WO2023121011A1 - Composition pharmaceutique complexe destinée au traitement d'une maladie du cerveau contenant de l'apigénine et un antioxydant - Google Patents
Composition pharmaceutique complexe destinée au traitement d'une maladie du cerveau contenant de l'apigénine et un antioxydant Download PDFInfo
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- WO2023121011A1 WO2023121011A1 PCT/KR2022/018558 KR2022018558W WO2023121011A1 WO 2023121011 A1 WO2023121011 A1 WO 2023121011A1 KR 2022018558 W KR2022018558 W KR 2022018558W WO 2023121011 A1 WO2023121011 A1 WO 2023121011A1
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- Prior art keywords
- apigenin
- pharmaceutically acceptable
- acceptable salt
- antioxidant
- disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composite composition for treating brain diseases containing an antioxidant, and more particularly, to prevention or treatment of brain diseases including apigenin and an antioxidant that exhibit synergistic effects in protecting/promoting differentiation of neurons and alleviating neuroinflammation. It relates to a composite composition for
- Cerebrovascular disease can be classified into two types. One is a hemorrhagic brain disease seen in cerebral hemorrhage, etc., and the other is an ischemic brain disease caused by occlusion of cerebral blood vessels. BACKGROUND OF THE INVENTION Hemorrhagic encephalopathy is mainly caused by a traffic accident, and ischemic encephalopathy is a disease that often appears in the elderly.
- cerebral ischemia causes excessive glutamate to accumulate outside cells, and this increased glutamate causes excessive intracellular calcium accumulation to induce neuronal cell death (Kang TC, et al., J. Neurocytol., 30: 945-955, 2001), and the other is oxidative neuronal cell death, which is caused by damage to DNA and cytoplasm due to an increase in radicals in vivo due to sudden oxygen supply during ischemia-reperfusion (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).
- microglia an immune cell present in the central nervous system, can be activated by various exogenous and endogenous substances, and activated microglia are inflammatory cytokines TNF- ⁇ and IL-1 ⁇ , nitric oxide, prostaglandin, and superoxide.
- activated microglia are inflammatory cytokines TNF- ⁇ and IL-1 ⁇ , nitric oxide, prostaglandin, and superoxide.
- microglial cells are related to various degenerative neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfelt-Jakob disease (CJD), and multiple sclerosis.
- the present inventors have conducted intensive research to develop a therapeutic combination that exhibits a synergistic effect in the treatment of ischemic brain disease and neurodegenerative disease among known substances whose safety has been confirmed clinically.
- the present invention was completed after discovering that it exhibits remarkably improved neuronal cell protection and differentiation promoting effects compared to the drug alone.
- an object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; And to provide a pharmaceutical composition for preventing or treating ischemic brain disease comprising an antioxidant as an active ingredient.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; And to provide a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising an antioxidant as an active ingredient.
- another object of the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And to provide a pharmaceutical composition for preventing or treating neurodegenerative diseases consisting of antioxidants.
- another object of the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And to provide a pharmaceutical composition for preventing or treating neurodegenerative diseases consisting essentially of antioxidants.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; And to provide a food composition for preventing or improving ischemic brain disease comprising an antioxidant as an active ingredient.
- another object of the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And to provide a food composition for preventing or improving ischemic brain disease consisting of antioxidants.
- another object of the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And to provide a food composition for preventing or improving ischemic brain disease consisting essentially of antioxidants.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; And to provide a food composition for preventing or improving neurodegenerative diseases comprising an antioxidant as an active ingredient.
- another object of the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And to provide a food composition for preventing or improving neurodegenerative diseases consisting of antioxidants.
- another object of the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And to provide a food composition for preventing or improving neurodegenerative diseases consisting essentially of antioxidants.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; and simultaneously (simultaneously), separately (separate) or sequentially (sequentially) administration, to provide a method for treating ischemic brain disease in animals other than humans.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; and simultaneously (simultaneously), separately (separate) or sequentially (sequential) administration, to provide a method for treating neurodegenerative diseases of animals other than humans.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof for preparing a composition for treating ischemic brain disease; and uses of antioxidants.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; And to provide an ischemic brain disease treatment method comprising administering an effective amount of a composition containing an antioxidant as an active ingredient to a subject in need thereof.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof for preparing a composition for treating neurodegenerative diseases; and uses of antioxidants.
- Another object of the present invention is apigenin or a pharmaceutically acceptable salt thereof; And to provide a method for treating neurodegenerative diseases comprising administering an effective amount of a composition containing an antioxidant as an active ingredient to a subject in need thereof.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating ischemic brain disease comprising an antioxidant as an active ingredient.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating ischemic brain disease consisting of an antioxidant.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating ischemic brain disease consisting essentially of an antioxidant.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising an antioxidant as an active ingredient.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating neurodegenerative diseases consisting of antioxidants.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating neurodegenerative diseases consisting essentially of antioxidants.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving ischemic brain disease comprising an antioxidant as an active ingredient.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving ischemic brain disease consisting of antioxidants.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving ischemic brain disease consisting essentially of an antioxidant.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving neurodegenerative diseases comprising an antioxidant as an active ingredient.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving neurodegenerative diseases consisting of antioxidants.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving neurodegenerative diseases consisting essentially of antioxidants.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; and simultaneously (simultaneously), separately (separate) or sequentially (sequentially) administering, it provides a method for treating ischemic brain disease in animals other than humans.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; and simultaneously (simultaneously), separately (separate) or sequentially (sequential) administration, providing a method for treating neurodegenerative diseases of animals other than humans.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof for preparing a composition for the treatment of ischemic brain disease; and uses of antioxidants.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And it provides a method for treating ischemic brain disease comprising administering an effective amount of a composition containing an antioxidant as an active ingredient to a subject in need thereof.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof for preparing a composition for the treatment of neurodegenerative diseases; and uses of antioxidants.
- the present invention is apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And it provides a method for treating neurodegenerative diseases comprising administering an effective amount of a composition containing an antioxidant as an active ingredient to a subject in need thereof.
- composition refers to a mixture of at least one compound useful within the present invention with a pharmaceutically acceptable carrier.
- a pharmaceutical composition facilitates administration of the compound to a patient or subject.
- a variety of techniques exist in the art for administering compounds including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary and topical administration.
- the terms "combination therapy” or “in combination” refer to the administration of two or more therapeutic agents to treat the conditions or disorders described herein (ie, ischemic brain disease or neurodegenerative disease). do.
- Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed proportion of the active ingredients.
- Such administration includes co-administration in multiple or separate containers (eg, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the desired dosage prior to administration.
- such administration includes sequential use of each type of therapeutic agent at about the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in the treatment of the conditions or disorders described herein.
- Combination therapy can provide a "synergistic effect" and can prove to be “synergistic.” That is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using the compounds individually.
- a synergistic effect occurs when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form; (2) when delivered alternately or in parallel as separate dosage forms; or (3) when delivered by some other initiative.
- a synergistic effect can be obtained when the compounds are administered or delivered sequentially, eg by different injections in separate syringes.
- effective doses of each active ingredient are administered sequentially, i.e.
- Synergistic effect refers to the action of two therapeutic agents to produce an effect greater than the simple sum of the effects of each drug administered alone. Synergistic effects are described, for example, by the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the Loewe additive equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)), and the median effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul.
- the present invention relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating ischemic brain disease comprising an antioxidant as an active ingredient.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising an antioxidant as an active ingredient.
- apigenin is a flavonoid having a structure represented by Chemical Formula 1 below and contained in various fruits and vegetables, and has an antioxidant function related to skin aging, diseases of the digestive system including gastrointestinal diseases, and inflammation. , it has been reported to have an effect on hypertension.
- apigenin is a metabolite having a function of suppressing the expression of cancer cells by inducing cell death (apoptosis) or inhibiting angiogenesis.
- apigenin exhibits antioxidant activity and antiviral activity. In particular, it increases the antiviral activity of acyclovir, an antiviral agent used for the treatment of herpes infection, and prevents immunodeficiency virus (HIV-1). It is known to act to prevent activation.
- the term "pharmaceutically acceptable” means that it does not interfere with the biological activity or properties of a compound and is relatively non-toxic, that is, a substance has an undesirable biological effect or any component of a composition it contains. Refers to a substance, such as a carrier or diluent, that can be administered to an individual without interacting in a detrimental way with the component.
- the term "pharmaceutically acceptable salt” refers to a salt of a compound to be administered prepared from non-toxic acids including pharmaceutically acceptable inorganic acids, organic acids, solvates, hydrates or clathrates thereof. indicate As the pharmaceutically acceptable salt of apigenin, an acid addition salt formed from a pharmaceutically acceptable free acid may be useful. Acid addition salts are formed with inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedios.
- non-toxic organic acids such as oxalates, aromatic acids, aliphatic and aromatic sulfonic acids.
- These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulphate, sulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Toxybenzo
- the 'antioxidant' is a substance that helps protect the human body from oxidative stress by removing active oxygen generated in the body, and its type is well known in the art.
- the antioxidant is N-acetylcysteine, ascorbic acid, alpha-lipoic acid, scopoletin, forsythin, isoferul Isoferulic acid, gamma-oryzanol, trans-anethol, thioctic acid, cysteamine, gallic acid, salvianolic acid ( salvianolic acid), vitamin E, rappaconitine, L-selenomethionine, selenium, coenzyme Q10, vitamin A, catechin, daltro, etc. , but not limited thereto, preferably N-acetylcysteine, alpha-lipoic acid, daltron or a salt thereof, and most preferably N-acetylcysteine or a salt thereof.
- N-acetylcysteine was developed about 50 years ago and is mainly used as an expectorant or used for the treatment of addiction to acetaminophen, an analgesic, and is a drug for inhibiting oxidative stress having the structure of Formula 2 below.
- N-acetylcysteine reduces oxidative stress by directly reacting with peroxide, hydrogen peroxide, hydroxyl radical, etc., or indirectly increases glutathione synthesis by providing cysteine, a raw material for glutathione biosynthesis. ⁇ ) It is known to show an oxidizing effect.
- N-acetylcysteine has been used for decades in various clinical fields such as treatment of acute respiratory distress syndrome, treatment of acute pulmonary oxygen toxicity, and prevention of acute renal failure by contrast agents, and is known as a safe drug that does not cause side effects.
- the combination preparation containing apigenin and N-acetylcysteine had remarkably excellent effects of protecting nerve cells, alleviating neuroinflammation, and promoting nerve cell differentiation compared to each single substance.
- the same effect was confirmed to have a synergistic effect compared to each single substance.
- composition of the present invention containing apigenin and N-acetylcysteine can exhibit more improved effects with a lower dose compared to using each drug alone, side effects are reduced and the treatment effect of brain diseases is improved. There is an advantage of being, that is, a synergic effect.
- the Bliss value defined as the difference between the experimental response and the calculated independent Bliss value, indicates whether the effect of the two components in combination is additive or synergistic.
- a bliss value of zero (0) is considered additive.
- additive means that the result of combining two types of target agents is the sum of each of the individual drugs.
- the term “synergy” or “synergistic” is used to mean that the response of the combination of the two agents is greater than the sum of the responses of the individual agents. More particularly, in an in vitro setting, one measure of synergism is known as “Bliss synergy”. The Bliss synergistic effect means "exceeding the Bliss independent value” determined by the previously defined Bliss value. If the bliss value is greater than zero, it is considered an indicator of synergy. Of course, the concept of “synergy” as used in the present invention includes in vitro synergy measured by additive and/or alternative methods.
- the fact that the biological effect of the combination of apigenin and antioxidants in vitro is greater than or equal to the sum of the individual components of the combination can be correlated with the Bliss value.
- “synergy” which includes cases where a combination of components exhibits an activity equal to or greater than the sum of the individual components, as used herein, can be measured by additional and/or alternative methods.
- the composition of the present invention is for treating brain diseases, and contains an effective amount of apigenin or a pharmaceutically effective salt, derivative or metabolite thereof, an effective amount of an antioxidant or a pharmaceutically effective amount thereof.
- the salt can be combined in an amount sufficient to achieve a synergistic effect.
- apigenin and antioxidants may be combined in a molar ratio of 1:0.1 to 100, preferably in a molar ratio of 1:0.1 to 50, more preferably in a molar ratio of 1:0.1 to 10, and more More preferably, they may be combined at a molar ratio of 1:0.1 to 5, and most preferably at a molar ratio of 1:0.3 to 5.
- the ischemic brain disease is also called cerebrovascular disease, and any pathological abnormality in the blood vessels supplying blood to the brain due to thrombosis, embolism, cerebrovascular thickening, cerebrovascular occlusion, etc. may be included without limitation.
- Non-limiting examples of the ischemic brain disease may include stroke, cerebral hemorrhage, cerebral infarction, head trauma, cerebral circulatory metabolic disorder, vascular dementia, and cerebral functional coma.
- the degenerative neurological diseases include Alzheimer's disease, Parkinson's disease, dementia, cognitive dysfunction, progressive supranuclear palsy, multiple system atrophy, olive-pons-cerebellar atrophy (OPCA), Shy-Drager syndrome, striatal-substantia nigra degeneration It may be selected from the group consisting of dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, cortico-basal ganglia degeneration, diffuse Lewy body disease, Parkinson's-ALS-dementia complex, Niemann-Pick's disease and Pick's disease, It is not limited thereto, and may preferably mean a neurodegenerative disease caused by neuroinflammation.
- ALS amyotrophic lateral sclerosis
- ALS amyotrophic lateral sclerosis
- cortico-basal ganglia degeneration diffuse Lewy body disease
- Parkinson's-ALS-dementia complex Niemann-Pick's disease and Pick's disease
- the cognitive dysfunction is a disease in which the death of abnormal nerve cells in a part of the nervous system or the entire brain rapidly occurs, unlike the normal aging process, and the function of the brain and spinal cord is lost, resulting in a decrease in cognitive ability while being deeply related to aging.
- Non-limiting examples of the cognitive dysfunction include mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, Lewy body disease, cortico-basal ganglia degeneration, learning disabilities, agnosia, amnesia, aphasia, apraxia and delirium.
- the '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 phenomenon in which the symptoms of carcinogenesis in the subject are reduced compared to the case where the composition is not used.
- the 'treatment' means any action that clinically intervenes to change the natural process of a target or cell to be treated, and can be performed while a clinical pathology is progressing or to prevent it.
- the desired therapeutic effect is to prevent the onset or recurrence of the disease, alleviate the symptoms, reduce any direct or indirect pathological consequences of the disease, slow the rate of disease progression, alleviate or temporarily relieve the disease state. alleviating or improving the prognosis.
- the apigenin and N-acetylcysteine may be administered simultaneously, separately, or sequentially, and the apigenin and N-acetylcysteine act synergistically in the body to the brain. It may exhibit disease preventive or therapeutic activity.
- the apigenin (apigenin) or a pharmaceutically acceptable salt thereof; And antioxidants will generally be administered simultaneously as a composition, but even if each active ingredient is administered to the human body with a time difference, an equivalent level of therapeutic activity can be achieved by acting simultaneously in the body as each individually administered active ingredient.
- 'simultaneous administration means administration of the two active ingredients through the same route of administration, or administration through the same or different routes of administration at substantially the same time (for example, 15 minutes or less between administration times). it means to do
- the individual administration means administration of the two active ingredients through the same or different administration routes at a predetermined time interval (eg, 3 days apart).
- the sequential means that the two active ingredients are administered through the same or different administration routes according to the patient's disease state with a certain ordering rule.
- Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraneural, intraventricular (subventricular area), intracerebrovascular, intraperitoneal It can be intranasal, intranasal, enteral, topical, sublingual or rectal administration.
- the pharmaceutical composition according to the present invention may contain only pharmaceutically effective amounts of apigenin and N-acetylcysteine, or may additionally contain a pharmaceutically acceptable carrier.
- the 'pharmaceutically effective amount' refers to an amount that exhibits a higher response than that of the negative control group, and preferably increases lifespan, improves motility, and suppresses neuroinflammation by administering the two active ingredients in combination in the treatment or prevention of brain diseases. , It means an amount sufficient to exhibit the effect of inhibiting neuronal cell death and promoting neuronal differentiation.
- the term "pharmaceutically acceptable carrier” refers to a liquid or solid filler, stabilizer, A pharmaceutically acceptable substance, composition or carrier such as a dispersing agent, suspending agent, diluent, additive, thickening agent, solvent or encapsulating material. Typically, these components are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formula, including compounds useful within the present invention, and not injurious to the patient.
- materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose used in pharmaceutical formulations; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; Surfactants; alginic acid; pyrogen-free water; isotonic solution; Ringer's solution; ethyl alcohol; phosphat
- pharmaceutically acceptable carrier is compatible with the activity of compounds useful within the present invention, and is physiologically acceptable to patients in part or in whole coating agent, antiviral and antibacterial agent, and absorption delaying agent. Include etc. Supplementary active compounds may also be incorporated into the compositions. Further “pharmaceutically acceptable carriers” may further include pharmaceutically acceptable salts of compounds useful within the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of this invention are known in the art.
- the pharmaceutical composition of the present invention may include apigenin or a pharmaceutically acceptable salt thereof; And antioxidants can be formulated in various ways according to the route of administration by a method known in the art, together with a pharmaceutically acceptable carrier to exhibit a synergistic effect according to the combined use.
- 'Pharmaceutically acceptable' refers to a non-toxic composition that is physiologically acceptable, does not inhibit the action of active ingredients when administered to humans, and does not usually cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions.
- Such carriers include all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and microsomes.
- compositions include those commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like, but are not limited thereto.
- pharmaceutically acceptable carriers reference may be made to those known in the art.
- the pharmaceutical composition may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
- a lubricant for oral administration, binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colors or flavors, etc. may be used.
- buffers, preservatives, pain relievers, solubilizers , isotonic agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, bases, excipients, lubricants, preservatives, etc. may be used.
- composition of the present invention can be used in the form of general pharmaceutical preparations.
- Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions or freeze-dried preparations, injections, transdermal preparations, nasal inhalations, etc.
- parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions or freeze-dried preparations, injections, transdermal preparations, nasal inhalations, etc.
- oral administration tablets, troches, capsules, elixirs, suspensions, syrups or wafers, etc.
- It can be manufactured in the form of
- In the case of an injection it can be prepared in a unit dosage ampoule or multiple dosage form. In the case of the injection, it must be sterilized and must be protected from contamination by microorganisms such as bacteria and fungi.
- suitable carriers for injections include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), mixtures thereof, and/or solvents or dispersion media containing vegetable oils.
- suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc. can be used.
- PBS phosphate buffered saline
- the injection may further include an isotonic agent such as sugar or sodium chloride.
- the pharmaceutical composition of the present invention can be administered by any device capable of moving an active substance to a target site.
- Preferred modes of administration and preparations are intravenous, subcutaneous, intradermal, intramuscular, or intravenous infusions.
- Injections include aqueous solvents such as physiological saline or IV, vegetable oils, higher fatty acid esters (eg, ethyl oleate, etc.), non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, or glycerin).
- Stabilizers for preventing deterioration eg, ascorbic acid, sodium hydrogensulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
- emulsifiers eg., ascorbic acid, sodium hydrogensulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
- emulsifiers eg., buffers for pH control, and antimicrobial growth
- Preservatives eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.
- a method of treating or preventing neurodegenerative diseases using the composition of the present invention includes administering an effective amount (pharmaceutically effective amount) of the composition for treatment of the present invention to a subject in need thereof.
- the pharmaceutically effective amount is well known in the medical field, such as the type of disease, the patient's age, weight, health, sex, the patient's sensitivity to drugs, the route of administration, the method of administration, the number of times of administration, the duration of treatment, drugs used in combination or concurrently, and the like. Depending on the factors, it can be easily determined by a person skilled in the art.
- composition of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
- the total effective amount of the composition of the present invention can be administered to the patient in a single dose or by a fractionated treatment protocol in which multiple doses are administered over a long period of time.
- the pharmaceutical composition of the present invention may vary the content of the active ingredient according to the severity of the disease.
- the preferred total dose of the pharmaceutical composition of the present invention may be about 0.01 ⁇ g to 10,000 mg, most preferably 0.1 ⁇ g to 500 mg per kg of patient body weight per day.
- the dose of the pharmaceutical composition is determined by considering various factors such as the formulation method, administration route, and number of treatments as well as the patient's age, weight, health condition, sex, severity of disease, diet, and excretion rate. Therefore, considering this point, those skilled in the art will be able to determine an appropriate effective dosage of the composition of the present invention.
- the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as it exhibits the effects of the present invention.
- the composition of the present invention may be formulated so that apigenin and antioxidants, which are components, are simultaneously included in one formulation, or each component is individually formulated and administered daily or once. Depending on the dosage unit, it may be included in one package. Formulations of individually formulated apigenin and antioxidants may or may not be the same.
- the specific formulation method of the pharmaceutical composition of the present invention and the pharmaceutically acceptable carrier that may be included in the formulation are as described above in the pharmaceutical composition and are known in the art.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving ischemic brain disease comprising an antioxidant as an active ingredient.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a food composition for preventing or improving neurodegenerative diseases comprising an antioxidant as an active ingredient.
- the food composition of the present invention includes all forms such as functional food, nutritional supplement, health food and food additives.
- Food compositions of this type can be prepared in various forms according to conventional methods known in the art. For example, but not limited thereto, as a health food, apigenin or a pharmaceutically acceptable salt thereof; And antioxidants can be ingested by preparing them in the form of tea, juice, and drink, liquefied, granulated, encapsulated, and powdered so that they can be consumed. In addition, it can be prepared in the form of a composition by mixing apigenin and antioxidants with known active ingredients known to be effective against infectious diseases.
- functional foods include, but are not limited to, beverages (including alcoholic beverages), fruits and their processed foods (e.g., canned fruits, bottled products, jams, marmalades, etc.), fish, meat, and their processed foods (e.g., ham, sausages). Corned beef, etc.), bread and noodles (e.g. udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, taffy, dairy products (e.g. butter, cheese, etc.), edible vegetable oil, margarine, vegetable apigenin or a pharmaceutically acceptable salt thereof; And it can be prepared by adding an antioxidant. In addition, apigenin or a pharmaceutically acceptable salt thereof; And in order to use the antioxidant in the form of an additive, it can be prepared and used in the form of a powder or concentrate.
- beverages including alcoholic beverages
- fruits and their processed foods e.g., canned fruits, bottled products, jams, marmalades, etc.
- Preferred contents of apigenin and antioxidants in the food composition of the present invention are not limited thereto, but are preferably 0.1 to 90% by weight of the finally prepared food. More preferably, apigenin of the present invention or a pharmaceutically acceptable salt thereof; And a food composition containing an antioxidant as an active ingredient may be prepared in the form of a health functional food or dietary supplement by mixing with an active ingredient known to be effective against infectious diseases.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof; and simultaneously (simultaneously), separately (separate) or sequentially (sequentially) administering, it provides a method for treating ischemic brain disease in animals other than humans.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof; and simultaneously (simultaneously), separately (separate) or sequentially (sequential) administration, providing a method for treating neurodegenerative diseases in animals other than humans.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof for preparing a composition for treating ischemic brain disease; and uses of antioxidants.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a method for treating ischemic brain disease comprising administering an effective amount of a composition containing an antioxidant as an active ingredient to a subject in need thereof.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof for preparing a composition for treating neurodegenerative diseases; and uses of antioxidants.
- the present invention also relates to apigenin or a pharmaceutically acceptable salt thereof; And it provides a method for treating neurodegenerative diseases comprising administering an effective amount of a composition containing an antioxidant as an active ingredient to a subject in need thereof.
- the 'effective amount' of the present invention refers to an amount that exhibits an effect of improving, treating, detecting, diagnosing, or inhibiting or reducing ischemic brain disease or neurodegenerative disease when administered to a subject, and the 'subject' refers to an animal, It may preferably be a mammal, especially an animal including a human, and may also be a cell, tissue, or organ derived from an animal. The subject may be a patient in need of the effect.
- the 'treatment' of the present invention comprehensively refers to ischemic brain disease or neurodegenerative disease or improving symptoms caused by the disease, which may include curing, substantially preventing, or improving the condition of the disease. It may alleviate, cure or prevent one or most of the symptoms resulting from the disease, but is not limited thereto.
- the term “comprising” is used in the same meaning as “including” or “characterized by”, and in the composition or method according to the present invention, specifically mentioned It does not exclude additional components or method steps not specified. Also, the term “consisting of” means excluding additional elements, steps or components not separately described. The term “essentially consisting of” means that in the scope of a composition or method, in addition to the described materials or steps, materials or steps that do not substantially affect the basic characteristics thereof may be included.
- composition according to the present invention may include apigenin or a pharmaceutically acceptable salt thereof; And antioxidants can exhibit increased preventive and therapeutic effects of ischemic brain disease and neurodegenerative diseases compared to single administration, and can reduce side effects that can be caused by excessive or long-term administration of each drug. It works.
- NAC N-acetylcysteine
- N-001 N-acetylcysteine
- LPS lipopolysaccharide
- Figure 2 measures the level of IL-6 (Interleukin-6) generated after apigenin alone, NAC alone or a combination thereof (NDC-001) together with LPS, an inflammatory response-inducing substance, in microglia to measure anti-neuro-inflammation This is the result of evaluating the effect.
- IL-6 Interleukin-6
- Figure 3 shows that after culturing neural precursor cells (ReNcell VM) with apigenin alone, NAC alone, or a combination thereof (NDC-001), the expression level of HB9, a motor neuron marker, was evaluated to evaluate the differentiation promoting effect of the drug. This is the result.
- Figure 4 shows the expression of Tuj-1, a neuronal differentiation marker, in cerebral cortical tissue after intravenous administration of apigenin alone, NAC alone, or apigenin + NAC combination (NDC-001) immediately after induction of a stroke-reperfusion animal model for 21 days. It is the result of measuring the quantity.
- Figure 5 shows the expression level of Caspase 3, a marker of apoptosis around the cerebral infarct, after intravenous administration of apigenin alone, NAC alone, or apigenin + NAC complex (NDC-001) immediately after induction of stroke-reperfusion animal model for 21 days is the result of measuring
- Figure 7 shows the intravenous administration of apigenin alone, NAC alone, or apigenin + NAC combination (NDC-001) immediately after induction of a stroke-reperfusion animal model for 21 days, on days 1, 3, 7, and 14 after induction of stroke. This is the result of performing the Rotarod latency test.
- microglia BV2 cells
- LPS liquid phase protein
- NO nitrogen monoxide
- NAC apigenin + NAC combined treatment
- IL-6 an inflammatory marker
- ReNcell VM (immortalized human neural progenitor cell line), a neural progenitor cell capable of differentiating into neurons and glial cells, was treated with apigenin alone, NAC alone, or apigenin + NAC complex treatment (NDC-001). Immunostaining was performed using an antibody (anti-HB9 antibody) capable of selectively binding to motor neurons. Thereafter, by analyzing the number of HB9 positive signals and confirming the number of motor neurons, the degree of differentiation of neural precursor cells into motor neurons was measured.
- Example 3 Apigenin + NAC complex promotes neuronal differentiation ( in vivo )
- a stroke model was constructed using a cerebral infarction-reperfusion model using Sprague-Dawley rats (SD rats), and apigenin alone, NAC alone, and apigenin + NAC combination (NDC- 001) was administered IV for 21 days immediately after induction of cerebral infarction-reperfusion injury, and the experiment was conducted.
- apigenin alone, NAC alone, or apigenin + NAC combined drug was administered for 21 days, and then the expression level of Tuj-1 protein, a neuronal differentiation marker, was confirmed by Western Blot in cortical tissue.
- Example 4 Neuronal cell protective effect of apigenin + NAC complex ( in vivo )
- brain tissue slices were stained with immunohistochemical staining using Caspase 3 antibody, a cell death marker, and the area around the damaged area was stained. Caspase 3 expression levels were analyzed in the penumbra region.
- apigenin alone, NAC alone, or apigenin + NAC combination drug (NDC-001) was administered for 21 days, and brain tissue slices were analyzed using neuronal (NeuN), microglia (GFAP) marker antibody, and cell nuclei.
- DAPI staining solution
- Example 5 Effect of restoring motor function of apigenin + NAC complex ( in vivo )
- apigenin alone, NAC alone, and apigenin + NAC combined drug were administered after stroke induction through a cerebral infarction-reperfusion model, and representative motor coordination evaluations The motor function of the animals was measured on days 1, 3, 7, and 14 after cerebral infarction-reperfusion modeling using the Rotarod latency test.
- composition according to the present invention may include apigenin or a pharmaceutically acceptable salt thereof; And the combined administration of antioxidants can exhibit increased preventive and therapeutic effects of brain diseases compared to single administration, and can reduce side effects that can be caused by excessive or long-term administration of each drug. Availability is high.
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Abstract
La présente invention se rapporte à une composition pharmaceutique complexe destinée au traitement d'une maladie du cerveau contenant : de l'apigénine ou un sel pharmaceutiquement acceptable de cette dernière ; et un antioxydant et, plus spécifiquement, à une composition pharmaceutique complexe destinée à la prévention ou au traitement d'une maladie du cerveau contenant de l'apigénine et un antioxydant, présentant des effets synergiques dans la protection des neurones/la promotion de la différenciation des neurones et l'atténuation de la neuro-inflammation.
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PANG QIONGYI, ZHAO YUN, CHEN XIANG, ZHAO KAIYI, ZHAI QIONGXIANG, TU FENGXIA: "Apigenin Protects the Brain against Ischemia/Reperfusion Injury via Caveolin-1/VEGF In Vitro and In Vivo", OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, HINDAWI PUBLISHING CORPORATION, US, vol. 2018, 3 December 2018 (2018-12-03), US , pages 7017204, XP093073646, ISSN: 1942-0900, DOI: 10.1155/2018/7017204 * |
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