Dementia Improvement Components

Abstract

To provide means to improve dementia. [Solution] A composition for improving dementia containing nicotinamide mononucleotide and rifampicin as active ingredients.

Description

Technical Field

[0001] The present invention relates to a composition for improving dementia.

Background Art

[0002] In Japan, with the progress of aging, the number of dementia patients is increasing. According to the "Study on Future Projections of the Elderly Population with Dementia in Japan" (Special Research Project of the Research Grant for Health and Labor Sciences), the prevalence rate of dementia among the elderly aged 65 and over is 17.2%, and the number of patients is about 6.02 million (in 2020). Approximately one in six elderly people has dementia. Also, according to the same study, in 2025, the above-mentioned prevalence rate of dementia will be 19.0% and the number of patients will be about 6.75 million, meaning that one in five Japanese people aged 65 and over will have dementia. Furthermore, it has been reported that the number of dementia patients will be about 8.75 million in 2040 and about 10 million in 2060. Thus, according to the projected results of future dementia patients, the number of dementia patients in Japan is predicted to increase with the passage of time.

[0003] On the other hand, dementia is not limited to the elderly, and even relatively young people can develop dementia. Dementia that develops before the age of 65 is called early-onset dementia, and the number of early-onset dementia patients is said to be nearly 40,000 nationwide. It is characteristic that while women are more likely to have dementia among the elderly, men are more likely to have early-onset dementia.

[0004] Dementia is a condition in which various acquired causes lead to the death or impaired function of brain cells, resulting in various disorders, and the normally developed intellectual functions continuously decline, causing difficulties in life. Specifically, in addition to memory impairment, there is one or more of aphasia, apraxia, agnosia, and executive function impairment. As a result, it clearly causes difficulties in social life or daily life, and there is an obvious decline in the previous ability level. In many cases, it is caused by brain diseases and is progressive.

[0005] Most cases of dementia are caused by the degeneration of nerve cells in the brain or by cerebrovascular disease, and combinations of both are also seen. There are several types of dementia, and the main ones, based on their causes, that are widely known include Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, and alcoholic dementia. In addition to these, many other diseases and stresses are said to be causes of dementia. Alzheimer's disease is the most common type of dementia and is a neurodegenerative disease that occurs as brain cells degenerate and parts of the brain atrophy. Symptoms often begin with memory loss and progress slowly. Vascular dementia is a type of dementia caused by cerebrovascular disorders such as cerebral infarction and cerebral hemorrhage. From the early stages, it is often accompanied by memory impairment as well as physical functional impairments such as gait disturbances, but because the symptoms vary depending on the area of ​​the brain affected, it is characterized by "patchy dementia," where some cognitive functions are preserved. Symptoms may progress slowly or rapidly in a step-like manner. Vascular dementia is often accompanied by Alzheimer's disease. It is the most common cause of early-onset dementia, accounting for approximately 40% of cases. Lewy body dementia is believed to be caused by the accumulation of a protein called Lewy bodies in the brain. In its early stages, cognitive impairments such as forgetfulness and impaired judgment are not noticeable, but characteristic symptoms such as hallucinations (seeing things that are not there), tremors in the hands and feet, short steps that increase the risk of falling (Parkinsonian symptoms), and abnormal behavior during sleep appear. Frontotemporal dementia is characterized by atrophy of the frontal and temporal lobes of the brain, resulting in distinctive symptoms. These symptoms include difficulty speaking fluently, frequent verbal errors, loss of emotional control, inability to follow social rules, indifference to personal appearance and surroundings, and repetitive behaviors in daily life. Alcoholic dementia is thought to be caused by malnutrition, vitamin deficiencies, and the direct effects of alcohol, which are seen in chronic alcoholism. Its symptoms include impaired consciousness, oculomotor dysfunction, and ataxia, and it is also known as Wernicke's encephalopathy.

[0006] Mild Cognitive Impairment (MCI) is a pre-dementia condition where a person is not yet fully cognitively healthy, but is likely to develop dementia within a few years. Because the symptoms are mild, it is often left untreated. Characteristics of MCI include a greater degree of forgetfulness compared to others of the same age, awareness of frequent forgetfulness, minimal impairment in daily life, and the presence of at least one cognitive impairment (aphasia, agnosia, apraxia, or executive function disorder) even without memory loss. It is said that about half of people with MCI will develop dementia within five years. Although MCI is often left untreated, leaving it untreated increases the likelihood of developing full-blown dementia, so it is desirable to take some kind of action at an early stage to delay the transition to dementia.

[0007] Treatment strategies for degenerative dementias such as Alzheimer's disease, Lewy body dementia, and frontotemporal dementia are generally considered from three perspectives: improvement of core symptoms such as memory impairment, executive function impairment, visuospatial cognitive impairment, language disorders, personality changes, and behavioral disorders; improvement of peripheral symptoms such as depression, hallucinations, delusions, wandering, verbal aggression, and violence; and suppression of disease progression. Currently, cholinesterase inhibitors (donepezil, galeantamine, rivastibmin) and NMDA receptor antagonists (memantine) are used to improve core symptoms, while antipsychotics, antidepressants, and anxiolytics are used as needed to improve peripheral symptoms. Furthermore, for vascular dementia caused by conditions such as cerebral infarction and cerebral hemorrhage, treatment of the underlying cause aims to prevent dementia and suppress its progression.

[0008] Numerous methods have been reported to improve dementia, but one example of a relatively simple, convenient, and safe method using natural ingredients is an oral composition for improving brain function related to dementia, which contains coral calcium, a cinnamic acid derivative, and a nicotinamide derivative, where the nicotinamide derivative is niacin or NAD, and the cinnamic acid derivative is selected from ferulic acid, caffeic acid, and / or sinapic acid, and is contained in a ratio of 1 to 4 parts by weight of the cinnamic acid derivative and 0.5 to 3 parts by weight of the nicotinamide derivative per 1 part by weight of coral calcium (Patent Document 1). In addition, an example of using resveratrol, a natural polyphenol, is a combination of rifampicins selected from the group consisting of rifampicin, its derivatives, and salts thereof, and resveratrols selected from the group consisting of resveratrol and its derivatives, which has been reported as a preventive or therapeutic agent for neurodegenerative diseases (Patent Document 2). [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 6940109, Japanese Patent Application Publication No. 2019-26585 [Patent Document 2] International Publication No. 2020 / 145331 [Overview of the project] [Problems that the invention aims to solve]

[0010] Most cases of dementia are considered difficult to cure once contracted, and currently there is no fundamental treatment. However, establishing countermeasures is urgently needed as we move towards a healthy super-aging society. Therefore, it is hoped that future dementia countermeasures will reduce the burden of care by treating dementia or starting appropriate activities to slow its progression as early as possible, so that people can continue to live their daily lives with minimal disruption for as long as possible. One possible activity in dementia countermeasures in this direction is to administer preparations to improve dementia to people with cognitive impairment, but in that case, it is desirable that the preparations be easy and convenient to take, highly safe, and easy to manufacture.

[0011] The present invention aims to provide a means of improving dementia that is easy and convenient to ingest, highly safe, and can be easily manufactured. [Means for solving the problem]

[0012] As a result of diligent research to solve the above problems, the inventors of this invention have found that combining nicotinamide mononucleotide, an intermediate metabolite involved in the biosynthesis of the coenzyme NAD (nicotinamide adenine dinucleotide), with rifampicin, a component whose safety has been confirmed, is effective in improving dementia, and have completed the present invention.

[0013] Thus, the present invention is as follows. [1] A composition for improving dementia, comprising nicotinamide mononucleotide and rifampicin as active ingredients. [2] The dementia-improving composition according to [1], wherein the cognitive impairment is Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, or alcoholic dementia. [3] The dementia treatment composition according to [1] or [2], comprising 0.002 mg or more of rifampicin per 1 mg of nicotinamide mononucleotide. [4] The composition for improving dementia according to any one of [1] to [3] above, wherein the amount of nicotinamide mononucleotide applied per day for an adult is 1 mg to 500 mg. [5] The composition for improving dementia according to any one of [1] to [4] above, wherein the amount of rifampicin applied per day for an adult is 0.002 mg to 600 mg. [6] The composition for improving dementia according to any one of [1] to [5] above, which is a composition for intranasal administration. [7] The composition for improving dementia according to any one of [1] to [6] above, wherein administration is started when the patient has mild cognitive impairment (MCI). [8] A pharmaceutical product comprising the composition for improving dementia according to any one of [1] to [7] above. [9] A method for producing the composition for improving dementia according to any one of [1] to [7] above, comprising adding rifampicin to an aqueous solvent, stirring, and dissolving to obtain a rifampicin solution, and then adding nicotinamide mononucleotide to the solution and stirring.

Advantages of the Invention

[0014] The present invention has two highly safe active ingredients, nicotinamide mononucleotide, an intermediate metabolite involved in the biosynthesis of NAD in vivo, and rifampicin, an old drug with accumulated information on side effects, and is effective in improving dementia (including mild cognitive impairment). +

Brief Description of the Drawings

[0015] [Figure 1] It is an explanatory diagram showing a metabolic pathway involving niacin (a general term for nicotinamide and nicotinic acid).

Modes for Carrying Out the Invention

[0016] As described above, the composition for improving dementia according to the present invention (hereinafter sometimes referred to as "this composition") contains nicotinamide mononucleotide and rifampicin as active ingredients. Regarding the mechanism of action of this composition, the whole picture has not necessarily been elucidated. However, rifampicin has an effect of suppressing the formation of oligomers of amyloid-β, tau, α-synuclein, etc., which are said to be causative proteins of dementia, in the brain and inhibiting the function of nerve cells. On the other hand, nicotinamide mononucleotide increases the amount of nicotinamide adenine dinucleotide (NAD), activates mitochondria, and increases ATP production in the energy metabolism process, thereby promoting the above-mentioned action of rifampicin and directly enhancing the function of nerve cells in the brain. In the present invention, "improvement of dementia" means not only that the degree of cognitive impairment is improved by the use of this composition, but also that the degree of progression of cognitive impairment is further suppressed (preventing the decline of cognitive function) compared to the case where this composition is not used.

[0017] Nicotinamide mononucleotide (chemical formula: C 11 H 15 N2O8P) is a compound represented by the following structural formula [Chemical Formula 1] and is produced in the bodies of many organisms including humans. It is generally called NMN (Nicotinamide mononucleotide) and is known as an intermediate metabolite involved in the biosynthesis of the coenzyme NAD + .

[0018]

Chemical Formula

[0019] Nicotinamide mononucleotide is produced in the body through the NAD metabolic pathway in liver tissue, specifically the pathway involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from quinolinic acid via the kynurenine pathway. This point will be explained in detail with reference to Figure 1. Figure 1 is an explanatory diagram showing the metabolic pathway involved in niacin (a collective term for nicotinamide and nicotinic acid), also known as vitamin B3. Nicotinic acid ingested from the diet is taken up by the liver, converted to nicotinamide, and supplied to the entire body via the bloodstream. Each cell takes up nicotinamide from the blood and converts it to NAD and NADP for use. Nicotinamide is also biosynthesized from tryptophan.

[0020] As shown in Figure 1, in vivo, when tryptophan is used as a starting material, it is converted to quinolinic acid (QA) via the kynurenine pathway, which is the tryptophan metabolic pathway, and then to nicotinic acid mononucleotide (NaMN). On the other hand, when nicotinic acid (Na) is used as a starting material, nicotinic acid is directly converted to NaMN. NaMN is then interconverted to NAD, nicotinamide (NaM), and nicotinamide mononucleotide via the NAD cycle, through nicotinic acid adenine dinucleotide (NaAD). Nicotinamide (NaM) is converted to nicotinamide mononucleotide by nicotinamide phosphoribosyltransferase (NAMPT), and then nicotinamide mononucleotide is converted to NAD by nicotinamide mononucleotide adenyltransferase (NMNAT). Nicotinamide mononucleotide is also produced from nicotinamide riboside (NR), an intermediate metabolite of NAD.

[0021] Nicotinamide mononucleotide exists as two optical isomers, the α-isomer and the β-isomer, but the β-isomer is used in this invention. Nicotinamide mononucleotide can be obtained, for example, by synthesizing nicotinamide riboside from nicotinamide and ribose (see Bioorg. Med. Chem. Lett., 12, 1135-1137 (2002)), and then phosphorylating the hydroxyl group at position 5 of the ribose moiety (see Chem. Comm., 1999, 729-730). Specifically, for example, first, nicotinamide and L-ribose tetraacetate are dissolved in anhydrous acetonitrile, an excess amount of trimethylsilyltrifluorosulfonic acid is added under a nitrogen atmosphere, the mixture is stirred at room temperature, and methanol is added to stop the reaction. The reaction solution is then passed through a column packed with activated carbon, washed with distilled water, and the product is recovered by elution with methanol. Next, to carry out the phosphorylation reaction of the hydroxyl group at position 5 of the L-ribose moiety of this product, the above product is dissolved in trimethoxyphosphate, phosphorus oxychloride is added dropwise under ice cooling, the mixture is stirred under a nitrogen stream, and an aqueous sodium hydroxide solution is added to neutralize it and stop the reaction. Then, a cold acetonitrile-ether solution is added to the reaction mixture. After that, the lower layer (aqueous phase) is passed through an anion exchange resin to recover the reaction product, and further purification with a cation exchange resin allows for the recovery of highly pure nicotinamide mononucleotide. Nicotinamide mononucleotide is commercially available, and these commercially available products can be purchased and used.

[0022] The nicotinamide mononucleotide is a purified product with a low impurity content, and its purity is preferably 90% or higher, and more preferably 95% or higher. If the purity is less than 90%, an off-odor may be generated, or the effect of the nicotinamide mononucleotide may be weakened, potentially preventing the full effect of the present invention from being obtained.

[0023] As mentioned above, the purity of nicotinamide mononucleotide is preferably 90% or higher, but its purity (mass ratio) is defined as the value obtained by subtracting impurities other than nicotinamide mononucleotide from 100% on an anhydrous basis. Therefore, the purity of nicotinamide mononucleotide can be determined by the formula: Purity of nicotinamide mononucleotide (%) = 100 - Impurities other than nicotinamide mononucleotide (%). Here, the impurities include metabolites other than nicotinamide mononucleotide that are involved in the NAD metabolic pathway, as shown in Figure 1, particularly nicotinamide and nicotinamide adenine dinucleotide. If contaminants such as the above metabolites involved in the NAD metabolic pathway are present in the nicotinamide mononucleotide used in the present invention, the uptake of nicotinamide mononucleotide into living cells may decrease, and as a result, the effect of the present invention may be weakened. The quantitative determination of the above impurities involved in the NAD metabolic pathway is performed by injecting a test solution of dried nicotinamide mononucleotide powder into an HPLC instrument, determining the peak area of ​​the resulting chromatograph, and using the absolute calibration curve method with standard samples (vertical axis: peak area, horizontal axis: concentration). For trace substances, peak height can be used for accurate quantification; therefore, the appropriate method should be selected according to the characteristics of the instrument being used. The separated substance is then identified by its retention time.

[0024] Rifampicin is an orange-red, semi-synthetic antibiotic that was synthesized in 1966 in collaboration with Ciba of Switzerland, by further modifying rifamycin, an antibiotic extracted in 1957 by the Italian company Repeci from the culture filtrate of the actinomycete Streptomyces mediterranei isolated from soil along the Mediterranean coast of France. It was included in Japan's medical standards in August 1971 and is generally known as a long-established basic treatment for tuberculosis. It is effective against infections caused by Mycobacterium tuberculosis as well as Gram-positive and Gram-negative bacteria, and is generally indicated for pulmonary tuberculosis and other tuberculous diseases, non-tuberculous mycobacterial infections including Mycobacterium avium complex (MAC) disease, and leprosy. Rifampicin is known to induce hepatic drug-metabolizing enzymes, including cytochrome P450 3A4 (CYP3A4), UDP-glucuronosyltransferase (UGT), and P-glycoprotein, as well as inhibit transporters (OATP1B1, OATP1B3). Rifampicin has been reported to interact with many drugs and to be effective in combination therapy, and its safety has been studied extensively and in detail. In this invention, the above-mentioned nicotinamide adenine dinucleotide and rifampicin also include pharmaceutically acceptable salts of each.

[0025] In this composition, the ratio of nicotinamide mononucleotide to rifampicin can be determined by comprehensively considering the dosage, dosage form, and frequency of administration of each component in the pharmaceutical described later. However, in order to obtain the effects of the present invention, it is preferable that the composition contains 0.002 mg or more, particularly 0.01 mg or more, of rifampicin per 1 mg of nicotinamide mononucleotide. On the other hand, it is preferable that the upper limit of rifampicin be 600 mg or less, particularly 300 mg or less.

[0026] This composition can be easily prepared by mixing nicotinamide mononucleotide, rifampicin, and other components as appropriate. The other components are not particularly limited as long as they achieve the effects of the present invention.

[0027] Other examples of ingredients include carnitine, chromium, glutathione, alpha-lipoic acid, coenzyme Q, and caffeine, which are known to enhance metabolism. In addition, commonly used auxiliary ingredients in the food industry, such as various vitamins, trace elements, citric acid, malic acid, flavorings, and inorganic salts, may also be included as other ingredients.

[0028] This composition can be used to improve dementia and mild cognitive impairment. This composition is applicable regardless of the cause of dementia or mild cognitive impairment, including the degenerative diseases and cerebrovascular diseases mentioned above, as well as dietary imbalances such as unbalanced diets and inappropriate meal times and intervals, unhealthy lifestyle habits such as stress, lack of sleep, and smoking, genetic predisposition, or the use of medications to treat diseases.

[0029] This composition can be in the form of a pharmaceutical product or the like. The effective amounts of nicotinamide mononucleotide and rifampicin in the composition can be appropriately determined depending on its form, the age, sex, weight of the target individual, and the expected effect; however, the effective amounts for pharmaceutical products, as described later, are usually referenced.

[0030] The method for producing this composition is not particularly limited, and a general manufacturing method used for producing it may be appropriately selected depending on its form. For example, if the form is a powder, it can be produced by uniformly kneading nicotinamide mononucleotide, rifampicin, and other components as needed. The active ingredient, nicotinamide mononucleotide, is available on the market and can be commercially obtained. In particular, quality control and mass production systems for nicotinamide mononucleotide have been established in recent years.

[0031] Furthermore, when selecting a form such as a nasal spray containing a liquid phase, the composition can be prepared by adding rifampicin to an aqueous solvent, stirring and dissolving it to obtain a rifampicin solution, and then adding nicotinamide mononucleotide to the solution and stirring. To increase absorption, it is preferable to adjust the pH of the rifampicin solution to about 7-8 by adding a pH adjusting agent such as a phosphate. The aqueous solvent can be water or an aqueous solution containing a water-soluble component. The stirring time when obtaining the rifampicin solution is preferably 1-10 minutes, particularly 2-5 minutes. On the other hand, the stirring time when adding nicotinamide mononucleotide to the rifampicin solution and stirring is preferably 1-5 minutes, particularly 2-3 minutes. Other operations such as filtration and encapsulation can be performed as appropriate during the above preparation.

[0032] This composition can be administered orally or parenterally in the pharmaceutical field as a medicine intended to improve dementia. The dosage form of the medicine is not particularly limited, but examples include orally administered preparations such as powders, tablets, sustained-release tablets, chewable tablets, effervescent tablets, lozenges, buccal tablets, sublingual tablets, capsules, granules, pills, dry syrups, liquids, suspensions, syrups, and elixirs, as well as injections, infusions, suppositories, and topical preparations. Of these, orally administered preparations such as powders, tablets, and capsules are preferred considering ease of administration and the stability of the active ingredient.

[0033] This composition is particularly preferred to be administered intranasally, i.e., used as a nasal spray. This is because intranasal administration allows for the simple and effective delivery of rifampicin and nicotinamide mononucleotide to the central nervous system through the nasal mucosa, and also avoids the risk of drug-induced liver injury and gastrointestinal disorders (such as stomach discomfort and vomiting) that can occur with oral administration of rifampicin. Generally, when a drug is administered intranasally, there are several routes of uptake into the body: a route from the olfactory epithelium through the olfactory bulb to the brain, a route of uptake from the respiratory epithelium, and a transneuronal route from the respiratory epithelium through the trigeminal nerve to the brainstem (pons). It is presumed that rifampicin and nicotinamide mononucleotide are efficiently taken up by the nerve cells of the trigeminal nerve. Intranasal administration can be done by direct application to the nasal mucosa, as well as by spraying, inhalation, and inhalation. Examples of dosage forms include sprays, liquids, drops, washes, lotions, creams, and ointments.

[0034] The aforementioned pharmaceuticals may be appropriately formulated with pharmaceutically acceptable known excipients suitable for their dosage form, taking into consideration their physicochemical and biological properties. Examples of such excipients include excipients (lactose, starch, crystalline cellulose, sodium phosphate, etc.), solvents (water, soybean oil, saline solution, non-aqueous solvents for injection, etc.), binders (starch, gelatin, acacia gum, sodium alginate, carmellose sodium, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), disintegrants (starch, carmellose sodium, etc.), lubricants (talc, magnesium stearate, calcium stearate, macrogol, sucrose fatty acid esters, etc.), coating agents (sucrose, HPC, shellac, gelatin, glycerin, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, etc.), and stabilizers (sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxypropyl methylcellulose). (e.g., Luen), preservatives (methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, thimerosal, etc.), thickeners (methylcellulose, carmellose sodium, chondroitin sulfate, sodium alginate, etc.), suspending agents (various nonionic surfactants, methylcellulose, carmellose sodium, etc.), Examples of additives include emulsifiers (such as gum arabic, cholesterol, sorbitan sesquioleate, polysorbate 80, and sodium lauryl sulfate), buffering agents (such as citric acid, acetic acid, sodium phosphate, and boric acid), surfactants (such as hydrogenated castor oil and polysorbate 80), colorants (such as water-soluble food colorings and lake colorings), flavoring agents (such as lactose, sucrose, glucose, and mannitol), deodorizing agents (such as aromatic essential oils), and plasticizers (such as phthalates, vegetable oils, and polyethylene glycol).

[0035] The dosage of the aforementioned pharmaceutical product varies depending on the age, weight, symptoms, and frequency of administration of the recipient, and cannot be uniformly prescribed. However, the amount of nicotinamide mononucleotide administered per day to an adult can typically be 1 mg to 500 mg, preferably 5 mg to 350 mg, and more preferably 50 mg to 300 mg. If the dosage is less than 1 mg, the effects of the present invention may not be obtained, while if the dosage is more than 500 mg, the effects obtained do not change significantly, making it economically disadvantageous. The proportion of nicotinamide mononucleotide in the aforementioned pharmaceutical product can be appropriately set according to the dosage form and dosage of the pharmaceutical product.

[0036] The daily dose of rifampicin contained in the aforementioned pharmaceutical product for adults varies depending on the age, weight, symptoms, and frequency of administration of the recipient and cannot be uniformly specified. However, it is usually between 0.002 mg and 600 mg, preferably between 5 mg and 450 mg, and more preferably between 50 mg and 300 mg. If the dose is less than 0.002 mg, the effects of the present invention will not be obtained, while if it is more than 600 mg, side effects may occur. The proportion of rifampicin in the aforementioned pharmaceutical product can be appropriately set according to the dosage form and dosage of the pharmaceutical product.

[0037] The number of times the aforementioned drug is administered can be appropriately determined according to the age, weight, symptoms, and the amount of the drug administered per dose of the patient. An example of the number of times the drug is administered per day is 1 to 3 times.

[0038] Furthermore, the present invention provides a method for improving dementia by administering therapeutically effective doses of nicotinamide mononucleotide and rifampicin in combination. In this method, the respective intake (administration) amounts of nicotinamide mononucleotide and rifampicin, the number of daily intakes, etc., are as described in the description of the composition above.

Claims

1. A composition for improving dementia, characterized by containing nicotinamide mononucleotide and rifampicin as active ingredients.

2. The dementia-improving composition according to claim 1, wherein the dementia is Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, or alcoholic dementia.

3. The dementia treatment composition according to claim 1 or 2, comprising 0.002 mg or more of rifampicin per 1 mg of nicotinamide mononucleotide.

4. The dementia-improving composition according to any one of claims 1 to 3, wherein the amount of nicotinamide mononucleotide applied per adult per day is 1 mg to 500 mg.

5. A dementia-improving composition according to any one of claims 1 to 4, wherein the amount of rifampicin applied per adult per day is 0.002 mg to 600 mg.

6. A composition for improving dementia according to any one of claims 1 to 5, which is a composition for intranasal administration.

7. A dementia-improving composition according to any one of claims 1 to 6, wherein administration is initiated when the patient has mild cognitive impairment (MCI).

8. A pharmaceutical product comprising the composition for improving dementia described in any one of claims 1 to 7.

9. A method for producing a dementia-improving composition according to any one of claims 1 to 7, comprising adding rifampicin to an aqueous solvent, stirring and dissolving it to obtain a rifampicin solution, and then adding nicotinamide mononucleotide to the solution and stirring.

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