aged society. As aging has become a significant social issue in recent years, public interest in the characteristics of the elderly population and their welfare (including housing, health, culture, and leisure) has increased, leading to a growing demand for statistical data.

[0005] At the heart of this shift is the growing aging population, which makes chronic degenerative diseases a bigger problem than acute infectious diseases, which have been the leading cause of death over the past 50 years. Among chronic degenerative diseases, cerebrovascular disease is particularly significant, ranking second in single-cause mortality.

[0006] These cerebrovascular diseases can be divided into two main types. One is hemorrhagic brain disease caused by cerebral hemorrhage, and the other is ischemic brain disease caused by blockage of blood vessels in the brain. Hemorrhagic brain disease is most common in traffic accidents, while ischemic brain disease is more common in the elderly.

[0007] In transient ischemic attacks (TIAs), the brain's oxygen and glucose supply is cut off, leading to ATP depletion and edema in neurons, resulting in extensive brain damage. Neuronal death occurs a considerable period after the ischemic attack, known as delayed neuronal death. Delayed neuronal death has been reported in experiments using a transient forebrain ischemia model in Mongolian gerbils, where neuronal death was observed in the CA1 region of the hippocampus four days after induced 5 minutes of ischemia (Kirino T, Sano K. Acta Neuropathol., 62: 201-208, 1984; Kirino T. Brain Res., 239: 57-69, 1982).

[0008] There are two generally accepted mechanisms for neuronal death caused by cerebral ischemia. One is the excitatory neuronal death mechanism, in which cerebral ischemia leads to excessive extracellular glutamate accumulation, and this increased glutamate leads to neuronal death due to excessive intracellular calcium accumulation (Kang TC et al., J. Neurocytol., 30: 945-955, 2001). The other is oxidative neuronal death, which is caused by DNA and cytoplasmic damage due to the sudden oxygenation during ischemia-reperfusion, which leads to an increase in free radicals (Won MH et al., Brain Res., 836: 70-78, 1999; Sub AY., Chen YM., J. Biomed. Sci., 5: 401-414, 1998; Flowers F, Zimmerman JJ. New Horiz. 6: 169-180, 1998).

[0009] Based on these mechanistic studies, numerous research efforts have been conducted to identify substances that effectively inhibit neuronal death during cerebral ischemia or to elucidate their mechanisms. However, currently, very few substances are found that can effectively inhibit neuronal death caused by cerebral ischemia.

[0010] Tissue plasminogen activator (TPA) is the only FDA-approved treatment for cerebral ischemia to date. It is a thrombolytic agent, meaning it dissolves the blood clots causing cerebral ischemia, allowing for a faster supply of oxygen and glucose. Therefore, it does not directly protect neurons, so it needs to be used rapidly. And because it is a thrombolytic agent, excessive or frequent use can thin blood vessel walls, ultimately leading to hemorrhagic cerebrovascular disease. Furthermore, in the case of MK-801 (a calcium channel blocker that effectively inhibits early calcium ion influx), clinical trials were conducted, but were abandoned due to the drug's side effects. In Japan, Mitsubishi's edaravone, a synthetic antioxidant, has been used exclusively in Japan as the world's only treatment for severe gout due to successful clinical trials there, generating annual sales of 300 billion won. However, it is arguably still in use due to a lack of other drugs, despite concerns about side effects.

[0011] On the other hand, since cognitive impairments such as Alzheimer's disease primarily occur in people over 60 years of age, research into the pathogenesis of these diseases is essential, given South Korea's rapidly aging population, severe psychological distress, and the economic burden they place on patients, their families, society, and the nation. Furthermore, this research urgently requires the development of effective drugs that can prevent or improve these diseases; current medications can only alleviate symptoms or slow disease progression.

[0012] The causes of Alzheimer's disease can be divided into external and internal factors. External factors include age, genetic causes, and toxic substances caused by environmental influences. Internal factors include reduced neurotransmission due to decreased acetylcholine concentration, neuroinflammation due to cytokines, cytotoxicity due to β-amyloid aggregation and tau protein hyperphosphorylation, and neuronal death due to oxidative stress. Neuronal death has been identified as a fundamental pathology in many brain diseases, and the factors and molecular mechanisms that trigger cell death have been extensively studied. However, previously developed proteolytic enzymes and broad-spectrum apoptosis inhibitors have been hampered by side effects and reduced clinical efficacy. Summary of the Invention

[0013] Technical issues Therefore, the inventors conducted preliminary research on the clinically safe disclosed substances to develop a synergistic therapeutic combination for the treatment of ischemic brain diseases and neurodegenerative diseases, and found that the combination of donepezil and N-acetylcysteine ​​had significantly enhanced neuroprotective and differentiation-promoting effects compared with the use of each drug alone, and thus completed the present invention.

[0014] Therefore, the object of the present invention is to provide a pharmaceutical composition comprising a cholinesterase inhibitor and an antioxidant as active ingredients for the prevention or treatment of ischemic cerebral diseases.

[0015] Furthermore, the object of the present invention is to provide a pharmaceutical composition consisting of a cholinesterase inhibitor and an antioxidant for the prevention or treatment of ischemic brain diseases.

[0016] Furthermore, the object of the present invention is to provide a pharmaceutical composition consisting essentially of a cholinesterase inhibitor and an antioxidant for the prevention or treatment of ischemic brain diseases.

[0017] Another object of the present invention is to provide a pharmaceutical composition comprising a cholinesterase inhibitor and an antioxidant as active ingredients for the prevention or treatment of neurodegenerative diseases.

[0018] Furthermore, the object of the present invention is to provide a pharmaceutical composition consisting of a cholinesterase inhibitor and an antioxidant for the prevention or treatment of neurodegenerative diseases.

[0019] Furthermore, the object of the present invention is to provide a pharmaceutical composition consisting essentially of a cholinesterase inhibitor and an antioxidant for the prevention or treatment of neurodegenerative diseases.

[0020] Another object of the present invention is to provide a food composition containing cholinesterase inhibitors and antioxidants as active ingredients for the prevention or improvement of ischemic brain diseases.

[0021] Furthermore, the object of the present invention is to provide a food composition consisting of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of ischemic brain diseases.

[0022] Furthermore, the object of the present invention is to provide a food composition consisting essentially of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of ischemic brain diseases.

[0023] Another object of the present invention is to provide a food composition comprising cholinesterase inhibitors and antioxidants as active ingredients for the prevention or improvement of neurodegenerative diseases.

[0024] Furthermore, the object of the present invention is to provide a food composition consisting of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of neurodegenerative diseases.

[0025] Furthermore, the object of the present invention is to provide a food composition consisting essentially of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of neurodegenerative diseases.

[0026] Another object of the present invention is to provide a method for treating ischemic brain disease in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately or sequentially.

[0027] Another object of the present invention is to provide a method for treating neurodegenerative diseases in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately, or sequentially.

[0028] Another object of the present invention is to provide the use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for treating ischemic brain diseases.

[0029] Another object of the present invention is to provide a method for treating ischemic brain disease, the method comprising administering to a patient in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

[0030] Another object of the present invention is to provide the use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for treating neurodegenerative diseases.

[0031] Another object of the present invention is to provide a method for treating neurodegenerative diseases, the method comprising administering to an individual in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

[0032] Technical solution In order to achieve the above-mentioned objectives of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of ischemic cerebral diseases comprising a cholinesterase inhibitor and an antioxidant as active ingredients.

[0033] Furthermore, the present invention provides a pharmaceutical composition comprising a cholinesterase inhibitor and an antioxidant for the prevention or treatment of ischemic brain diseases.

[0034] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of ischemic brain diseases, which is essentially composed of a cholinesterase inhibitor and an antioxidant.

[0035] To achieve the above-mentioned objectives of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising a cholinesterase inhibitor and an antioxidant as active ingredients.

[0036] Furthermore, the present invention provides a pharmaceutical composition consisting of a cholinesterase inhibitor and an antioxidant for the prevention or treatment of neurodegenerative diseases.

[0037] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, which is essentially composed of a cholinesterase inhibitor and an antioxidant.

[0038] In order to achieve the above-mentioned objectives of the present invention, the present invention provides a food composition for preventing or improving ischemic cerebral diseases, comprising cholinesterase inhibitors and antioxidants as active ingredients.

[0039] Furthermore, the present invention provides a food composition consisting of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of ischemic brain diseases.

[0040] Furthermore, the present invention provides a food composition consisting essentially of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of ischemic brain diseases.

[0041] To achieve the above-mentioned objectives of the present invention, the present invention provides a food composition for preventing or improving neurodegenerative diseases, comprising cholinesterase inhibitors and antioxidants as active ingredients.

[0042] Furthermore, the present invention provides a food composition consisting of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of neurodegenerative diseases.

[0043] Furthermore, the present invention provides a food composition consisting essentially of a cholinesterase inhibitor and an antioxidant for the prevention or improvement of neurodegenerative diseases.

[0044] To achieve the above-mentioned objectives of the present invention, the present invention provides a method for treating ischemic brain diseases in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately or sequentially.

[0045] In order to achieve the above-mentioned objectives of the present invention, the present invention provides a method for treating neurodegenerative diseases in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately or sequentially.

[0046] To achieve the above-mentioned objectives of the present invention, the present invention provides the use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for treating ischemic brain diseases.

[0047] To achieve the above-mentioned objectives of the present invention, the present invention provides a method for treating ischemic brain diseases, the method comprising administering to an individual in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

[0048] To achieve the above-mentioned objectives of the present invention, the present invention provides the use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for treating neurodegenerative diseases.

[0049] To achieve the above-mentioned objectives of the present invention, the present invention provides a method for treating neurodegenerative diseases, the method comprising administering to an individual in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

[0050] The present invention will now be described in detail.

[0051] The present invention provides a pharmaceutical composition comprising a cholinesterase inhibitor and an antioxidant as active ingredients for the prevention or treatment of ischemic brain diseases.

[0052] The present invention provides a pharmaceutical composition comprising a cholinesterase inhibitor and an antioxidant as active ingredients for the prevention or treatment of neurodegenerative diseases.

[0053] In this invention, "cholinesterase inhibitor" refers to a compound that inhibits the enzymatic degradation of the neurotransmitter acetylcholine, thereby increasing the duration and level of acetylcholine's action in the synaptic cleft. Two enzymes are primarily responsible for the breakdown of acetylcholine: acetylcholinesterase and butyrylcholinesterase. "Cholinesterase inhibitor" includes substances that inhibit or reduce the action of one or both of these enzymes.

[0054] In the compositions and methods of the present invention, the cholinesterase inhibitor is considered pharmaceutically effective. As used herein, "pharmaceutically effective" means that the cholinesterase inhibitor is therapeutically useful to humans. Therefore, this term does not include cholinesterase inhibitors used as insecticides, such as aldicarb (2-methyl-2-(methylthio)propanal-O-(methylcarbamoyl)oxime), carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-methylcarbamate), and methylnaphthylcarbamate (1-naphthyl methylcarbamate), nor does it include cholinesterase inhibitors that are lethal to humans, such as sarin (2-(fluoro-methylphosphoryl)oxypropane), VX (S-[2-(diisopropylamino)ethyl]-O-ethylmethylthiophosphonate), and soman (3-(fluoro-methyl-phosphoryl)oxy-2,2-dimethyl-butane). Most cholinesterase inhibitors and pesticides are quasi-reversible or irreversible; most pharmaceutically effective cholinesterase inhibitors are reversible.

[0055] Pharmaceutically effective cholinesterase inhibitors are well known in the art. Examples include, but are not limited to, 7-methoxytacrine, avamirin, ambenonium, anseculin, arecoline, ceftazidime, citicoline, demacarium, donepezil, edrophonium, ethacrymine, fasciculin, hepta-physostigmine, huperzine A and its analogues, icopidate, ipilidacrine, linoptilolone, metrioxane, and mepiquat. Motrin, neostigmine, nomoostigmine, pyridostigmine, norpyridostigmine, tacrine, physostigmine, rivastigmine, subcomeline, suloacrine, tacrine analogs, tacrine, tasalidin, vesacrine, zenomelinine, zifrosilone, itopride, acotiamide, huperzine, galantamine, and their salts, and most preferably, the cholinesterase inhibitor may be donepezil.

[0056] Donepezil is an acetylcholinesterase (AChE) inhibitor with the structure shown in Formula 1, used to treat mild to moderate dementia in Alzheimer's disease. In Alzheimer's disease, cholinergic neurological disorders have been reported in the brain, and donepezil activates cholinergic neurons in the brain by increasing acetylcholine levels. Currently, donepezil is commercially available in tablet (pill) form and is administered orally to patients with Alzheimer's disease.

[0057] [Formula 1] .

[0058] As a pharmaceutically acceptable salt of donepezil, acid addition salts formed with pharmaceutically acceptable free acids are available. Acid addition salts are obtained from the following acids: inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid; and non-toxic organic acids, such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids. These pharmaceutically non-toxic salts that can be used include: sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprates, acrylates, formates, isobutyrate, caprate, heptanoates, propynate, oxalates, malonates, succinates, caprylates, sebate, fumarates, maleates, butyn-1,4-diacidate, and hexane- 1,6-Diosyl salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate, but not limited to these.

[0059] In this invention, an "antioxidant" is a substance that helps protect the human body from oxidative stress by removing reactive oxygen species produced in the body, and its types are well known in the art. For example, antioxidants may include N-acetylcysteine, ascorbic acid, alpha-lipoic acid, scopolamine, forsythoside, isoflavone, γ-oryzanol, trans-anisole, lipoic acid, cysteine, gallic acid, salvianolic acid, vitamin E, eugenol, L-selenomethionine, selenium, coenzyme Q10, vitamin A, catechins, daltro, etc., but are not limited to these. Preferably, it may be N-acetylcysteine, alpha-lipoic acid, daltron, or their salts. Most preferably, it may be N-acetylcysteine ​​or its salts.

[0060] N-acetylcysteine ​​is a drug with the structure of Formula 2 used to inhibit oxidative stress. Developed approximately 50 years ago, it was primarily used as an expectorant or to treat acetaminophen (an analgesic) poisoning. N-acetylcysteine ​​is known to exhibit antioxidant activity by directly reacting with peroxides, hydrogen peroxide, and hydroxyl radicals to reduce oxidative stress, or by indirectly promoting glutathione synthesis by providing cysteine ​​(a raw material for glutathione biosynthesis). For decades, N-acetylcysteine ​​has been widely used in various clinical fields, such as the treatment of acute respiratory distress syndrome, acute pulmonary oxygen toxicity, and the prevention of contrast-induced acute renal failure, and is considered a safe drug with no side effects.

[0061] [Equation 2] .

[0062] According to one embodiment of the present invention, it has been demonstrated that the combination drug comprising donepezil and N-acetylcysteine ​​has significantly better neuronal cell protection and differentiation promotion effects compared with the drugs alone.

[0063] Therefore, compared with using each drug alone, the composition of the present invention containing donepezil and N-acetylcysteine ​​can exhibit more improved effects at lower doses, thus having the advantage of reducing side effects and improving the therapeutic effect of brain diseases (i.e., synergistic effect).

[0064] The Bliss drug combination response C, consisting of two single compounds with effects A and B, is given by: C = A + B – A * B, where each effect is represented as a graded inhibition value from 0 to 1 (see Bliss (1939) Annals of Applied Biology). The Bliss value is defined as the difference between the experimental response and the calculated independent Bliss value, indicating whether the effects of the two combined components are additive or synergistic.

[0065] A Bliss value of zero (0) is considered additive. The term "additive" means that combining two types of target drugs results in the sum of the individual effects of each drug.

[0066] The term "synergistic effect" or "synergistic" is used to indicate that the response of a combination of two drugs is greater than the sum of the responses of the individual drugs. More specifically, in an in vitro setting, one measure of synergy is called "Bliss synergy." Bliss synergy refers to a "Bliss independence value" that exceeds the "Bliss independence value" determined by a previously defined Bliss value. A Bliss value greater than 0 is considered an indication of synergy. Of course, the concept of "synergy" used in this invention includes in vitro synergy measured by other and / or alternative methods.

[0067] In this invention, the fact that the combined biological effects (including, but not limited to, anti-inflammatory effects) of the cholinesterase inhibitor and antioxidant in vitro are greater than or equal to the sum of the individual components of the combination may be related to the Bliss value. Furthermore, the term "synergistic effect" as used herein includes cases where the combination of components exhibits activity equal to or greater than the sum of the individual components, which can be measured by other and / or alternative methods.

[0068] In one embodiment of the invention, the composition of the invention is used to treat brain diseases, wherein an effective amount of a cholinesterase inhibitor or a pharmaceutically effective salt, derivative or metabolite thereof may be combined with an effective amount of an antioxidant or a pharmaceutically effective salt thereof in an amount sufficient to achieve a synergistic effect.

[0069] In one embodiment of the invention, the cholinesterase inhibitor and the antioxidant can be combined in a molar ratio of 1:0.1 to 2000, preferably in a molar ratio of 1:1 to 1000, more preferably in a molar ratio of 1:50 to 500, even more preferably in a molar ratio of 1:100 to 400, and most preferably in a molar ratio of 1:100 to 350.

[0070] In this invention, ischemic brain disease is also referred to as cerebrovascular disease, and may include, but is not limited to, any pathological abnormality in the blood vessels supplying the brain caused by thrombosis, embolism, thickening of cerebral blood vessels, occlusion of cerebral blood vessels, etc. Non-limiting examples of ischemic brain disease may include stroke, cerebral hemorrhage, cerebral infarction, head trauma, cerebral circulatory and metabolic disorders, vascular dementia, and functional coma.

[0071] In this invention, neurodegenerative diseases may be selected from the following: Alzheimer's disease, Parkinson's disease, dementia, cognitive impairment, progressive supranuclear palsy, multiple system atrophy, olivary-pontine-cerebellar atrophy (OPCA), Shy-Drager syndrome, striatal substantia nigra degeneration, Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, corticobasal degeneration, diffuse Lewy body disease, Parkinson-ALS-dementia syndrome, Niemann-Pick disease, and Pick's disease, but are not limited to these.

[0072] Cognitive impairment, because it is closely related to aging, can include, but is not limited to, any disease in which the rapid, abnormal death of nerve cells occurs in parts of the nervous system or the entire brain, leading to loss of brain and spinal cord function and thus impairing cognitive ability, which differs from the normal aging process. Non-limiting examples of cognitive impairment may include mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, Lewy body disease, corticobasal degeneration, learning disabilities, agnosia, amnesia, aphasia, apraxia, and delirium.

[0073] "Prevention" refers to any action that reduces the frequency or severity of pathological phenomena. Prevention can be complete or partial. In this case, it may mean a reduction in the symptoms of an individual's cancer compared to not using the combination.

[0074] "Treatment" refers to any clinical intervention to alter the natural processes of a target or cell being treated, which can be performed or stopped as the clinical condition progresses.

[0075] Desired therapeutic effects may include preventing the onset or recurrence of the disease, relieving symptoms, reducing any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, alleviating or temporarily relieving the disease condition, or improving prognosis.

[0076] In the compositions of the present invention, donepezil and N-acetylcysteine ​​may be administered simultaneously, separately, or sequentially, and donepezil and N-acetylcysteine ​​may work together in vivo to exhibit preventive or therapeutic activity against brain diseases.

[0077] Typically, cholinesterase inhibitors and antioxidants are administered simultaneously as a combination. However, even when each active agent is administered to the body at staggered times, equivalent levels of therapeutic activity can be achieved by the simultaneous action of each active ingredient administered separately in the body.

[0078] Specifically, "simultaneous administration" means administering two active ingredients together via the same route of administration, or administering them separately via the same or different routes of administration, substantially simultaneously (e.g., with an interval of 15 minutes or less between two administrations). Separate administration means administering two active ingredients at certain time intervals (e.g., 3 days apart) via the same or different routes of administration. Sequential administration means administering two active ingredients via the same or different routes of administration according to certain rules as described above and below, depending on the patient's disease state.

[0079] The route of administration can be oral or parenteral. Parenteral administration may include, but is not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, percutaneous, subcutaneous, intrathecal, intraventricular (subventricular region), intracerebral, intraperitoneal, intranasal, intraintestinal, local, sublingual, or rectal administration.

[0080] The pharmaceutical compositions of the present invention may contain only pharmaceutically effective amounts of donepezil and N-acetylcysteine, or may further contain a pharmaceutically acceptable carrier. "Pharmaceutically effective amount" refers to an amount that produces a response greater than or equal to that of a negative control, preferably an amount sufficient to prolong life, improve motor function, inhibit neuroinflammation, inhibit neuronal cell death, or promote neuronal cell differentiation when the two active ingredients are co-administered in the treatment or prevention of brain diseases.

[0081] Depending on the route of administration, the pharmaceutical compositions of the present invention can be formulated in various ways with pharmaceutically acceptable carriers using methods known in the art to produce a synergistic effect of combined cholinesterase inhibitors and antioxidants. "Pharmaceutically acceptable" means a physiologically acceptable composition that is non-toxic when administered to humans, does not interfere with the action of the active ingredient, and generally does not cause gastrointestinal disturbances, allergic reactions (e.g., dizziness), or similar reactions. Carriers include all types of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads, and microbodies.

[0082] The pharmaceutically acceptable carriers contained in this composition are those commonly used in pharmaceutical formulations, including but not limited to lactose, dextrose, 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. Other pharmaceutically acceptable carriers are known in the art.

[0083] In addition to the components mentioned above, the pharmaceutical composition may also include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. Specifically, for oral administration, binders, active agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, or flavoring agents may be used; for injections, mixtures of buffers, preservatives, non-flowing agents, solubilizers, isotonic agents, stabilizers, etc., may be used; for topical administration, a matrix, excipients, lubricants, preservatives, etc., may be used.

[0084] Furthermore, the compositions of the present invention can be used in the form of conventional pharmaceutical formulations. Parenteral formulations include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions or lyophilized formulations, injections, transdermal formulations, nasal inhalers, etc., and for oral administration, they can be formulated as tablets, lozenges, capsules, elixirs, suspensions, syrups, or rice paper formulations. In the case of injections, they can be prepared as single-dose ampoules or multi-dose formulations. In the case of injections, they must be sterile and protected from contamination by microorganisms such as bacteria and fungi. Examples of suitable carriers for injections include, but are not limited to, solvents or dispersion media, including water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), mixtures thereof, and / or vegetable oils. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate-buffered saline (PBS) containing triethanolamine, or isotonic solutions, such as sterile water for injection, 10% ethanol, 40% propylene glycol, and 5% dextran. To protect injectables from microbial contamination, they may also contain various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In addition, in most cases, injectables may contain isotonic agents, such as sugar or sodium chloride.

[0085] Furthermore, the pharmaceutical compositions of the present invention can be administered via any device that allows the active substance to be transported to the target site. Preferred administration methods and formulations include intravenous, subcutaneous, intradermal, intramuscular, or infusion. Injectable formulations can be prepared using aqueous solvents (e.g., saline or intravenous solutions), non-aqueous solvents (e.g., vegetable oils, higher fatty acid esters (e.g., ethyl oleate), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, or glycerol), etc.), and contain a pharmaceutical carrier, such as a preservative stabilizer (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, BHA, tocopherol, EDTA, etc.), an emulsifier, a pH-adjusting buffer, and a preservative that inhibits microbial growth (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.). Methods of treating or preventing neurodegenerative diseases using the compositions of the present invention include administering an effective amount (pharmaceutical effective amount) of the therapeutic composition of the present invention to an individual in need. The pharmaceutically effective dose can be readily determined by those skilled in the art based on factors known in the medical field, such as disease type, patient age, weight, health status, sex, patient sensitivity to the drug, route of administration, method of administration, dose number, duration of treatment, and drugs used in combination or simultaneously.

[0086] Furthermore, the pharmaceutical compositions of the present invention can be formulated using methods known in the art to provide a rapid, sustained, or delayed release of the active ingredient upon administration to mammals.

[0087] The total effective amount of the composition of the present invention can be administered to the patient in a single dose or in multiple doses over a prolonged period. Depending on the severity of the disease, the pharmaceutical composition of the present invention may contain varying amounts of the active ingredient. A preferred total dose of the pharmaceutical composition of the present invention may be from about 0.01 μg to 10,000 mg per kilogram of patient body weight per day, most preferably from 0.1 μg to 500 mg. However, it should be noted that the effective dose of the pharmaceutical composition administered to the patient is determined not only by the method of formulation, route of administration, and number of treatments, but also by a variety of factors, including the patient's age, weight, health status, sex, severity of disease, diet, and excretion rate. Based on these considerations, those skilled in the art will be able to determine the appropriate effective dose of the composition of the present invention. There are no particular limitations on the formulation, route of administration, and method of administration of the pharmaceutical compositions of the present invention, as long as they exhibit the effects of the present invention.

[0088] Depending on the method and route of administration, the compositions of the present invention can be formulated such that donepezil and N-acetylcysteine ​​are simultaneously contained in one formulation, or each component can be formulated separately and contained in one package according to the dosage unit (e.g., daily or once daily). The dosage forms of the separately formulated donepezil and N-acetylcysteine ​​can be the same or different. Specific methods for formulating the pharmaceutical compositions of the present invention and pharmaceutically acceptable carriers that can be contained in such formulations are as described above regarding pharmaceutical compositions, and reference is made to those known in the art.

[0089] The present invention also provides a food composition comprising cholinesterase inhibitor and antioxidant as active ingredients for the prevention or improvement of ischemic cerebral diseases.

[0090] The present invention also provides a food composition comprising cholinesterase inhibitors and antioxidants as active ingredients for the prevention or improvement of neurodegenerative diseases.

[0091] The food compositions of the present invention include all forms of functional foods, nutritional supplements, health foods, and food additives.

[0092] Food compositions of the above types can be prepared in various forms according to conventional methods known in the art. For example, but not limited to, cholinesterase inhibitors and antioxidants can be liquefied, granulated, encapsulated, and powdered for consumption in the form of tea, juice, and beverages. Furthermore, donepezil and N-acetylcysteine ​​can be formulated into compositions by mixing them with active ingredients currently known to be effective against infectious diseases. In addition, cholinesterase inhibitors and antioxidants can be added to beverages (including alcoholic beverages), fruits and their processed products (e.g., canned, bottled, jams, marmalade, etc.), fish, meat and their processed products (e.g., ham, corned beef sausages, etc.), bread and noodles (e.g., udon noodles, soba noodles, ramen, pasta, macaroni, etc.), juices, various beverages, biscuits, malt, dairy products (e.g., butter, cheese, etc.), edible vegetable oils, margarine, vegetable proteins, cooked foods, frozen foods, various condiments (e.g., miso, soy sauce, seasoning sauces, etc.), etc., including but not limited to functional foods. Furthermore, cholinesterase inhibitors and antioxidants can be formulated as powders or concentrates for use as additives.

[0093] The preferred amounts of donepezil and N-acetylcysteine ​​in the food compositions of the present invention include, but are not limited to, 0.1 to 90% by weight of the final prepared food. More preferably, the food compositions of the present invention containing cholinesterase inhibitors and antioxidants as active ingredients can be prepared in the form of health functional foods or dietary supplements, particularly in combination with active ingredients known to be effective against infectious diseases.

[0094] The present invention also provides a method for treating ischemic brain disease in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately or sequentially.

[0095] The present invention also provides a method for treating neurodegenerative diseases in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately, or sequentially.

[0096] This invention provides the use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for the treatment of ischemic brain diseases.

[0097] The present invention provides a method for treating ischemic brain disease, the method comprising administering to an individual in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

[0098] This invention provides the use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for the treatment of neurodegenerative diseases.

[0099] The present invention provides a method for treating neurodegenerative diseases, the method comprising administering to an individual in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

[0100] The "effective amount" of this invention refers to the amount that, when applied to an individual, exhibits effects of improving, treating, preventing, detecting, diagnosing, or inhibiting or reducing ischemic brain diseases and neurodegenerative diseases. The "individual" can be an animal, preferably an animal, including mammals, particularly humans, and can be derived from animal cells, tissues, organs, etc. The individual can be a patient who requires the stated effects.

[0101] The term "treatment" in this invention refers comprehensively to improving the symptoms of ischemic brain diseases and neurodegenerative diseases, which may include curing, substantially preventing, or improving the condition of ischemic brain diseases and neurodegenerative diseases, and includes alleviating, curing, or preventing one or most symptoms caused by said diseases, but is not limited to these.

[0102] In this invention, the term "comprising" is used synonymously with "including" or "characterized in," and in a composition or method, other unmentioned component elements or method steps are not excluded. The term "consisting of" means excluding other elements, steps, or ingredients not otherwise specified. The term "consisting substantially of" means, within the scope of the composition or method, including the described component elements or steps, as well as component elements or steps that substantially do not affect its essential properties.

[0103] Beneficial effects Compared with single administration, the combination of cholinesterase inhibitors and antioxidants can exhibit enhanced preventive and therapeutic effects against ischemic brain diseases and neurodegenerative diseases, and has the effect of reducing side effects caused by overdose or prolonged use of each drug. Attached Figure Description

[0104] Figure 1 This study evaluates the reduction in reactive oxygen species (antioxidant effect) after treatment with donepezil alone, N-acetylcysteine ​​(NAC) alone, or donepezil + NAC combination (NDC-002) following oxidative stress in induced neural cells (SH-SY5Y).

[0105] Figure 2 The anti-inflammatory effect was evaluated by measuring the levels of interleukin-6 (IL-6) produced in microglia (BV2 cells) after treatment with donepezil or NAC alone or in combination with lipopolysaccharide (LPS) (an inflammatory response inducer).

[0106] Figure 3 The results measure the NO concentration produced in microglia after treatment with LPS following donepezil alone, NAC alone, or donepezil + NAC combination therapy.

[0107] Figure 4 The results of evaluating the anti-inflammatory effect of NAC-like drugs on microglia were obtained by measuring the amount of NO produced after treatment with LPS in combination with donepezil and antioxidant drugs.

[0108] Figure 5 The results of evaluating the cytotoxicity of NAC-like drugs on microglia were obtained by measuring the number of viable cells after LPS treatment with donepezil and antioxidant drugs in combination.

[0109] Figure 6 It measures the concentration of NO produced in microglia after LPS treatment with donepezil alone, antioxidant drugs alone, or donepezil plus antioxidant drugs in combination.

[0110] Figure 7 This study evaluates the expression levels of the motor neuron marker HB9 in neural progenitor cells (ReNcell VM) after treatment with donepezil alone, NAC alone, or a combination of donepezil and NAC.

[0111] Figure 8 The results of donepezil-like drugs were evaluated by measuring the expression level of the motor neuron marker HB9 and the number of viable cells after combined treatment with cholinesterase inhibitors and NAC in neural progenitor cells.

[0112] Figure 9 The results were evaluated by measuring the expression level of the motor neuron marker HB9 in neural progenitor cells after combined treatment with donepezil and antioxidant drugs to assess the differentiation-promoting effect of NAC-like drugs.

[0113] Figure 10 The cytotoxicity of NAC-like drugs is evaluated by measuring the number of viable cells in neural progenitor cells after combined treatment with donepezil and antioxidant drugs.

[0114] Figure 11 The results were obtained by measuring the expression differences of PSD-95 and pCREB, which are involved in the regulation of synaptic plasticity, in primary cultured neurons of mouse fetal brain after treatment with donepezil alone, NAC alone, or donepezil + NAC.

[0115] Figure 12 The results evaluated the motor function recovery effect of the combination compounds compared with the single compounds by the increase in recovery on days 1, 3, 7, 14, and 21 after donepezil alone, NAC alone, or donepezil + NAC combination therapy, 21 days after stroke-reperfusion animal model induction.

[0116] Figure 13 This is a quantitative result of the degree of brain injury after immediate treatment with donepezil alone, NAC alone, or donepezil + NAC 21 days after induction in a stroke-reperfusion animal model. Detailed Implementation

[0117] The present invention has been described in detail below through the embodiments described. However, the embodiments described below are intended to illustrate the invention, and the invention is not limited thereto.

[0118] Example 1: Antioxidant effect of donepezil + NAC combination drug In cerebrovascular diseases, ischemic stroke generates a large number of free radicals due to reduced blood flow to the ischemic area, leading to the accumulation of oxidative metabolites. These free radicals can cause oxidative stress, which can affect many organs, including brain cells. To minimize damage from free radicals, cells activate antioxidants and antioxidant enzymes to remove free radical intermediates and inhibit oxidative reactions to protect cells and the body.

[0119] In this invention, neuronal cells (SH-SY5Y) were treated with H2O2 to induce oxidative stress, and the production of reactive oxygen species (ROS) was measured after treatment with control, donepezil alone (5 μM), N-acetylcysteine ​​alone (NAC) (5 μM), and donepezil (2.5 μM) + NAC (2.5 μM).

[0120] As a result, Figure 1 As shown, ROS were significantly reduced in the combination therapy group compared to the control group, and the reduction rate was significantly higher in the combination therapy group compared to donepezil and NAC monotherapy groups, indicating that the combination therapy has a synergistic effect on antioxidant activity (**). P<0.01， **** P<0.0001, one-way ANOVA ).

[0121] Example 2: Anti-inflammatory effect of donepezil + NAC combination drug In this invention, microglia (BV2 cells) are treated with LPS to induce an inflammatory response, and the expression of nitric oxide (NO) or the inflammatory marker (IL-6) is measured after donepezil alone, NAC alone, or donepezil + NAC combination therapy to determine the neuroinflammatory relief effect of the drugs.

[0122] Microglia were treated with LPS to induce an inflammatory response, and the expression of the inflammatory marker IL-6 was measured after donepezil alone, NAC alone, or donepezil + NAC combination therapy. The anti-inflammatory effect of donepezil + NAC combination therapy was observed to be the most significant. Figure 2 As shown (****) P< 0.0001 (one-way ANOVA).

[0123] like Figure 3 As shown, the reduction in NO production after LPS treatment of microglia was quantified in donepezil alone, NAC alone, or donepezil + NAC combination therapy, confirming that the donepezil + NAC combination exhibited a significantly enhanced anti-inflammatory effect compared to the same concentration of single drug (*). P< 0.05, ** P <0.01, *** P <0.001, **** P <0.0001, one-way ANOVA).

[0124] To confirm whether the anti-inflammatory effect observed in the combination therapy of donepezil and NAC was also observed in the combination of donepezil, NAC and similar drugs, the anti-inflammatory effect was confirmed at concentrations at which no cytotoxicity was observed in the combination of donepezil, NAC and similar drugs by measuring the amount of NO produced and the number of viable cells in microglia treated with LPS after combination therapy with a combination of antioxidant drugs similar to donepezil (22 types) + NAC.

[0125] As a result, Figure 4 and 5 As shown, compared with the LPS-only group, donepezil plus antioxidant combination therapy also showed a significant reduction in NO, such as Figure 6As shown, donepezil plus an antioxidant combination therapy was demonstrated to be synergistic compared to single-drug therapy at the same concentration (*). P< 0.05, ** P <0.01, *** P <0.001, **** P <0.0001, one-way ANOVA).

[0126] Example 3: The neural progenitor cell differentiation effect of donepezil + NAC combination drug Donepezil alone, NAC alone, and a combination of donepezil and NAC were used to treat ReNcell VM (immortalized human neural progenitor cell line), which can differentiate into neurons and glial cells. Immunostaining was then performed using an antibody that selectively and specifically binds to motor neurons (anti-HB9 antibody). The number of motor neurons was then determined by analyzing the level of HB9 positive signal, and the degree of differentiation of neural progenitor cells into motor neurons was measured.

[0127] The results confirmed that the combination therapy group showed a synergistic effect in promoting neural progenitor cell differentiation compared with each individual substance treatment group, such as... Figure 7 As shown (*) P< 0.05, ** P <0.01, *** P <0.001, **** P <0.0001, one-way ANOVA).

[0128] To confirm whether neural progenitor cells have the ability to differentiate into motor neurons in combination therapy with acetylcholinesterase inhibitors other than donepezil plus NAC, and in combination therapy with donepezil plus antioxidants, neural progenitor cells were treated with acetylcholinesterase inhibitors similar to donepezil (8 types) plus NAC, or donepezil plus antioxidants similar to NAC (15 types). HB-9 levels and viable cell counts were measured, confirming the effect of similar drug combinations in promoting motor neuron cell differentiation and cytotoxicity.

[0129] As a result, Figure 8 As shown, compared with the control group, the combination therapy of eight donepezil-like drugs plus NAC showed a significantly increased promoting effect on differentiation into motor neurons. Furthermore, as... Figure 9 and Figure 10 As shown, compared with the control group, combination therapy with 15 donepezil + NAC-like drugs also demonstrated a significantly increased promoting effect on differentiation into motor neurons, as seen in combination therapy with donepezil + NAC (*). P< 0.05, ** P <0.01, *** P<0.001, **** P <0.0001, one-way ANOVA).

[0130] Example 4: Enhancement of synaptic plasticity by donepezil + NAC combination drug Donepezil alone, NAC alone, or donepezil + NAC combination therapy was used to treat primary neuronal cultures in mice, and the expression of synaptic plasticity biomarkers PSD-95 and pCREB was determined by Western blotting.

[0131] As a result, Figure 11 As shown, compared with the control group, the increase in PSD-95 expression and pCREB expression in the donepezil + NAC combination therapy group showed a synergistic trend, confirming the synaptic plasticity-enhancing effect of the donepezil + NAC combination drug (** P< 0.01 (one-way ANOVA).

[0132] For reference, there are type-specific biomarkers for identifying enhancements in cognitive and memory functions. These include neuroprotective effects through inhibiting neuronal cell death, suppressing β-amyloid formation and accumulation, inhibiting neuroinflammation, regulating neurotransmitter production, secretion and metabolism, and modulating synaptic plasticity.

[0133] The regulation of synaptic plasticity is an important cognitive effect that participates in signal transduction between neurons. Its biomarkers include postsynaptic compact protein-95 (PSD-95), CREB, and BDNF.

[0134] Postsynaptic density protein-95 (PSD-95) is an important family of functional molecules that form part of the postsynaptic density (PSD) and play a crucial role in inducing long-term potentiation (LTP). These proteins include NMDA receptors and CaMKII. By directly or indirectly binding to neuroligins, NMDA receptors, AMPA receptors, and potassium channels, they play a vital role in synaptic plasticity and the safety of synaptic changes during LTP (Ehrlich et al., PSD-95 is required for activity-driven synapse stabilization, PNAS 2007. / Nagura et al., Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 and PDZ2 ligand binding deficient PSD-95 knockin mice, Molecular Brain, 2012.).

[0135] On the other hand, cAMP response element binding protein (CREB) is a transcription factor that binds to promoter sites of various genes involved in memory and synaptic plasticity, and its activation is known to induce transcription of genes involved in memory formation and consolidation (e.g., BDNF) (Mizuno et al., CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behavioural Brain Research, 2002. / Kida et al., Functional roles of CREB as a positive regulator in the formation and enhanced of memory, Brain Research Bulletin, 2014).

[0136] Therefore, it can be concluded that donepezil + NAC combination therapy synergistically increases PSD-95 and pCREB expression, which will have a synergistic effect on improving cognition and memory.

[0137] Example 5: Demonstrating the synergistic effect of donepezil + NAC combination therapy compared to single-drug therapy in an in vivo experimental model. A stroke model was established using a Sprague-Dowley rat (SD rat) infarction-reperfusion model, and donepezil alone, NAC alone, and donepezil + NAC combination (NDC-002) were administered intravenously for 21 days immediately after the infarction-reperfusion model was established.

[0138] The representative test of motor coordination in an experimental animal model of stroke, namely the rotarod latency test, was used. Motor function of the animals was measured on days 1, 3, 7, 14 and 21 after donepezil monotherapy, NAC monotherapy and donepezil + NAC combination therapy. The recovery rate of motor function was analyzed relative to the results on day 1.

[0139] As a result, Figure 12 As shown, only the NDC-002 administration group exhibited a significant increase in recovery rate compared to the solvent administration group, indicating the therapeutic effect of the NDC-002 combination drug on motor function recovery. (**) P <0.01, one-way ANOVA).

[0140] Furthermore, compared with the groups treated with donepezil alone or NAC alone, the group treated with the donepezil + NAC combination drug showed a significant increase in the recovery rate of motor function, confirming the synergistic effect of the NDC-002 combination drug in the recovery of motor function. ### P< 0.001 (one-way ANOVA).

[0141] In a stroke-reperfusion model, donepezil alone, NAC alone, and donepezil + NAC combination drugs were administered immediately after the stroke. Following this, brain tissue was subjected to immunohistochemical staining using neuronal (NeuN) and microglia (GFAP) labeled antibodies and nuclear immunoassay (DAPI) to analyze the extent of brain injury. P< 0.05 (one-way ANOVA).

[0142] like Figure 13 As shown, only the NDC-002 combination drug administration group showed a significant reduction in the degree of brain injury compared to the solvent administration group.

[0143] Industrial applicability Compared with single administration, the composition of the present invention exhibits enhanced preventive and therapeutic effects on brain diseases by co-administering cholinesterase inhibitors and antioxidants, and reduces side effects caused by overdose or prolonged administration of each drug, thus having high industrial applicability.

[0144] Implementation plan: 1. A pharmaceutical composition for the prevention or treatment of ischemic brain diseases, comprising a cholinesterase inhibitor and an antioxidant as active ingredients.

[0145] 2. The pharmaceutical composition according to embodiment 1, wherein the ischemic brain disease is selected from the following: stroke, cerebral hemorrhage, cerebral infarction, head trauma, cerebral circulatory and metabolic disorders, vascular dementia, and functional coma.

[0146] 3. The pharmaceutical composition according to Embodiment 1, wherein the cholinesterase inhibitor is at least one substance selected from the following: 7-methoxytacrine, avamirin, ampicillin, aceclazine, arecoline, cevalmirin, citicoline, demeton-methylbromide, donepezil, phenoxychloride, istigmine, tubocurarine, heptyl-physostigmine, huperzine A and its analogues, icopiezil, ipilidacrine, linopyridine, metriphosphatidylcholine, miramarin, neostigmine, nomostigmine, pyridostigmine, norpyridostigmine, tacrine, physostigmine, rivastigmine, subcomeline, suloacrine, tacrine analogues, tacrine, tasalidin, veclosine, zanomilin, itopride, acotiamide, huperzine, galantamine, and zirosilone, or salts thereof.

[0147] 4. The pharmaceutical composition according to embodiment 1, wherein the antioxidant is at least one substance selected from the following: N-acetylcysteine, ascorbic acid, α-lipoic acid, scopolamine, forsythoside, isoflavone, γ-oryzanol, trans-anisole, lipoic acid, cysteine, gallic acid, salvianolic acid, vitamin E, eugenol, selenium, coenzyme Q10, vitamin A, catechin, daltron, and L-selenomethionine, or salts thereof.

[0148] 5. A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, comprising cholinesterase inhibitors and antioxidants as active ingredients.

[0149] 6. The pharmaceutical composition according to embodiment 5, wherein the neurodegenerative disease is selected from the following: Alzheimer's disease, Parkinson's disease, dementia, cognitive impairment, progressive supranuclear palsy, multiple system atrophy, olivary-pontine-cerebellar atrophy (OPCA), Shy-Drager syndrome, striatal substantia nigra degeneration, Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, corticobasal degeneration, diffuse Lewy body disease, Parkinson-ALS-dementia syndrome, Niemann-Pick disease, and Pick's disease.

[0150] 7. The pharmaceutical composition according to any one of embodiments 1 to 6, wherein the composition exhibits a neuronal differentiation promoting effect.

[0151] 8. The pharmaceutical composition according to any one of embodiments 1 to 6, wherein the cholinesterase inhibitor and the antioxidant are administered simultaneously, separately, or sequentially.

[0152] 9. A food composition for the prevention or improvement of ischemic cerebral diseases, comprising cholinesterase inhibitors and antioxidants as active ingredients.

[0153] 10. A food composition for the prevention or improvement of neurodegenerative diseases, comprising cholinesterase inhibitors and antioxidants as active ingredients.

[0154] 11. The food composition according to embodiment 9 or 10, wherein the food is a health functional food.

[0155] 12. A method for treating ischemic brain disease in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately, or sequentially.

[0156] 13. A method for treating neurodegenerative diseases in animals other than humans, the method comprising administering cholinesterase inhibitors and antioxidants simultaneously, separately, or sequentially.

[0157] 14. Use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for the treatment of ischemic brain diseases.

[0158] 15. A method for treating ischemic brain disease, the method comprising administering to an individual in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

[0159] 16. Use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for the treatment of neurodegenerative diseases.

[0160] 17. A method for treating neurodegenerative diseases, the method comprising administering to an individual in need an effective amount of a composition comprising a cholinesterase inhibitor and an antioxidant.

Claims

1. Use of cholinesterase inhibitors and antioxidants in the preparation of medicaments for the treatment of ischemic brain diseases.

2. The use according to claim 1, wherein the ischemic brain disease is selected from the following: cerebral hemorrhage, cerebral infarction, head trauma, cerebral circulatory and metabolic disorders, vascular dementia, and functional coma.

3. The use according to claim 1, wherein the cholinesterase inhibitor is at least one substance selected from the following: 7-methoxytacrine, avamirin, ampicillin, aceclazine, arecoline, cevalmirin, citicoline, demeton-methylbromide, donepezil, phenoxychloride, istigmine, tubocurarine, heptyl-physostigmine, huperzine A and its analogues, icopiezil, ipilidacrine, linopyridine, metriphosphatidylcholine, miramarin, neostigmine, nomostigmine, pyridostigmine, norpyridostigmine, tacrine, physostigmine, rivastigmine, subcomeline, sulfamethoxazole, tacrine analogues, tacrine, tasalidin, veclomethasone, zanomilin, itopride, acotiamide, huperzine, galantamine, and zirosilone, or salts thereof.

4. The use according to claim 1, wherein the antioxidant is at least one substance selected from the following: N-acetylcysteine, ascorbic acid, α-lipoic acid, scopolamine, forsythoside, isoflavone, γ-oryzanol, trans-anisole, lipoic acid, cysteine, gallic acid, salvianolic acid, vitamin E, eugenol, selenium, coenzyme Q10, vitamin A, catechin, daltron, and L-selenomethionine, or salts thereof.

5. The use according to any one of claims 1 to 4, wherein the drug exhibits a neuronal differentiation-promoting effect.

6. The use according to any one of claims 1 to 4, wherein the cholinesterase inhibitor and the antioxidant are applied simultaneously, separately, or sequentially.

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