Modafinil combinations for the treatment of alzheimer's disease

Abstract

The combination for treating Alzheimer's disease and its application, in particular, the combination based on modafinil and acetaminophen and its use in preparing drugs for treating Alzheimer's disease. In the study, it is found that when modafinil and acetaminophen are combined to treat Alzheimer's disease, the effect of modafinil can be significantly enhanced by acetaminophen, and the test results show that the combination of the two plays a synergistic role; and acetaminophen also eliminates some adverse reactions of modafinil, such as anxiety, tension, etc.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a combination for treating Alzheimer's disease and use thereof. BACKGROUND

[0002] Alzheimer's disease (AD) is a neurodegenerative disease, the cause of which is unknown. The main clinical manifestations are persistent cognitive impairment, social life function reduction, personality and behavior changes, and mental abnormalities. Cognitive impairment mainly manifests as memory impairment, aphasia, apraxia, agnosia, and executive function disorder. Mental abnormalities mainly manifest as agitation, delusion, hallucination, depression, apathy, etc. The pathological changes mainly include cerebral cortex atrophy, sulcal widening, ventricle enlargement, massive reduction of neurons, β-amyloid protein aggregation to form senile plaques, Tau protein hyperphosphorylation to form neurofibrillary tangles, and significant reduction of choline acetyltransferase and acetylcholine content.

[0003] The main population of Alzheimer's disease is people over 65 years old. The reduction of life function and the changes of personality and behavior of patients have brought a very heavy burden to the society and the patient's family. Since Alzheimer's disease was discovered in 1906, scientists have conducted a large number of related researches. In particular, in the past 10 years, the development of β-amyloid protein inhibitors has been very popular. Unfortunately, the cause of Alzheimer's disease is still unknown, and the failure of many β-amyloid protein inhibitors has cast a shadow on the follow-up drug research and development. There are few drugs approved for the treatment of Alzheimer's disease on the market, and the therapeutic effect is limited. The existing drugs on the market mainly include cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora modulators. The drugs under research mainly include β-amyloid protein inhibitors and Tau protein aggregation inhibitors. These drugs are either symptomatic treatment or only improve a few pathological indicators, and few can truly improve the cognitive impairment caused by Alzheimer's disease, and there are many adverse reactions.

[0004] Modafinil is a drug for the treatment of narcolepsy, which was launched in the 1990s and can promote wakefulness in patients with narcolepsy. Since Modafinil is considered to have a psychostimulant effect and has a low possibility of abuse, many studies have focused on the improvement of cognitive function by Modafinil since its launch. However, until now, there has been no consistent view in the field. For example: some studies have shown that Modafinil can enhance the ability in digital span test, visual pattern recognition memory, spatial planning and stop signal reaction time test in healthy subjects [1]. Many studies have shown that Modafinil can improve the function of some cognitive areas, including working memory and episodic memory, as well as other processes dependent on the prefrontal cortex and cognitive control [2]. But some studies have shown that Modafinil does not affect the cognitive function of healthy young volunteers, and produces more adverse emotions such as mental anxiety, aggressiveness, etc. [3]. A double-blind trial showed that Modafinil has no excitatory effect on human motor neurons and cannot improve attention, agility and alertness [4]. In patients with schizophrenia, Modafinil cannot improve cognitive function, reduce fatigue, enhance activity and improve negative symptoms [5]. In a phase III clinical trial, Modafinil failed to improve the symptoms of apathy and activities of daily living in patients with Alzheimer's disease [6]. Some studies have reported that in Df(h22q11) / + male mice with gene knockout (compared with wild-type mice, these gene knockout mice have reduced synchronization of prefrontal cortex-hippocampal oscillations, which can be used as an animal model of cognitive dysfunction), Modafinil exacerbates cognitive impairment in mice [7]. There is no test to show whether Modafinil can improve cognitive impairment caused by Alzheimer's disease. The patent application CN03816595.3 of Cephalon Company in 2003 mentioned that Modafinil can treat Alzheimer's disease, but it was only an assertion or speculation without relevant test data. Therefore, for many years, the industry has not formed a consistent view on whether Modafinil can improve cognition, whether for healthy people or patients with nervous system diseases, some studies have shown that it can enhance cognitive function, and some studies have shown that it does not achieve cognitive improvement.

[0005] Acetaminophen (APAP) belongs to Nonsteroidal anti-inflammatory drugs (NSAIDs), which is mainly used for fever caused by common cold or influenza in children, and for relieving mild to moderate pain. Acetaminophen has a certain central nervous system protective effect. Some people believe that the relief of neuroinflammation by acetaminophen may help treat neurological diseases. The role of neuroinflammation in the pathogenesis of AD has always been a concern. A large number of clinical and laboratory studies have confirmed that there is an inflammatory process in the occurrence and development of AD, but whether inflammation is a beneficial factor or a harmful factor in the occurrence and development of AD, and whether it is a pathogenic factor or a pathological result is still unclear. The research literature on the relationship between NSAIDs and AD is not consistent. So far, a number of epidemiological studies have shown that NSAIDs can significantly reduce the risk of AD or delay the onset of AD (i.e. prevention), but there are also research conclusions that the use of NSAIDs is not associated with the occurrence of dementia and the decline of cognitive function. Unlike the results of most epidemiological studies, clinical studies of NSAIDs for the treatment of AD have not shown that they have a therapeutic effect on AD[8]. In addition, patent EP0946162 suggests that acetaminophen can treat Alzheimer's disease, and in vitro experiments show that acetaminophen can reduce the expression of various inflammatory factors in brain glioma cells T98G, but lack of further animal experiments or human trials to prove effectiveness. Many other studies still have opposite conclusions, for example, animal experiments show that acetaminophen causes damage to mouse memory[9], retrospective clinical studies show that acetaminophen can increase the risk of Alzheimer's disease

[10] , and Cochrane, an authoritative evidence-based medicine organization, conducted a Meta analysis of 604 human studies and concluded that non-steroidal anti-inflammatory drugs including acetaminophen cannot be used to treat Alzheimer's disease

[11] .

[0006] Therefore, the existing drugs for treating Alzheimer's disease still have problems such as uncertain efficacy and many adverse reactions. SUMMARY

[0007] The present application aims to at least solve one of the technical problems existing in the prior art. To this end, the present application provides a combination, composition, kit, use, treatment method, etc. for Alzheimer's disease. More specifically, a combination comprising modafinil and acetaminophen is provided.

[0008] The present inventors surprisingly found in their research that when modafinil and acetaminophen are combined to treat Alzheimer's disease, the effect of modafinil can be significantly enhanced by acetaminophen, and in a number of tests, it was shown that the combination of the two played a synergistic role; and acetaminophen also eliminated certain adverse reactions of modafinil, such as anxiety, tension, etc.

[0009] Accordingly, the technical solution of the present application is as follows.

[0010] The first aspect of the present application provides a use of a combination in the manufacture of a medicament or a kit for treating Alzheimer's disease, the combination comprising active substances, the active substances comprising modafinil and acetaminophen, wherein the weight ratio of modafinil to acetaminophen is 100:1 to 1:50.

[0011] According to some embodiments of the use of the present application, the treating Alzheimer's disease comprises improving one or more symptoms of cognitive dysfunction, sleep disturbance, tension or anxiety, cholinergic dysfunction, brain metabolic disturbance or amyloid beta disturbance caused by Alzheimer's disease; preferably improving cognitive dysfunction caused by Alzheimer's disease, and improving one or more symptoms of sleep disturbance, tension or anxiety, cholinergic dysfunction, brain metabolic disturbance or amyloid beta disturbance caused by Alzheimer's disease.

[0012] According to some embodiments of the use of the present application, the weight ratio of modafinil to acetaminophen is 50:1 to 1:20, for example, the weight ratio is 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15 or 1:20.

[0013] According to some embodiments of the use of the present application, the active substances consist of modafinil and acetaminophen.

[0014] According to some embodiments of the use of the present application, the active substances in the combination further comprise other active ingredients that can be used for treating Alzheimer's disease.

[0015] According to some embodiments of the use of the present application, the active substances consist of modafinil, acetaminophen and other active substances that can be used for treating Alzheimer's disease.

[0016] According to some embodiments of the application, the other active ingredient useful for treating Alzheimer's disease is selected from one or more of cholinesterase inhibitors, beta amyloid inhibitors, tau protein aggregation inhibitors, N-methyl-D-aspartate receptor antagonists, brain metabolism promoters, intestinal flora modulators; more preferably, the other active ingredient useful for treating Alzheimer's disease is selected from one or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromoglicic acid, LMTX, memantine, NAMZARIC, oxiracetam, meclofenoxate, GV971; most preferably donepezil, memantine or NAMZARIC.

[0017] According to some embodiments of the application, the active ingredients consist of modafinil, acetaminophen and donepezil; or consist of modafinil, acetaminophen and memantine; or consist of modafinil, acetaminophen, memantine and donepezil.

[0018] According to some embodiments of the application, the medicament or the kit comprises one or more pharmaceutical agents.

[0019] According to some embodiments of the application, the active ingredients in the combination are present together in the same pharmaceutical agent, or are present separately in different pharmaceutical agents.

[0020] According to some embodiments of the application, the medicament is an oral preparation, an intraoral preparation, an injectable preparation, an inhalable preparation, or a topical preparation.

[0021] According to some embodiments of the application, the medicament is a conventional release preparation, a delayed release preparation, a sustained release preparation or a targeted release preparation.

[0022] According to some embodiments of the application, the medicament further comprises pharmaceutically acceptable excipients.

[0023] The second aspect of the present application provides a pharmaceutical composition comprising active ingredients, wherein the active ingredients comprise modafinil and acetaminophen, and the weight ratio of modafinil to acetaminophen is 100:1 to 1:50.

[0024] According to some embodiments of the pharmaceutical composition of the present application, the active ingredients consist of modafinil and acetaminophen.

[0025] According to some embodiments of the pharmaceutical composition of the present application, preferably, the weight ratio of the modafinil and the acetaminophen is 50:1 to 1:20. For example, the weight ratio is 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, or 1:20. According to some embodiments of the present application, some preferred embodiments can have better effects.

[0026] According to some embodiments of the pharmaceutical composition of the present application, the pharmaceutical composition is used for treating Alzheimer's disease.

[0027] According to some embodiments of the pharmaceutical composition of the present application, the treatment of Alzheimer's disease includes improving one or more symptoms of cognitive dysfunction, sleep disorder, tension or anxiety, cholinergic dysfunction, brain metabolic disorder, or β-amyloid protein disorder caused by Alzheimer's disease; preferably, improving cognitive dysfunction caused by Alzheimer's disease, and improving one or more symptoms of sleep disorder, tension or anxiety, cholinergic dysfunction, brain metabolic disorder, or β-amyloid protein disorder caused by Alzheimer's disease.

[0028] According to some embodiments of the pharmaceutical composition of the present application, the active substance further comprises other active ingredients that can be used for treating Alzheimer's disease.

[0029] According to some embodiments of the pharmaceutical composition of the present application, the other active ingredients that can be used for treating Alzheimer's disease are selected from one or more of cholinesterase inhibitors, β-amyloid protein inhibitors, Tau protein aggregation inhibitors, N-methyl-D-aspartate receptor antagonists, brain metabolic promoters, intestinal flora modulators; more preferably, the other active ingredients that can be used for treating Alzheimer's disease are selected from one or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromoglicic acid, LMTX, memantine, NAMZARIC, oxiracetam, meclofenoxate, GV971; most preferably, donepezil, memantine, or NAMZARIC.

[0030] According to some embodiments of the pharmaceutical composition of the present application, the active substance consists of modafinil, acetaminophen, and other active ingredients that can be used for treating Alzheimer's disease.

[0031] According to some embodiments of the pharmaceutical composition of the present application, the active substance consists of modafinil, acetaminophen, and donepezil; or consists of modafinil, acetaminophen, and memantine; or consists of modafinil, acetaminophen, donepezil, and memantine.

[0032] According to some embodiments of the pharmaceutical composition of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient can be selected from any pharmaceutically acceptable excipient known in the art according to the actual need. In some examples, the pharmaceutically acceptable excipient is selected from at least one of a filler, a binder, a base, a disintegrant, a lubricant, a solvent, a solubilizer, a flavoring agent, a coloring agent, a taste-masking agent, a pH adjusting agent, an isotonic agent, a suspending agent, a thickening agent, a preservative, a stabilizer, an antioxidant, a wetting agent, a surfactant, a suspending agent, a propellant, an absorption enhancer, an absorption retarder, and a coating material.

[0033] According to some embodiments of the pharmaceutical composition of the present application, the pharmaceutical composition is an oral preparation, an intraoral preparation, an injection preparation, an inhalation preparation, or a topical preparation. In some examples, the oral preparation is selected from a tablet, a capsule, a granule, a powder, a pill, a drop, a syrup, an oral solution, an oral suspension, or an oral emulsion; the intraoral preparation is selected from a sublingual preparation, a buccal preparation, or a buccal preparation; the injection preparation is selected from an injection powder, an injection emulsion, or an injection solution; the inhalation preparation is an inhalation solution, an inhalation powder, etc.; and the topical preparation is selected from a patch, a cream, an ointment, an oil paste, a gel, or an external solution.

[0034] According to some embodiments of the pharmaceutical composition of the present application, the pharmaceutical composition is a normal release preparation, a delayed release preparation, a sustained release preparation, or a targeted release preparation.

[0035] The third aspect of the present application provides a kit for treating Alzheimer's disease, comprising an active substance, wherein the active substance comprises modafinil and acetaminophen, and the weight ratio of modafinil to acetaminophen is 100:1 to 1:50.

[0036] According to some embodiments of the kit of the present application, the weight ratio of modafinil to acetaminophen is 50:1 to 1:20. For example, the weight ratio is 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, or 1:20.

[0037] According to some embodiments of the kit of the present application, the treatment of Alzheimer's disease comprises improvement of one or more symptoms of cognitive dysfunction, sleep disturbance, tension or anxiety, cholinergic dysfunction, brain metabolic disturbance, or β-amyloid protein disturbance caused by Alzheimer's disease; preferably improvement of cognitive dysfunction caused by Alzheimer's disease, and improvement of one or more symptoms of sleep disturbance, tension or anxiety, cholinergic dysfunction, brain metabolic disturbance, or β-amyloid protein disturbance caused by Alzheimer's disease.

[0038] According to some embodiments of the kit of the present application, the active substance further comprises other active ingredients useful for the treatment of Alzheimer's disease.

[0039] According to some embodiments of the kit of the present application, the other active ingredients useful for the treatment of Alzheimer's disease are selected from one or more of cholinesterase inhibitors, β-amyloid protein inhibitors, Tau protein aggregation inhibitors, N-methyl-D-aspartate receptor antagonists, brain metabolic promoters, intestinal flora modulators; more preferably, the other active ingredients useful for the treatment of Alzheimer's disease are selected from one or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromoglicic acid, LMTX, memantine, NAMZARIC, oxiracetam, meclofenoxate, GV971; most preferably donepezil, memantine or NAMZARIC.

[0040] A fourth aspect of the present application provides a method for treating Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of the combination of any one of the first aspect of the present application or the pharmaceutical composition of any one of the second aspect of the present application, or using the kit of any one of the third aspect of the present application for treatment.

[0041] According to some embodiments of the method of the present application, comprising administering to a subject in need thereof a therapeutically effective amount of active substances, the active substances comprising modafinil and acetaminophen, wherein the weight ratio of modafinil to acetaminophen is 100:1 to 1:50.

[0042] According to some embodiments of the method of the present application, wherein the weight ratio of modafinil to acetaminophen is 50:1 to 1:20. For example, the weight ratio is 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15 or 1:20.

[0043] According to some embodiments of the method of the present application, wherein modafinil and acetaminophen are administered simultaneously or separately.

[0044] According to some embodiments of the method of the present application, the subject is an Alzheimer's disease patient. The present application can be used to treat any patient at any stage of the disease, improving the symptoms of the patient.

[0045] According to some embodiments of the method of the present application, the subject presents one or more symptoms of cognitive dysfunction, sleep disorder, tension or anxiety, cholinergic dysfunction, brain metabolism disorder or amyloid beta disorder; preferably the subject presents cognitive dysfunction, and also presents one or more symptoms of sleep disorder, tension or anxiety, cholinergic dysfunction, brain metabolism disorder or amyloid beta disorder.

[0046] According to some embodiments of the method of the present application, the active substance further comprises other active ingredients useful for the treatment of Alzheimer's disease.

[0047] According to some embodiments of the method of the present application, the other active ingredients useful for the treatment of Alzheimer's disease are selected from one or more of cholinesterase inhibitors, amyloid beta inhibitors, Tau protein aggregation inhibitors, N-methyl-D-aspartate receptor antagonists, brain metabolism promoters, intestinal flora modulators; more preferably, the other active ingredients useful for the treatment of Alzheimer's disease are selected from one or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromoglicic acid, LMTX, memantine, NAMZARIC, oxiracetam, meclofenoxate, GV971; most preferably donepezil, memantine or NAMZARIC.

[0048] A therapeutically effective amount of the active substances according to the present application can be readily determined by a person skilled in the art based on the results of the present application. According to some embodiments of the method of the present application, a therapeutically effective amount of modafinil can be in the range of 10 mg to 1000 mg, preferably 20 mg to 800 mg, more preferably 50 mg to 500 mg per day. For example, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg per day. A therapeutically effective amount of acetaminophen can be in the range of 1 mg to 2000 mg, preferably 5 mg to 2000 mg, more preferably 20 mg to 1200 mg per day. For example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1500 mg or 2000 mg per day.

[0049] The dosage of the other active ingredients useful in the treatment of Alzheimer's disease can be the clinically routine dosage or less than the clinically routine dosage in order to achieve the optimal therapeutic effect. The clinically routine dosage is well known in the art and can be found in many treatises. The adjustment of the dosage of the other active ingredients useful in the treatment of Alzheimer's disease is readily determined by a clinician in the art based on his clinical experience. According to some embodiments of the method of the present application, the dosage can be in the range of 0.5 mg to 50 mg, preferably 1 mg to 20 mg, for example 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 30 mg, 40 mg and 50 mg per day.

[0050] The specific dosage of the active substances according to the present application can need to be adjusted according to various factors, including but not limited to the severity of the condition of the subject, the age, gender, weight of the subject, the route of administration and the pharmaceutical dosage form, etc.

[0051] According to some embodiments of the method of the present application, the active substances can be administered simultaneously or separately.

[0052] Definitions

[0053] As used herein, the term "Alzheimer's disease" refers to Alzheimer's disease as determined according to clinical diagnostic criteria. Diagnostic criteria and methods for diagnosing Alzheimer's disease are well known in the art.

[0054] As used herein, the term "active substance" refers to a compound that can exert a certain desired pharmacological activity in a medical or pharmaceutical sense. The "active substance" includes not only the compound molecule itself, but also any pharmaceutically acceptable salt, polymorph, solvate, hydrate, derivative, active metabolite, prodrug, spatial isomer thereof in any chemical purity. The "pharmaceutically acceptable salt" refers to an inorganic / organic acid addition salt or base addition salt of the compound that is pharmaceutically acceptable and relatively non-toxic. The "polymorph" refers to a substance formed by different ordered arrangements of multiple compound molecules in a microscopic manner without changing the structure of the individual compound molecule. The "solvate" refers to a substance formed by non-covalent combination of the compound molecule with a solvent, which can also be referred to as "hydrate" when the solvent is water. The "derivative" includes a new compound related to the function of the compound by retaining the structure of the parent nucleus of the compound and substituting certain groups, such as acid, amide, ester, ether, acetylated variant, hydroxylated variant, glycosylated variant, or alkylated (C1-C6) variant, etc. of the compound. The "derivative" also includes active metabolites and prodrugs of the compound. The "spatial isomer" refers to a substance formed by changing the three-dimensional structure of the molecule without changing the planar structure of the compound molecule.

[0055] Based on the description of the present application, those skilled in the art can understand that, since the pharmaceutically acceptable salt, polymorph, solvate, hydrate, derivative, active metabolite, prodrug, spatial isomer, etc. of the "active substance" also has the core structure of the "active substance", and thus has similar pharmacological activity, the purpose of the present application can be achieved in a similar manner to the present application according to the rules described in the present application.

[0056] As used herein, "modafinil" includes at least the molecule with chemical name 2-[(diphenylmethyl)sulfinyl]acetamide, and also includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates, active metabolites, prodrugs, spatial isomers of any chemical purity. In some embodiments, modafinil in the present application can be the R chiral isomer 2-[(R)-(diphenylmethyl)sulfinyl]acetamide, the S chiral isomer 2-[(S)-(diphenylmethyl)sulfinyl]acetamide, or the racemate 2-[(R,S)-(diphenylmethyl)sulfinyl]acetamide. The racemate 2-[(R,S)-(diphenylmethyl)sulfinyl]acetamide of modafinil is marketed under the trade name of PROVIGIL (USA), Modalert (China), etc. The R isomer 2-[(R)-(diphenylmethyl)sulfinyl]acetamide is marketed under the trade name of NUVIGIL (USA). The S isomer can be prepared according to the methods disclosed in the prior art. Modafinil is marketed in the world in the dosage forms of capsules, tablets, orally disintegrating tablets, suspensions, oral solutions, etc., and can be obtained through legal commercialization channels.

[0057] As used herein, "acetaminophen" includes at least the molecule with chemical name N-acetyl-p-aminophenol, and also includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates, active metabolites, prodrugs, spatial isomers of any chemical purity. Acetaminophen is a non-steroidal anti-inflammatory drug widely used in the world for antipyretic and anti-inflammatory purposes, etc. Acetaminophen is marketed in the world in the dosage forms of capsules, tablets, sustained-release tablets, orally disintegrating tablets, sublingual tablets, enemas, granules, sustained-release granules, injections, drops, solutions, lozenges, patches, powders, suppositories, suspensions, etc., and can be obtained through legal commercialization channels.

[0058] As used herein, "LMTX" refers to: a Tau protein aggregation inhibitor developed by TauRx Pharmaceuticals, as a potential therapeutic drug for Alzheimer's disease, which is currently in the clinical phase III.

[0059] As used herein, "donepezil" includes at least the molecule with chemical name (±) 2,3-dihydro-5,6-dimethoxy-2-{[(1-methyl-4-piperidyl)methyl]-1H-inden-1-one, and also includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates, active metabolites, prodrugs, spatial isomers of any chemical purity, such as donepezil hydrochloride. Donepezil is a marketed cholinesterase inhibitor for the treatment of Alzheimer's disease.

[0060] As used herein, "memantine" includes at least the molecule with the chemical name 1- amino-3,5-dimethyladamantane amine, and also includes any pharmaceutically acceptable salt, polymorph, solvate, hydrate, active metabolite, prodrug, spatial isomer thereof, of any chemical purity, for example memantine hydrochloride. Memantine is a marketed N-methyl-D-aspartate receptor antagonist for the treatment of Alzheimer's disease.

[0061] As used herein, "NAMZARIC" refers to a combination drug of donepezil and memantine, which is marketed in the United States under the trade name NAMZARIC.

[0062] As used herein, "GV971" refers to: a manno-oligosaccharide diacid, possibly a gut microbiota modulator, which was marketed in China in 2019 for the treatment of Alzheimer's disease.

[0063] As used herein, the term "treatment" includes delaying or reducing symptoms caused by a given disease. The term treatment particularly includes controlling the progression of the disease and associated symptoms.

[0064] As used herein, the term "combination therapy" refers to the administration of more than one active agent to a subject to elicit a biological effect. In combination therapy, the active agents can be administered simultaneously or separately. By "simultaneously" is meant within about the same time, and by "separately" is meant within different times.

[0065] As used herein, the term "therapeutically effective amount" refers to an amount that is sufficient to cure, reduce, or partially arrest the clinical manifestations of a given disease. An amount that is suitable to accomplish this objective is defined as "therapeutically effective amount". The effective amount for each purpose is dependent on the severity of the disease or injury as well as the stage of the disease or injury, the weight and general health state of the subject, and other factors.

[0066] As used herein, the term "combination" refers to the association between more than one component. The components can be physically mixed together or physically separated from each other. For "combination" of more than one active component, these active components can be present in the same pharmaceutical agent or in different pharmaceutical agents, respectively.

[0067] As used herein, the term "composition" refers to a mixture of one or more components. For a pharmaceutical composition, the composition can include one or more active components, and optionally one or more inert components.

[0068] As used herein, the term "pharmaceutical agent" refers to a finished pharmaceutical preparation containing an active agent, and is ready for use by a patient or a physician.

[0069] As used herein, the term "kit" refers to a container or containers that hold a pharmaceutical agent for storage, transport, formulation, and use of the pharmaceutical agent. A "kit" can be one container or multiple containers. A "kit" can include one pharmaceutical agent or multiple pharmaceutical agents to facilitate separate or combined clinical use. In the present invention, multiple active agents, such as modafinil, acetaminophen, or other active ingredients useful for treating Alzheimer's disease, can be present in separate dosage forms in a kit for simultaneous or sequential administration.

[0070] As used herein, the term "pharmaceutically acceptable" generally refers to something that is acceptable to the pharmaceutical art for use with humans and mammals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio.

[0071] As used herein, the term "excipient" can be any conventional excipient in the pharmaceutical art. The selection of a specific excipient depends on the form of the pharmaceutical preparation or / and the mode of administration.

[0072] As used herein, the terms "a," "an," and "the" and similar articles are to be construed to cover both the singular and plural unless otherwise indicated by context or ambiguities.

[0073] Advantages of the present invention:

[0074] The present invention provides a combination for treating Alzheimer's disease. More specifically, the present invention combines modafinil and acetaminophen, and finds that the two can synergistically reduce adverse reactions and significantly improve the symptoms associated with Alzheimer's disease.

[0075] The present invention combines modafinil and acetaminophen, significantly improves cholinergic dysfunction, brain energy metabolism disorder in patients with Alzheimer's disease, reduces the level of beta amyloid in the brain, effectively improves learning ability, memory ability, self behavior ability, exploration ability, and other cognitive functions, and reduces tension and anxiety, which can treat Alzheimer's disease from multiple aspects and improve clinical efficacy. In addition, the modafinil and acetaminophen of the present invention can also be combined with other existing drugs that can be used to treat Alzheimer's disease to further improve the efficacy of existing drugs. DETAILED DESCRIPTION

[0076] The technical solutions and technical effects of the present invention are further described and explained below in conjunction with specific examples, but the present invention is not limited to these specific embodiments. In the examples, the test methods used are conventional methods unless otherwise specified; and the materials, reagents, and the like used are commercially available unless otherwise specified.

[0077] Example 1: Effect of modafinil combined with acetaminophen on Alzheimer's disease model animals with sleep disorders associated with aging

[0078] Animals: Clean grade Wister rats, half male and half female, weighing 220-250 g.

[0079] Drugs: Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), ibuprofen (commercially available), acetaminophen (commercially available).

[0080] Methods:

[0081] Grouping: After one week of adaptive feeding of the test animals, they were randomly divided into the following groups: blank control group, model control group, modafinil group (MDF), ibuprofen group (IBU), acetaminophen group (APAP), modafinil + ibuprofen group 1 (MDF / IBU-1), modafinil + ibuprofen group 2 (MDF / IBU-2), modafinil + acetaminophen group 1 (MDF / APAP-1), modafinil + acetaminophen group 2 (MDF / APAP-2), and modafinil + acetaminophen group 3 (MDF / APAP-3), with 12 animals in each group.

[0082] Modeling: The animals in each group were fed in heat-resistant cages under natural light and given normal diet. The blank control group was intraperitoneally injected with 0.5 mL of normal saline daily for 6 consecutive weeks. The animals in the other groups were intraperitoneally injected with D-galactose at a dose of 50 mg / kg daily for 6 consecutive weeks, during which artificial light (intensity of 600 lx) was added every night (from 19:00 to 7:00 the next day) from the fourth week.

[0083] Drug administration: After the modeling was completed, the animals were continuously given gavage for 2 weeks. The animals in the MDF group were given modafinil at a dose of 5 mg / kg daily, the animals in the IBU group were given ibuprofen at a dose of 100 mg / kg daily, the animals in the APAP group were given acetaminophen at a dose of 100 mg / kg daily, the animals in the MDF / IBU-1 group were given modafinil at a dose of 5 mg / kg and ibuprofen at a dose of 0.1 mg / kg daily, the animals in the MDF / IBU-2 group were given modafinil at a dose of 5 mg / kg and ibuprofen at a dose of 100 mg / kg daily, the animals in the MDF / APAP-1 group were given modafinil at a dose of 5 mg / kg and acetaminophen at a dose of 0.1 mg / kg daily, the animals in the MDF / APAP-2 group were given modafinil at a dose of 5 mg / kg and acetaminophen at a dose of 100 mg / kg daily, and the animals in the MDF / APAP-3 group were given modafinil at a dose of 5 mg / kg and acetaminophen at a dose of 200 mg / kg daily. The blank control group and the model control group were given the same volume of normal saline daily.

[0084] Testing: After the drug administration was completed, the animals in each group were subjected to the open field test and the Morris water maze test.

[0085] Open field test: Animals were placed into a square box with the size of 25 cm in length, 25 cm in width and 40 cm in height. The bottom of the box was divided into 25 small squares. The number of crossing, standing, defecating and grooming (scratching, face washing, licking foot, etc.) were recorded within 5 minutes.

[0086] Morris water maze test: After the open field test, the Morris water maze test was performed. First, place navigation training was performed: a platform was set in the fourth quadrant of the water maze circular pool, and the platform was set 1 cm under the water. Animals were placed into the water from other quadrants and faced the pool wall. Within 60 seconds, animals were trained to find the platform. Training was performed twice a day for 5 consecutive days. On the 6th day, the spatial probe test was performed: the platform was removed, and the animals were placed into the water and faced the pool wall. The test was performed for 60 seconds, and the number of times that the animals reached the original platform position (crossing times) and the percentage of time spent in the fourth quadrant (the percentage of time spent in the fourth quadrant) were recorded.

[0087] Results: Table 1 lists the main results of the open field test. Table 2 lists the main results of the Morris water maze test.

[0088] Table 1 Open field test results

[0089]

[0090]

[0091] Note: compared with the model control group, * : P < 0.05, ** : P < 0.01. Compared with the blank group, # : P < 0.05, ## : P < 0.01.

[0092] Table 2 Morris water maze test results

[0093] Group Number of animals Number of crossing The time of the fourth quadrant accounted for the percentage Blank control 12 3.42±1.68 42.75±11.08 Model control 12 0.67 ± 0.78 ## ]] 17.83 ± 4.95 ## ]] Modafinil (MDF) 12 0.83±0.58 19.58±5.74 Ibuprofen (IBU) 12 0.75±0.45 20.42±6.47 Acetaminophen (APAP) 12 0.67±0.49 19.33±5.61 MDF / IBU-1 12 0.83±0.58 20.17±5.06 MDF / IBU-2 12 0.92±0.51 22.58±9.60 MDF / APAP-1 12 2.42 ± 0.90 ** ]] 28.67 ± 11.56 * ]] MDF / APAP-2 12 3.08 ± 1.24 ** ]] 33.42 ± 10.67 ** ]] MDF / APAP-3 12 1.00±0.43 21.17±6.21

[0094] Note: compared with the model control group, * : P < 0.05, ** : P < 0.01. Compared with the blank group, # : P < 0.05, ## : P < 0.01.

[0095] Analysis:

[0096] The rats were made subacute aging by galactose and sleep disturbance by artificial light source. The rats after modeling showed disheveled hair color, slow movement, and listless spirit, and the animal's autonomous behavior, exploration ability, and learning and memory ability decreased significantly, indicating that the cognitive ability decreased significantly, which was consistent with the clinical manifestations and pathological characteristics of human Alzheimer's disease. In addition, the chronic onset characteristics were also consistent with the process of human Alzheimer's disease. Therefore, the animal model can be used to evaluate the effect of Alzheimer's disease drugs.

[0097] The open field test can detect the animal's autonomous behavior and mental state. The more the number of crossing and standing, the stronger the animal's autonomous behavior and exploration ability. The more the number of urine and feces and modification, the stronger the animal's nervousness and anxiety. The Morris water maze test can detect the animal's learning and memory ability. The more the number of crossing and the larger the percentage of staying in the fourth quadrant, the better the animal's learning and memory ability. In this experiment, the effect of modafinil combined with acetaminophen was studied. It was found that acetaminophen can significantly enhance the effect of modafinil, and the combination of the two can significantly improve the animal's autonomous behavior, exploration ability, and learning and memory ability, which has statistical significance compared with the model group. This experiment also compared the effects of ibuprofen and acetaminophen, two non-steroidal anti-inflammatory drugs, and found that acetaminophen can significantly enhance the effect of modafinil, while ibuprofen can hardly enhance the effect of modafinil. It is worth noting that the use of modafinil alone can increase the animal's nervousness and anxiety, but the combination of modafinil and acetaminophen can significantly reduce this nervousness and anxiety.

[0098] Example 2: Effect of modafinil combined with acetaminophen on cholinergic dysfunction in Alzheimer's disease model animals

[0099] Animals: Male Kunming mice, half male and half female, weighing 30-40g.

[0100] Drugs: Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), acetaminophen (marketed), donepezil (marketed).

[0101] Method:

[0102] Grouping: After one week of adaptive feeding, the animals were randomly divided into 8 groups: blank control group, model control group, modafinil group (MDF), acetaminophen group (APAP), donepezil group (DNP), modafinil + acetaminophen low-dose group (MDF / APAP-l), modafinil + acetaminophen high-dose group (MDF / APAP-h), modafinil + acetaminophen + donepezil group (MDF / APAP / DNP), 12 animals in each group.

[0103] Dosing: MDF group was given 5 mg / kg of modafinil per day, APAP group was given 30 mg / kg of acetaminophen per day, DNP group was given 1 mg / kg of donepezil per day, MDF / APAP-l group was given 5 mg / kg of modafinil and 30 mg / kg of acetaminophen per day, MDF / APAP-h group was given 10 mg / kg of modafinil and 60 mg / kg of acetaminophen per day, MDF / APAP / DNP group was given 10 mg / kg of modafinil, 60 mg / kg of acetaminophen and 1 mg / kg of donepezil per day. The blank control group and the model control group were given the same volume of normal saline per day. Each group was given intragastric administration continuously for 1 week.

[0104] Modeling: One hour after the end of the last administration, the animals in each group were injected intraperitoneally with 3 mg / kg of scopolamine, except for the blank control group, which was injected with the same amount of normal saline.

[0105] Testing: One hour after the completion of modeling, the avoidance step reflex experiment was performed: the animals were placed in the step response box (the bottom of the box was a copper grid that could be electrified, and a plastic safety platform was provided in the box), and after 3 minutes of adaptation, 36V alternating current was turned on, and the time from the animal receiving the electric shock to jumping onto the safety platform was recorded (reaction time). The animals were placed in the step response box again 24 hours later, 36V alternating current was turned on, and the time from the animal jumping onto the safety platform to the first time jumping off the safety platform was recorded (step latency).

[0106] Cholinergic index determination: After the step reflex experiment, the mice were decapitated and the brain tissue was quickly separated on ice, 10% concentration brain homogenate was prepared by adding normal saline, low-temperature centrifugation for 10 minutes, and the supernatant was used to determine the acetylcholinesterase content by an enzyme marker.

[0107] Results: Table 3 lists the main results of the avoidance step reflex experiment, and Table 4 lists the main results of the cholinergic index determination.

[0108] Table 3 Results of the avoidance step reflex experiment

[0109] Group Number of animals Reaction time (s) Jumping platform latency (s) Blank control 12 16.25±7.46 212.00±58.69 Model control 12 43.42 ± 18.56 ## ]] 123.08 ± 22.71 ## ]] Modafinil (MDF) 12 37.92±16.44 136.08±38.36 Acetaminophen (APAP) 12 38.67±10.75 131.25±33.34 Donepezil (DNP) 12 27.25 ± 8.65 ** ]] 169.50 ± 37.02 * ]] MDF / APAP-l 12 30.75 ± 7.96 ** ]] 154.75±47.75 MDF / APAP-h 12 26.25 ± 9.01 ** ]] 173.08 ± 42.20 * ]] MDF / APAP / DNP 12 20.08 ± 6.46 **& ]] 195.67 ± 43.99 ** ]]

[0110] Note: compared with the model control group, * : P < 0.05, ** : P < 0.01. Compared with the blank group, # : P < 0.05, ## : P < 0.01. Compared with the donepezil group, & : P < 0.05, && : P < 0.01.

[0111] Table 4 Results of the cholinergic index test

[0112] Group Number of animals Acetylcholinesterase activity (U / mgprot) Blank control 12 0.34±0.10 Model control 12 0.80 ± 0.08 ## ]] Modafinil (MDF) 12 0.76±0.15 Acetaminophen (APAP) 12 0.75±0.10 Donepezil (DNP) 12 0.55 ± 0.13 ** ]] MDF / APAP-l 12 0.66 ± 0.17 * ]] MDF / APAP-h 12 0.62 ± 0.08 ** ]] MDF / APAP / DNP 12 0.45 ± 0.06 **& ]]

[0113] Note: compared with the model control group, * : P<0.05, compared with the blank group, ** : P<0.01. compared with the donepezil group, # : P<0.05, compared with the blank group, ## : P<0.01. compared with the donepezil group, & : P<0.05, compared with the blank group, && : P<0.01. compared with the donepezil group.

[0114] Analysis:

[0115] In this experiment, scopolamine was used to cause cholinergic dysfunction in animals, which can be manifested as increased acetylcholinesterase activity, resulting in decreased acetylcholine content. The acetylcholinesterase activity of the model group was significantly increased, and the reaction time was prolonged and the jump platform latency was shortened in the avoidance jump platform reflex experiment, indicating that the animals had cholinergic dysfunction and decreased cognitive ability. The positive drug for treating Alzheimer's disease, donepezil, is a known acetylcholinesterase inhibitor. This experiment showed that it can reduce the acetylcholinesterase activity of animals and improve the learning and memory ability. This model can be used to evaluate the effect of drugs for Alzheimer's disease.

[0116] The avoidance jump platform reflex experiment can reflect the learning ability and memory ability of animals by testing their response to electric shock. The shorter the time between the animal receiving the electric shock and jumping onto the safe platform (reaction time) indicates better learning ability. After 24 hours of learning, the time between the animal jumping onto the safe platform and the first time jumping off the safe platform (jump platform latency) is tested. The longer the jump platform latency, the better the animal's memory. In this experiment, modafinil combined with acetaminophen also showed positive effects. Low and high doses both showed that they can reduce acetylcholinesterase activity, protect against scopolamine-induced cholinergic dysfunction, and improve learning and memory ability. In addition, this experiment also combined donepezil, modafinil and acetaminophen, and the effect of the combination of the three was significantly better than that of donepezil, indicating that the combination of modafinil and acetaminophen has the potential to be used as a synergist for existing Alzheimer's disease drugs.

[0117] Example 3: Effect of modafinil combined with acetaminophen on animals with brain metabolic disorder Alzheimer's disease model

[0118] Drugs: modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), acetaminophen (marketed), memantine (marketed).

[0119] Method:

[0120] Grouping: The animals were randomly divided into 8 groups: blank group, model group, modafinil group (MDF), acetaminophen group (APAP), memantine group (MEM), modafinil + acetaminophen a group (MDF / APAP-a), modafinil + acetaminophen b group (MDF / APAP-b), modafinil + acetaminophen + memantine group (MDF / APAP / MEM). Each group had 18 animals.

[0121] Modeling: On the first day, after anesthesia, the animals in each group were fixed on the positioning instrument, the scalp was cut after shaving the top of the head, the periosteum was separated, the skull was drilled, and the dura mater was exposed. A microsyringe was used to slowly inject streptozotocin 3 mg / kg (10 μL) into the right lateral ventricle, the wound was treated, and routine feeding and antibiotic anti-infection were performed. On the third day, the same operation was performed, and streptozotocin was injected again. The blank group underwent the same operation, but the right lateral ventricle was injected with an equal amount of normal saline.

[0122] Drug administration: The next day after modeling was completed, drug administration began. The MDF group was given 20 mg / kg of modafinil daily, the APAP group was given 10 mg / kg of acetaminophen daily, the MEM group was given 0.5 mg / kg of memantine daily, the MDF / APAP-a group was given 20 mg / kg of modafinil and 10 mg / kg of acetaminophen daily, the MDF / APAP-b group was given 20 mg / kg of modafinil and 120 mg / kg of acetaminophen daily, and the MDF / APAP / MEM group was given 20 mg / kg of modafinil, 120 mg / kg of acetaminophen, and 0.5 mg / kg of memantine daily. The blank group and the model group were given the same volume of normal saline daily. Each group was given intragastric administration continuously for 1 week.

[0123] Testing: The next day after the last administration, the Morris water maze test was performed. In the place navigation training, a platform was set in the water maze circular pool, the platform was set 1 cm under the water, and the animals were placed in the water facing the pool wall. The time for the animals to find the platform was recorded (platform search latency), and the animals that found the platform within 60 seconds were guided to stand on the platform for 15 seconds. Training was performed twice a day for 5 consecutive days, and the average value of the 5 days was taken as the platform search latency. On the sixth day, the spatial probe test was performed, the platform was removed, the animals were placed in the water facing the pool wall, and the test was performed for 60 seconds. The number of times the animals reached the original platform position within 60 seconds (platform crossing times) was recorded.

[0124] Energy metabolism determination: After the Morris water maze test, 9 animals were randomly selected from each group and executed by decapitation. The brain was separated on ice and 100 mg of brain tissue was added to perchloric acid solution. The mixture was ground and centrifuged. The supernatant was added to potassium hydrogen phosphate solution to adjust the pH value to 6.5. The mixture was centrifuged again and the supernatant was used for determination. The content of adenosine triphosphate (ATP) in the sample was determined by high performance liquid chromatography (HPLC) (column, mobile phase 0.05 mol / L potassium hydrogen phosphate buffer, detection wavelength 254 nm). 18 Column, mobile phase 0.05 mol / L potassium hydrogen phosphate buffer, detection wavelength 254 nm).

[0125] β amyloid protein expression positive cell count: After the Morris water maze test, the remaining animals except those used for energy metabolism determination were perfused with paraformaldehyde after anesthesia. The brain was taken and the hippocampus was separated. The tissue section was stained with HE and immunohistochemical staining. The section was observed under a 400-fold microscope and the number of light yellow or brown cells in 5 randomly selected areas was recorded, which was the number of β amyloid protein expression positive cells. Two sections were made for each animal and the average value was obtained by repeated observation.

[0126] Results: Table 5 lists the main results of the Morris water maze test, Table 6 lists the main results of the energy metabolism determination, and Table 7 lists the β amyloid protein expression positive cell count.

[0127] Table 5 Results of Morris water maze test

[0128] Group Number of animals Platform searching latency (seconds) Crossing number (times) Blank 18 24.39±7.75 3.11±1.13 Model 18 47.11 ± 9.93 ## ]] 0.44 ± 0.51 ## ]] Modafinil (MDF) 18 42.50±10.89 0.50±0.62 Acetaminophen (APAP) 18 46.72±9.40 0.61±0.50 Memantine (MEM) 18 34.56 ± 6.88 ** ]] 2.28 ± 1.13 ** ]] MDF / APAP-a 18 38.61 ± 8.16 * ]] 1.89 ± 0.58 ** ]] MDF / APAP-b 18 32.72 ± 8.40 ** ]] 2.11 ± 0.76 ** ]] MDF / APAP / MEM 18 29.17 ± 5.73 **& ]] 2.67 ± 1.24 ** ]]

[0129] Note: compared with the model group, * : P < 0.05, ** : P < 0.01. Compared with the blank group, # : P < 0.05, ## : P < 0.01. Compared with the memantine group, & : P < 0.05, && : P < 0.01.

[0130] Table 6 Results of energy metabolism determination

[0131]

[0132]

[0133] Note: compared with the model group, * : P < 0.05, ** : P < 0.01. Compared with the blank group, # : P < 0.05, ## : P < 0.01. Compared with the memantine group, & : P < 0.05, &&P<0.01.

[0134] Table 7 Cell count of Aβ protein expression positive

[0135] Group Number of animals Beta amyloid expressing cell count (cells / mm2 2 )]]> Blank 9 9.67±1.17 Model 9 30.67 ± 2.90 ## ]]> Modafinil (MDF) 9 28.39±2.38 Acetaminophen (APAP) 9 27.50 ± 2.24 * <!-- 13 -->]]> Memantine (MEM) 9 19.33 ± 2.94 ** ]] MDF / APAP-a 9 22.72 ± 1.82 ** ]] MDF / APAP-b 9 21.00 ± 2.77 ** ]] MDF / APAP / MEM 9 14.00 ± 2.47 **&& ]]>

[0136] Note: compared with the model group, * P<0.05, ** P<0.01. Compared with the blank group, # P<0.05, ## P<0.01. Compared with the memantine group, & P<0.05, && P<0.01.

[0137] Analysis:

[0138] In this experiment, the brain metabolism disorder of animals was caused by local injection of streptozotocin in the ventricle. Streptozotocin can block the autophosphorylation of insulin receptor and the intrinsic tyrosine kinase activity, resulting in insulin signal transduction disorder. Many studies have shown that a small dose of streptozotocin injected into the lateral ventricle of rats can cause persistent glucose metabolism disorder and energy disorder and cognitive impairment, which is a commonly used animal model of Alzheimer's disease. In this experiment, the water maze test found that the model group animals had longer platform search latency and significantly reduced platform crossing times, indicating that the modeling was successful. In addition, it was also found that the brain energy metabolism of animals was significantly reduced (adenosine triphosphate content was significantly reduced), and the expression of β-amyloid protein was significantly increased. These phenomena are also very consistent with the pathological manifestations of human Alzheimer's disease.

[0139] The shorter the platform search latency in the positioning navigation stage of the Morris water maze test indicates that the learning ability of the animal is stronger, and the more the number of platform crossing times in the spatial search test stage indicates that the memory ability of the animal is better. In this experiment, the effect of modafinil combined with acetaminophen on brain metabolism disorder in Alzheimer's disease model animals was studied. It was found that modafinil combined with acetaminophen could reduce the expression of β-amyloid protein, improve brain energy metabolism, and improve learning and memory ability. A comparative study was conducted using memantine, and it was found that modafinil combined with acetaminophen could achieve or be better than memantine. In addition, the combination of memantine, modafinil and acetaminophen was better than memantine, indicating that the combination of modafinil and acetaminophen can be used as a synergist for existing drugs for treating Alzheimer's disease.

[0140] While the application has been disclosed with reference to particular embodiments, it is apparent that other embodiments and variations of the application can be devised by others skilled in the art without departing from the true spirit and scope of the application. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

[0141] References:

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[0143] [2] Minzenberg, Michael J., and Cameron S. Carter. "Modafinil: a review of neurochemical actions and effects on cognition." Neuropsychopharmacology 33, no. 7 (2008): 1477-1502.

[0144] [3] Randall, Delia C, John M. Shneerson, Komal K. Plaha, and Sandra E. File. "Modafinil affects mood, but not cognitive function, in healthy young volunteers." Human Psychopharmacology: Clinical and Experimental 18, no. 3 (2003): 163-173.

[0145] [4] Liepert, J., J. Allstadt-Schmitz, and C. Weiller. "Motor excitability and motor behaviour after modafinil ingestion - a double-blind placebo-controlled cross-over trial." Journal of neural transmission 111, no. 6 (2004): 703-711.

[0146] [5] Wittkampf, Laura Christina, Johannes Arends, Leo Timmerman, and Marike Lancel. "A review of modafinil and armodafinil as add-on therapy in antipsychotic-treated patients with schizophrenia." Therapeutic advances in psychopharmacology 2, no. 3 (2012): 115-125.

[0147] [6] Frakey, Laura L., Stephen Salloway, Melissa Buelow, and Paul Malloy. "A randomized, double-blind, placebo-controlled trial of modafinil for the treatment of apathy in individuals with mild-to-moderate Alzheimer's disease." Journal of Clinical Psychiatry 73, no. 6 (2012): 796-801.

[0148] [7] Nilsson, Simon RO, Christopher J. Heath, Samir Takillah, Steve Didienne, Kim Fejgin, Vibeke Nielsen, Jacob Nielsen et al. "Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine." Translational psychiatry 8, no. 1 (2018): 1-14.

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[0151]

[10] Stewart, Walter F., Claudia Kawas, Maria Corrada, and E. Jeffrey Metter. "Risk of Alzheimer's disease and duration of NSAID use." Neurology 48, no. 3 (1997): 626-632.

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[11] Jaturapatporn, Darin, Mokhtar Gad El Kareem Nasr Isaac, Jenny McCleery, and Naji Tabet. "Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease." Cochrane Database of Systematic Reviews 2 (2012).

Claims

1. A pharmaceutical composition comprising an active substance, said active substance comprising modafinil and acetaminophen, wherein the weight ratio of modafinil to acetaminophen is 50:1 or 1:

20.

2. The pharmaceutical composition according to claim 1, wherein the active substance further comprises other active ingredients that can be used to treat Alzheimer's disease, wherein the other active ingredients that can be used to treat Alzheimer's disease are donepezil, memantine, or namozac.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral preparation, an intraoral preparation, an injectable preparation, an inhaled preparation, or a topical preparation.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an immediate-release formulation, a delayed-release formulation, a sustained-release formulation, or a targeted-release formulation.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

6. Use of the pharmaceutical composition according to any one of claims 1-5 in the preparation of a medicament for treating Alzheimer's disease.

7. In the application according to claim 6, the active substances in the composition coexist in the same pharmaceutical agent or exist separately in different pharmaceutical agents.

8. A medicine box for treating Alzheimer's disease, comprising the pharmaceutical composition according to any one of claims 1-5.

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