Therapeutic agent of mild cognitive impairment

Abstract

To provide a novel therapeutic agent of mild cognitive impairment.SOLUTION: A therapeutic agent of mild cognitive impairment or dementia is a composition that contains cilostazol or salt thereof as an active ingredient, where in order to determine a second dosage of the active ingredient for treating mild cognitive impairment or dementia by administering it to a subject, the active ingredient is administered to the subject by an initial dosage prior to the determination, or the active ingredient is administered to the subject by the second dosage after administration to the subject by the initial dosage.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of Japanese Application No. 2020-83163, filed with the Japan Patent Office on May 11, 2020. The Japanese application is hereby incorporated by reference for all purposes as if the entire application documents (specification, claims, drawings, abstract) were set forth herein. The present invention belongs to the technical field of cognitive impairment treatment. The present invention relates to a mild cognitive impairment treatment containing cilostazol as an active ingredient. More specifically, the present invention relates to a mild cognitive impairment treatment containing cilostazol as an active ingredient, and to the dosage of said cilostazol. [Background technology]

[0002] Mild cognitive impairment (MCI) is a condition just before dementia. Although memory impairment such as forgetfulness occurs in dementia, symptoms are still mild, and it is a disease that is intermediate between a normal state and dementia. In MCI, regardless of the type of harmful protein that accumulates, mild cognitive impairment is observed in the early stages, but irreversible degeneration of brain nerve tissue often has not yet occurred at this point. MCI is clinically diagnosed based on the following factors: - Whether the memory loss is acknowledged by the person or their family -Is there objective evidence of impairment in one or more cognitive functions (memory, orientation, etc.)? -Are activities of daily living normal? - Dementia

[0003] On the other hand, there are several types of dementia, depending on the location of abnormalities in the brain, including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia, Parkinson's disease dementia, etc. Many of these dementias are pathologically characterized by irreversible neurodegeneration. The most typical dementia is Alzheimer's type, which accounts for about 50% to 70% of dementia (Non-Patent Document 1). Even in the stage of MCI, which is just before Alzheimer's type dementia, accumulation of amyloid beta in the brain, which is the cause of Alzheimer's disease, has been observed, just like Alzheimer's type dementia. Therefore, if MCI is left untreated, it is thought that Alzheimer's type dementia will develop within a few years. It is difficult to completely cure Alzheimer's disease, but with appropriate therapeutic intervention, it is possible to delay the onset of MCI due to Alzheimer's disease.

[0004] One known test method for screening for MCI is the Montreal Cognitive Assessment (MOCA). The MOCA is a test method that consists of visual-spatial and executive functions, naming, memory, attention, repetition, word recall, abstract concepts, delayed recall, and orientation. On the MOCA, a score of 25 or less indicates MCI, with a sensitivity of 80-100% and a specificity of 50-87%. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Blennow K, de Leon MJ, Zetterberg H.: Alzheimer's disease. Lancet. 2006 Jul 29; 368(9533): 387-403 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to provide a method and a therapeutic agent for preventing or delaying the progression of mild cognitive impairment to dementia. Another objective of the present invention is to provide a method and a therapeutic agent that are effective in improving cognitive function in patients with mild cognitive impairment. [Means for solving the problem]

[0007] As a result of intensive research, the inventors have developed a new method for monitoring the therapeutic effect of cilostazol in the treatment of MCI and improving cognitive function, thereby finding that the above-mentioned problems can be solved, and have thus completed the present invention. The present invention can include, for example, the following aspects.

[0008] [1] A therapeutic agent for mild cognitive impairment or dementia, comprising a composition comprising cilostazol or a salt thereof as an active ingredient, wherein the active ingredient is administered to a subject at an initial dose prior to determining a second dose of the active ingredient to be administered to the subject to treat mild cognitive impairment or dementia, or wherein the active ingredient is administered to the subject at the initial dose and then at the second dose. [2] The therapeutic agent for mild cognitive impairment or dementia described in [1] above, wherein the presence of cilostazol, OPC-13015, and / or other metabolites in a sample from the subject is measured after administration of an initial dose of the active ingredient to the subject. [3] The therapeutic agent for mild cognitive impairment or dementia according to the above item [2], wherein after administration of an initial dose of the active ingredient to the subject, the abundance ratio of cilostazol or OPC-13015 to the total abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the total abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a sample derived from the subject is calculated. [4] The therapeutic agent for mild cognitive impairment or dementia according to the above-mentioned [3], wherein the second dose of the active ingredient is determined within a medicamentously acceptable dose range of cilostazol based on the above-mentioned ratio of cilostazol or OPC-13015. [5] The therapeutic agent for mild cognitive impairment or dementia according to the above item [4], wherein the second dose of the active ingredient is determined to be a dose higher than the initial dose within a medicamentically acceptable dose range of cilostazol when the abundance ratio of cilostazol in the subject is higher than the reference level, or when the abundance ratio of OPC-13015 in the subject is lower than the reference level, where the abundance ratio of cilostazol or OPC-13015 in a cognitive impairment improvement / maintenance group known to have improved or maintained cognitive impairment is set as the reference level. [6] The therapeutic agent for mild cognitive impairment or dementia according to the above [4] or [5], wherein the second dose of the active ingredient is determined to be a dose higher than the initial dose within a medicamentically acceptable dose range of cilostazol when the abundance ratio of cilostazol in the subject is higher than the reference level, or when the abundance ratio of OPC-13015 in the subject is lower than the reference level, where the abundance ratio of cilostazol or OPC-13015 in a cognitive impairment worsening group known to have worsening cognitive impairment is set as the reference level. [7] The therapeutic agent for mild cognitive impairment or dementia according to any one of the above [1] to [6], wherein the initial dose of the active ingredient is 50 mg twice a day, and the second dose is 100 mg twice a day or 150 mg twice a day. [8] The therapeutic agent for mild cognitive impairment or dementia according to any one of [2] to [7] above, wherein sampling from the subject is carried out within 1 to 7 hours after administration of the initial dose of the active ingredient. [9] The therapeutic agent for mild cognitive impairment or dementia according to any one of [2] to [8] above, wherein the sample is plasma.

[10] The therapeutic agent for mild cognitive impairment or dementia described in [9] above, wherein the sample is pretreated by a deproteinization method using an organic solvent.

[11] The therapeutic agent for mild cognitive impairment or dementia according to any one of [2] to

[10] above, wherein the abundance or abundance ratio is measured by a method selected from the group consisting of LC, ELISA, and LC-MS.

[12] The therapeutic agent for mild cognitive impairment or dementia according to any one of [1] to

[11] above, wherein the dementia is Alzheimer's dementia.

[13] The therapeutic agent for mild cognitive impairment or dementia according to any one of [1] to

[11] above, wherein the mild cognitive impairment is a decrease in orientation.

[14] The therapeutic agent for mild cognitive impairment or dementia according to any one of the above [1] to

[13] , wherein the agent is an oral administration formulation.

[15] The therapeutic agent for mild cognitive impairment or dementia according to any one of [1] to

[14] above, wherein the subject has not been diagnosed with intermittent claudication or stroke.

[0009]

[16] A method for determining a second dose of cilostazol for treating mild cognitive impairment or dementia, comprising the following steps 1 to 3: 1. A step of measuring the amount of cilostazol and OPC-13015 present, or the amount of OPC-13213 and / or OPC-13217 present in a sample from a subject who has been administered an initial dose of a composition containing cilostazol or a salt thereof as an active ingredient; 2. Calculating the abundance ratio of cilostazol or OPC-13015 to the sum of the abundances of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the sum of the abundances of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217; 3. Determining a second dose of cilostazol within the pharma- ceutically acceptable dose range of cilostazol based on the above-mentioned abundance ratio.

[17] The method according to the above-mentioned

[16] , further comprising a step of comparing the abundance ratio of cilostazol or OPC-13015 to the sum of the abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the sum of the abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a cognitive impairment improvement / maintenance group known to have improved or maintained cognitive impairment, with the abundance ratio of cilostazol or the abundance ratio of OPC-13015 in the subject.

[18] The method according to

[16] or

[17] above, further comprising a step of comparing the abundance ratio of cilostazol or OPC-13015 to the sum of the abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the sum of the abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a cognitive impairment worsening group known to have worsening cognitive impairment, with the abundance ratio of cilostazol or the abundance ratio of OPC-13015 in the subject.

[19] The method according to any one of

[16] to

[18] above, wherein the sample from the subject is sampled within 1 to 7 hours after administration of the initial dose of the active ingredient.

[20] The method according to any one of

[16] to

[19] above, wherein the sample is plasma.

[21] The method according to

[20] above, wherein the sample is pretreated by a deproteinization method using an organic solvent.

[22] The method according to any one of

[16] to

[21] above, wherein the abundance or abundance ratio is measured by a method selected from the group consisting of LC, ELISA, and LC-MS.

[23] The method according to any one of

[16] to

[22] above, wherein the dementia is Alzheimer's disease.

[24] The method according to any one of

[16] to

[22] above, wherein the mild cognitive impairment is a decrease in orientation.

[0010]

[25] The therapeutic agent for mild cognitive impairment or dementia according to any one of [1] to

[15] above; and A system for treating mild cognitive impairment or dementia, comprising an analytical device for measuring the presence of cilostazol, OPC-13015, and / or other metabolites in a sample from the subject after administration of an initial dose of the active ingredient to the subject.

[26] The treatment system for mild cognitive impairment or dementia described in

[25] above, further comprising a sample pretreatment device.

[27] The treatment system for mild cognitive impairment or dementia described in

[25] or

[26] above, wherein the analytical device is an apparatus selected from the group consisting of LC, LC-MS, LC-MS / MS, and ELISA analytical devices. Effect of the Invention

[0011] According to the present invention, in the treatment of mild cognitive impairment or dementia, it is possible to prevent or delay the progression of dementia. It is also expected to improve the cognitive function of patients with mild cognitive impairment. [Brief description of the drawings]

[0012] [Figure 1] This shows the relationship between the plasma concentration ratio of cilostazol or its metabolites and improvement of cognitive function. The upper left figure shows the results for cilostazol, the upper right figure shows the results for OPC-13015, and the lower figure shows the results for OPC-13213 + OPC-13217. In each figure, the vertical axis shows the ratio of the plasma concentration of each compound to the sum (Total) of the plasma concentrations of cilostazol, OPC-13015, and OPC-13213 + OPC-13217. [Diagram 2] This shows the relationship between the plasma concentration ratio of cilostazol or its metabolites and improvement of cognitive function. The left figure shows the results for cilostazol, and the right figure shows the results for OPC-13015. In each figure, the vertical axis shows the ratio of the plasma concentration of each compound to the sum (Total) of the plasma concentrations of cilostazol and OPC-13015. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention will be described in detail below. 1. Definitions In this specification, "cilostazol" is the generic name of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydroquinolin-2(1H)-one, which has the structure shown in Chemical Formula 1 below, and is sold in Japan by Otsuka Pharmaceutical Co., Ltd. under the trade name "Pletal (registered trademark)" as an antiplatelet agent.

[0014] [ka]

[0015] The approved dosage of cilostazol for adults is usually 100 mg of cilostazol administered orally twice a day. This dosage can be increased or decreased depending on age and symptoms. Cilostazol has a high platelet aggregation inhibitory effect, as well as phosphodiesterase inhibitory effect, antiulcer effect, antihypertensive effect, and anti-inflammatory effect, and is therefore widely used as an antithrombotic agent, cerebral circulation improver, anti-inflammatory agent, antiulcer agent, antihypertensive agent, antiasthmatic agent, and phosphodiesterase inhibitor. Cilostazol has also been shown to be effective in preventing the progression of Alzheimer's disease and improving cognitive function (Ihara M, et al; PLoS One. 2014; 9(2): e89516).

[0016] As used herein, "OPC-13015", "OPC-13213", "OPC-13217", and "OPC-13326" are metabolites of cilostazol having the structures shown below. The generic name of OPC-13015 is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-2(1H)-quinolinone, the generic name of OPC-13213 is 3,4-dihydro-6-[4-[1-(trans-4-hydroxycyclohexyl)-1H-tetrazol-5-yl)butoxy]-2(1H)-quinolinone, and the generic name of OPC-13217 is 3,4-dihydro-6-[4-[1-(cis-4-hydroxycyclohexyl)-1H-tetrazol-5-yl)butoxy]-2(1H)-quinolinone.

[0017] [ka]

[0018] Cilostazol is metabolized in the liver after absorption in the body, and the main metabolites are the four compounds shown in Chemical formula 2 above (PNVTata, et al.; J. Pharm. Biomed. Anal.; 18 (1998) 441-451). Of these, OPC-13015 is 3,4-dehydrocilostazol, and OPC-13213 and OPC-13217 are 4'-hydroxycilostazol.

[0019] In the present invention, "mild cognitive impairment" (MCI) refers to a pre-stage state of dementia, which is mainly accompanied by memory impairment, as described above. MCI can be determined by screening psychological tests of cognitive function, such as MOCA, Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Hasegawa Dementia Rating Scale-Revised (HDS-R), Clock Drawing Test (CDT), Mini-Cog, and ABC Dementia Scale (ABC-DS).

[0020] According to MOCA, mild cognitive impairment (MCI) can be judged to be present when the score is 25 or less. The MMSE is a cognitive function test with a maximum score of 30 points, consisting of 11 items: time orientation, place orientation, immediate and delayed recall of three words, calculation, object naming, sentence repetition, three-step verbal command, written command, sentence writing, and figure copying. MMSE scores of 23 or less are suspected of dementia (sensitivity 81%, specificity 89%). Score of 27 or less is suspected of mild cognitive impairment (MCI) (sensitivity 45-60%, specificity 65-90%). Score of 22-26 is a level at which mild cognitive impairment is suspected, but scores above 20 are at a level where the patient can maintain independence (not dementia), and scores below 20 are at a level at which dementia is suspected. Score below 14 is at a level where guardianship is required, and scores between 14 and 20 are at a level where curatorship and assistance are required.

[0021] The CDR assesses the severity of six items (memory, orientation, judgment and problem solving, social adaptation, family situation, hobbies and interests, and caregiving situation) on a five-point scale. Based on these, the patient is assessed as healthy (CDR: 0), suspected dementia (CDR: 0.5), mild dementia (CDR: 1), moderate dementia (CDR: 2), or severe dementia (CDR: 3). The HDS-R is a cognitive function test with a maximum score of 30 points, consisting of nine items: age, orientation, immediate memory and delayed recall of three words, calculation, digit recitation, object memory, and verbal fluency.

[0022] Examples of "dementia" include Alzheimer's disease (AD), vascular (cerebrovascular) dementia (VD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), semantic dementia (SD), progressive aphasia (PA), and dementia associated with Parkinson's disease. Among these, Alzheimer's disease (AD) is a representative example.

[0023] The "therapeutic agent" according to the present invention treats mild cognitive impairment or dementia, and such treatment also includes, for example, prevention and amelioration. Therefore, the "therapeutic agent" also includes concepts such as "prophylactic agent" and "ameliorator".

[0024] The entire contents of all documents cited in this specification are incorporated herein by reference.

[0025] 1. Therapeutic agent for mild cognitive impairment or dementia according to the present invention The therapeutic agent for mild cognitive impairment or dementia according to the present invention (hereinafter referred to as "the therapeutic agent of the present invention") is a composition containing cilostazol or a salt thereof as an active ingredient, and in order to determine a second dose of the active ingredient to be administered to a subject to treat mild cognitive impairment or dementia, the active ingredient is administered to the subject at an initial dose prior to said determination, or the active ingredient is administered to the subject at the initial dose and then at the second dose.

[0026] The therapeutic agent of the present invention is preferably an oral administration preparation, more preferably a solid oral administration preparation such as a tablet, capsule or powder, and the following description will be focused on oral administration preparations unless otherwise specified. The "subject" according to the present invention is usually a human suffering from mild cognitive impairment or dementia, but may also be a person not suffering from mild cognitive impairment or dementia. It may also be a mammal other than a human, specifically, for example, primates (monkeys, marmosets), rodents (mouse, rats, guinea pigs, etc.), rabbits, dogs, cats, pigs, cows, sheep, and horses.

[0027] Cilostazol in the therapeutic agent of the present invention is preferably in the free form, but may be a salt of cilostazol. Such salts are not particularly limited as long as they are pharma- ceutically acceptable salts, and include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, hydrobromide, and hydroiodide, and organic acid salts such as formate, acetate, propionate, trifluoroacetate, citrate, lactate, tartrate, oxalate, maleate, fumarate, mandelate, glutarate, malate, benzoate, phthalate, ascorbate, methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, aspartate, and glutamate. The salts also include hydrates and solvates. Hereinafter, cilostazol will also be simply referred to as cilostazol, including its salts.

[0028] 1.1 Initial dose The initial dose according to the present invention is a dose of cilostazol administered prior to determining a second dose (described below) of the active ingredient to be administered to a subject to treat mild cognitive impairment or dementia. The initial dose can be determined by a doctor based on the diagnosis of a regular doctor, and in some cases, on the results of an appropriate psychological test.Specifically, for example, 50 mg or 100 mg of cilostazol is suitable for administration once or twice a day.Depending on the symptoms of the subject, the dose may be higher or lower than this, and the number of administrations may be higher or lower.

[0029] 1.2 Second dose The second dose according to the present invention is a dose of cilostazol determined based on the results after the initial dose of cilostazol is administered. The second dose is usually determined by administering the initial dose of cilostazol to a subject, and then measuring the amount of cilostazol, OPC-13015, and / or other metabolites present in a sample derived from the subject. Specifically, the second dose is determined within the range of a medicamentously acceptable dose of cilostazol based on the ratio of cilostazol or OPC-13015 to the total amount of cilostazol and OPC-13015 present in a sample derived from the subject after the initial dose of cilostazol is administered to the subject, or the ratio of OPC-13015 to the total amount of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 present in the sample derived from the subject.

[0030] Furthermore, the second dose can be determined to be a dose higher than the initial dose within the range of pharmacologic acceptable doses of cilostazol when the abundance ratio of cilostazol or OPC-13015 in the subject is higher than the reference level, or when the abundance ratio of OPC-13015 is lower than the reference level, using the above abundance ratio of cilostazol or OPC-13015 in the cognitive impairment improvement / maintenance group, where it is known that cognitive impairment has been improved or maintained, as the reference level.

[0031] Furthermore, in addition to or independently of the above-mentioned reference level, the second dose can also be determined to be a dose higher than the initial dose within the range of pharmacologic acceptable doses of cilostazol when the abundance ratio of cilostazol in the subject is higher than the reference level or the abundance ratio of OPC-13015 is lower than the reference level, using the above-mentioned abundance ratio of cilostazol or OPC-13015 in a cognitive impairment worsening group known to have worsening cognitive impairment as the reference level.

[0032] In addition, the second dose can be determined by determining a cutoff value from the values ​​of cilostazol or OPC-13015 in both the cognitive impairment improvement / maintenance group, in which it is known that cognitive impairment has improved or been maintained, and the cognitive impairment worsening group, in which it is known that cognitive impairment has worsened, in addition to or independently of the above-mentioned reference level, and using that value as a reference level, if the abundance ratio of cilostazol in the subject is higher than that reference level, or if the abundance ratio of OPC-13015 is lower than that reference level, the second dose can be determined to be a dose higher than the initial dose within the range of pharma- ceutically acceptable doses of cilostazol.

[0033] The second dose is usually higher than the initial dose, but may be the same or lower depending on the circumstances in terms of side effects, efficacy, etc. Specifically, the second dose varies depending on the amounts of cilostazol, OPC-13015, etc. present in the sample derived from the subject, and may be, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, about once to three times a day.

[0034] Sampling from the subject is suitably carried out within 1 to 7 hours, preferably within 30 minutes to 2 hours, after administration of the initial dose of cilostazol, but can also be carried out at shorter or longer times as necessary.

[0035] The sample from the subject is not particularly limited as long as the amount of cilostazol, OPC-13015, etc. present in the body can be measured, but plasma and serum are suitable, and plasma is preferable. When the sample is plasma, the "amount present" usually refers to the plasma concentration.

[0036] When the sample is a blood sample, it can be a plasma sample obtained by separating and removing blood cell components by a method such as centrifugation. It is preferable that proteins are removed from the plasma sample by pretreatment using a deproteinization method. Examples of the deproteinization method include a method that utilizes insolubilization by denaturation of proteins, physical removal, and the like.

[0037] Examples of methods that utilize insolubilization due to denaturation of the protein include a method using an organic solvent, a method using an acid, and a method using thermal denaturation (heating, cooling, etc.). Among these, the method using an organic solvent is preferred.

[0038] The organic solvent is preferably a polar solvent miscible with water, such as methanol, ethanol, acetonitrile, and acetone, with methanol and acetonitrile being preferred.

[0039] Such deproteinization can be carried out using, for example, the following means or methods: sample dispensing, reagent dispensing, stirring, suction filtration, heating, and centrifugation.

[0040] Suitable methods for measuring the amount or ratio of cilostazol, OPC-13015, etc. in the sample include, for example, LC (Liquid Chromatography), LC-MS (Liquid Chromatography-Mass Spectrometry), immunological analysis, and ECL (Electrochemiluminescence).

[0041] Examples of the LC method include methods in which the amount or ratio of a compound present is quantified from the peak area of ​​a chromatogram using various detectors, such as an absorption detector such as an ultraviolet-visible absorption detector, or an emission detector such as a fluorescence detector.

[0042] Examples of the LC-MS method include the SIM (Selected Ion Monitoring) method using a single mass spectrometry (MS) detector, and the MRM (Multiple Reaction Monitoring) or SRM (Selected Reaction Monitoring) method using a tandem mass spectrometry (MS / MS, etc.) detector. Among these, the MRM (SRM) method is preferred from the viewpoint of high-sensitivity analysis.

[0043] Examples of the immunological analysis method include immunoassay methods such as ELISA (Enzyme-Linked Immunosorbent Assay), FLISA (Fluorescence Linked Immunosorbent Assay), RIA (Radioimmunoassay), etc. Among these, ELISA and FLISA are preferred from the viewpoint of safety, etc.

[0044] Appropriate devices for measuring the amount or ratio of cilostazol, OPC-13015, etc. in the sample include, for example, LC (Liquid Chromatograph), LC-MS (Liquid Chromatograph-Mass Spectrometer), LC-MS / MS, ELISA analyzer, and ECL analyzer, corresponding to each of the above methods. Among these, LC-MS and LC-MS / MS are preferred.

[0045] 1.3 Application The therapeutic agent of the present invention can be used for the treatment of mild cognitive impairment (MCI) or dementia. Mild cognitive impairment and dementia are as described above. The therapeutic agent of the present invention is preferably used for the treatment of mild cognitive impairment. In addition, it is more preferable to use the therapeutic agent of the present invention for the treatment of disorientation and recent memory impairment among mild cognitive impairment. By treating mild cognitive impairment, which is a precursor to dementia, with the therapeutic agent of the present invention, progression to dementia can be prevented. Furthermore, the therapeutic agent of the present invention is preferably used in subjects who have not been diagnosed with intermittent claudication or stroke, or subjects who have stroke and mild cognitive impairment.

[0046] 1.4 Preparation The therapeutic agent of the present invention may be a commercially available cilostazol preparation as it is, or may be produced and used by blending cilostazol as it is or in a medicamentously acceptable non-toxic and inactive carrier in an amount of 0.01 to 99.5% by weight, preferably 0.5 to 90% by weight. The carrier may be a solid, semi-solid or liquid diluent, a filler or other formulation auxiliary, and may be used alone or in combination of two or more.

[0047] The dosage form of the therapeutic agent of the present invention may be, for example, any of the following dosage units in solid or liquid form: oral preparations such as powders, capsules, tablets (including oral rapid disintegrating tablets OD), sugar-coated tablets, granules, powders, suspensions, liquids, syrups, elixirs, and lozenges; and parenteral preparations such as injections, drip preparations, and suppositories. It may also be a sustained release preparation. The injection may be an injection kit or drip kit that is prepared just before use.

[0048] The powdered preparation can be produced by finely grinding cilostazol to an appropriate size. When cilostazol is made into a fine powder, the average particle size is usually 10 μm or less, preferably 7 μm or less, and more preferably 5 μm or less. Here, the "average particle size" refers to the volume average particle size, which is the particle size (D 50 The pulverization may be either dry pulverization or wet pulverization, and can be carried out using, for example, a jet mill, a hammer mill, a rotary ball mill, a vibrating ball mill, a shaker mill, a rod mill, a tube mill, or the like.

[0049] Powders can be prepared by grinding cilostazol to a suitable fineness and then mixing it with a similarly fine pharmaceutical carrier, for example, an edible carbohydrate such as starch, mannitol, etc. Optionally, flavorings, preservatives, dispersing agents, coloring agents, fragrances, etc. can be added.

[0050] Capsules can be produced by first filling the powdered or powdered medicine or the granulated medicine as described in the section on tablets into the capsule shell such as a gelatin capsule. They can also be produced by mixing a lubricant or a flow agent, such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, with the powdered medicine and then filling the capsule. Adding a disintegrant or a solubilizer, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, or sodium carbonate, can improve the effectiveness of the medicine when the capsule is ingested. Also, cilostazol fine powder can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and then wrapped in a gelatin sheet to produce a soft capsule.

[0051] Tablets can be produced by adding an excipient to prepare a powder mixture, granulating or slugging, adding a disintegrant or lubricant, and then compressing the mixture into tablets. Powder mixtures can be prepared by mixing the appropriate powdered material with the above-mentioned diluents and bases, and optionally adding binders (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution retardants (e.g., paraffin), resorbents (e.g., quaternary salts), adsorbents (e.g., bentonite, kaolin), and the like.

[0052] The powder mixture can be first moistened with a binder, e.g., syrup, starch paste, gum arabic, cellulose solutions or polymer solutions, mixed by stirring, dried and milled to form granules. As an alternative to granulating the powder in this way, it is also possible to first run the powder through a tablet press and then break the resulting imperfectly formed slugs into granules. The granules thus produced can be lubricated with the addition of stearic acid, stearates, talc, mineral oil, etc. as a lubricant to prevent them from sticking together. Alternatively, tablets can be produced by mixing cilostazol with a flowable inert carrier and then directly compressing the mixture into tablets, without going through the above-mentioned granulation or slugging steps.

[0053] The tablets thus produced may be film coated or sugar coated. Transparent or translucent protective coatings such as a sealing coating of shellac, coatings of sugar or polymeric materials, and polishing coatings made of wax may also be used.

[0054] Other oral administration preparations, such as liquids, syrups, troches, and elixirs, can also be made into dosage unit forms so that a fixed amount of each contains a fixed amount of cilostazol.

[0055] Syrups can be prepared by dissolving cilostazol or the like in a suitable flavored aqueous solution, while elixirs can be prepared by using a non-toxic alcoholic carrier. Suspensions can be prepared by dispersing cilostazol, etc., in a non-toxic carrier. If necessary, solubilizers, emulsifiers (e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (e.g., peppermint oil, saccharin), etc. can be added. If necessary, the dosage unit formulation for oral administration can be microencapsulated. The formulation can also be coated or embedded in a polymer, wax, etc., to provide extended action or sustained release.

[0056] The parenteral preparation can be in the form of a liquid dosage unit for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension. The parenteral preparation can be prepared by suspending or dissolving a certain amount of cilostazol in a non-toxic liquid carrier suitable for the purpose of injection, for example, an aqueous or oily medium, and then sterilizing the suspension or solution. Non-toxic salts or salt solutions can be added to make the injection isotonic. Stabilizers, preservatives, emulsifiers, etc. can also be added. It can also be made into an infusion preparation.

[0057] Suppositories can be prepared by dissolving or suspending cilostazol in a low-melting water-soluble or insoluble solid, such as polyethylene glycol, cacao butter, semi-synthetic fats and oils (e.g., Witepsol (registered trademark)), higher esters (e.g., myristyl palmitate), or a mixture thereof.

[0058] Methods for administering the therapeutic agent of the present invention include, for example, oral administration, intravenous administration, intraportal administration, subcutaneous administration, drip administration, and local administration (e.g., transmucosal administration, intranasal administration, inhalation administration, transdermal administration). The number of administrations varies depending on the type and dose of the active ingredient, dosage form, and patient condition, but can be, for example, administered once to several times a day or at intervals of one to several days.

[0059] 2. Method for determining a second dose of cilostazol for treating mild cognitive impairment or dementia according to the present invention The method of the present invention for determining a second dose of cilostazol for treating mild cognitive impairment or dementia (hereinafter referred to as the "method of the present invention") comprises the following 1 to 3 steps. 1. A step of measuring the amount of cilostazol and OPC-13015 present, or the amount of OPC-13213 and / or OPC-13217 present in a sample from a subject who has been administered an initial dose of a composition containing cilostazol or a salt thereof as an active ingredient; 2. Calculating the abundance ratio of cilostazol or OPC-13015 to the sum of the abundances of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the sum of the abundances of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217; 3. Determining a second dose of cilostazol within the pharma- ceutically acceptable dose range of cilostazol based on the above-mentioned abundance ratio.

[0060] Here, the meanings of the terms "mild cognitive impairment," "dementia," "initial dose," "second dose," and the like are the same as those defined above.

[0061] The method of the present invention may further include a step of comparing the abundance ratio of cilostazol or OPC-13015 to the total abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the total abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a cognitive impairment improvement / maintenance group known to have improved or maintained cognitive impairment, with the abundance ratio of cilostazol or the abundance ratio of OPC-13015 in the subject. By including this step, the second dose can be determined to be a dose higher than the initial dose within the range of medicamentically acceptable doses of cilostazol, when the abundance ratio of cilostazol in the subject is higher than the reference level, or when the abundance ratio of OPC-13015 is lower than the reference level, using the abundance ratio of cilostazol or OPC-13015 in a cognitive impairment improvement / maintenance group known to have improved or maintained cognitive impairment.

[0062] The method of the present invention may further include a step of comparing the abundance ratio of cilostazol or OPC-13015 to the total abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the total abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a cognitive impairment worsening group known to have worsening cognitive impairment, with the abundance ratio of cilostazol or the abundance ratio of OPC-13015 in the subject. By including this step, the second dose may be determined to be a dose higher than the initial dose within the range of medicamentically acceptable doses of cilostazol, in addition to or independently of the above-mentioned reference level, when the abundance ratio of cilostazol in the subject is higher than the reference level, or when the abundance ratio of OPC-13015 is lower than the reference level, using the above-mentioned abundance ratio of cilostazol or OPC-13015 in a cognitive impairment worsening group known to have worsening cognitive impairment.

[0063] Although cilostazol is known to be effective in preventing the progression of Alzheimer's disease or improving cognitive function, and is also known to be effective for MCI, until now, a fixed amount of cilostazol was administered to each patient regardless of the patient, resulting in individual differences in the degree of improvement in dementia function, and also in the possibility of side effects such as headaches occurring if the dose of cilostazol was increased. However, by including these steps, the second dose can be determined more accurately, and the appropriate dose of cilostazol for improving cognitive function for each patient can be determined.

[0064] The subject-derived sample in step 1 is suitably sampled within 1 to 7 hours, preferably within 30 minutes to 2 hours, after administration of the initial dose of cilostazol. If necessary, the sample may be sampled at a shorter or longer time. The sample is not particularly limited as long as it allows measurement of the amount of cilostazol, OPC-13015, etc. present in the living body, but plasma or serum is suitable, and plasma is preferred. When the sample is plasma, the "amount present" usually refers to the plasma concentration.

[0065] When the sample is a blood sample, blood cell components can be removed by centrifugation or the like to obtain a plasma sample. The plasma sample is preferably pretreated. Examples of the pretreatment include those already described in the description of the therapeutic agent of the present invention. Similarly, pretreatment by a deproteinization method using an organic solvent such as methanol or acetonitrile is preferable. The deproteinization can also be performed by sample dispensing, reagent dispensing, stirring, suction filtration, heating, centrifugation, etc.

[0066] Suitable methods for measuring the amount or ratio of cilostazol, OPC-13015, etc. in the sample are similar to those described above, and examples thereof include the LC method, the LC-MS method (e.g., the SIM method, the MRM method (SRM method)), the immunological analysis method (e.g., the ELISA method, the FLISA method), and the ECL method.

[0067] Appropriate devices for measuring the abundance or abundance ratio of cilostazol, OPC-13015, etc. in the sample include, for example, LC, LC-MS, LC-MS / MS, ELISA analyzer, and ECL analyzer, corresponding to each of the above methods. Among these, LC-MS and LC-MS / MS are preferred.

[0068] The method of the present invention can determine the second dose of cilostazol for treating mild cognitive impairment or dementia, and the method of the present invention is preferably used to determine the second dose of cilostazol for treating subjects with mild cognitive impairment, such as those with reduced orientation or those with mild cognitive impairment complicated by stroke.As for dementia, the method of the present invention is preferably used to determine the second dose of cilostazol for treating Alzheimer's dementia.

[0069] 3. Treatment system for mild cognitive impairment or dementia according to the present invention The treatment system for mild cognitive impairment or dementia according to the present invention (hereinafter referred to as the "system of the present invention") comprises a therapeutic agent of the present invention and an analytical device for measuring the presence of cilostazol, OPC-13015, and / or other metabolites in a sample from a subject after administration of an initial dose of the active ingredient to the subject.

[0070] The system of the present invention may further include a specimen pretreatment device. Specific examples of such specimen pretreatment devices include a sample dispensing device, a reagent dispensing device, a stirring device, a suction filtration device, a heating device, and a centrifugal device. Also included are specimen pretreatment devices that integrate the functions of all of these devices, or at least any of them. From the viewpoints of ease of operation and reduction of the risk of infection from biological samples, a fully automatic specimen pretreatment device equipped with the functions of sample dispensing, reagent dispensing, stirring, suction filtration or centrifugation, and heating is preferred. Examples of the analytical device in the system of the present invention include LC, LC-MS, LC-MS / MS, ELISA analytical device, and ECL analytical device. Among these, LC-MS and LC-MS / MS are preferred.

[0071] 4. Therapeutic method for patients with mild cognitive impairment or dementia according to the present invention The method for treating a patient with mild cognitive impairment or dementia according to the present invention (hereinafter referred to as the "method of the present invention") comprises the step of administering a second dose of cilostazol or a salt thereof to the patient to whom an initial dose of cilostazol or a salt thereof has been administered.

[0072] Here, the meanings of the terms "mild cognitive impairment," "dementia," "initial dose," "second dose," and the like are the same as those defined above.

[0073] In the method of the present invention, the total amount of the initial dose and the second dose of cilostazol or a salt thereof may be greater than 100 mg, which is the oral dose of cilostazol or a salt thereof per administration. According to the method of the present invention, treatment with a dose of cilostazol greater than the initial dose within the range of the medicamentously acceptable dose of cilostazol can be performed, and in the treatment of mild cognitive impairment or dementia, prevention of progression to dementia or delay of progression, and improvement of cognitive function can be expected.

[0074] In the method of the present invention, the total amount of the initial dose and the second dose of cilostazol or its salt may be within 200 mg per day. According to the method of the present invention, treatment with a dose higher than the initial dose within the range of medicamentically acceptable doses of cilostazol can be performed, and in the treatment of mild cognitive impairment or dementia, prevention or delay of progression to dementia and improvement of cognitive function can be expected.

[0075] The method of the present invention may further include the step of collecting a biological sample from the patient after administering an initial dose of cilostazol or a salt thereof to the patient and before administering a second dose, and detecting OPC-13015 in the biological sample. The method may further include the step of collecting a biological sample from the patient after administering an initial dose of cilostazol or a salt thereof to the patient and before administering a second dose, and detecting OPC-13213 in the biological sample. In addition, the time for detecting OPC-13015 and / or OPC-13213 may be within a range of 1 hour to 7 hours after administration of the initial dose.

[0076] The method of the present invention further comprises measuring the relative amounts of cilostazol or a salt thereof, OPC-13015, and / or OPC-13213. The method of the present invention further comprises calculating the abundance ratio of any one of cilostazol, a salt thereof, and OPC-13015 based on the total amount of cilostazol or a salt thereof, OPC-13015, and / or OPC-13213.

[0077] 5. Method of detecting OPC-13015 in patients with mild cognitive impairment or dementia according to the present invention The method of the present invention for detecting OPC-13015 in a patient with mild cognitive impairment or dementia comprises the steps of detecting cilostazol or a salt thereof in a biological sample collected from the patient with mild cognitive impairment or dementia, and detecting OPC-13015 in the biological sample collected from the patient with mild cognitive impairment or dementia.

[0078] Here, the meanings of the terms "mild cognitive impairment," "dementia," "initial dose," "second dose," and the like are the same as those defined above. EXAMPLES

[0079] The present invention will be described in more detail below with reference to test examples, but the present invention is not limited to the invention shown below.

[0080] [Test Example] Effect of cilostazol on MCI (1) Subjects Thirteen subjects with a CDR of 0.5 were considered to have mild cognitive impairment (MCI). The MOCA score before administration of cilostazol was 25 points or less in all subjects.

[0081] (2) Experimental method Each subject underwent a MOCA psychological test before taking cilostazol. Then, each subject took 50 mg or 100 mg cilostazol tablets twice a day for 6 months. After 6 months, each subject underwent a MOCA psychological test again. In addition to the MOCA psychological test, blood was collected from each subject after 6 months. The blood samples were pretreated with a sample pretreatment device (CLAM-2000, Shimadzu Corporation) to obtain plasma samples. Then, the plasma concentrations of cilostazol and its metabolites in each sample were measured using an ultrafast triple quadrupole LC / MS / MS system (LCMS-8040, Shimadzu Corporation).

[0082] (3) Evaluation method The relationship between the difference in the MOCA psychological test score before taking cilostazol (pre-MOCA) and the MOCA psychological test score 6 months after taking cilostazol (post-MOCA) and the plasma concentration ratio of cilostazol and its metabolites was evaluated. Patients who had a post-administration MOCA minus pre-administration MOCA score of 0 or less were classified as having maintained / worsened cognitive function, and those who had a post-administration MOCA minus pre-administration MOCA score of 0 or more were classified as having improved cognitive function.

[0083] (4) Results (4-1) The relationship between the plasma concentration ratio of each compound to the sum of the plasma concentrations of cilostazol, OPC-13015, and OPC-13213 + OPC-13217 and the cognitive function maintenance / worsening group and cognitive function improvement group was examined. The results are shown in Figure 1. In the figure, the star indicates a significant difference of p<0.05 in the t-test or Mann-Whitney test.

[0084] (4-2) The relationship between the plasma concentration of cilostazol and the ratio of the plasma concentration of each compound to the sum of the plasma concentrations of OPC-13015 and the cognitive function maintenance / worsening group and cognitive function improvement group was examined. The results are shown in Figure 2. In the figure, the asterisk indicates a significant difference of p<0.05 in the t-test or Mann-Whitney test.

[0085] As is clear from the results shown in the figure (4-3), the plasma concentrations of cilostazol, OPC-13015, and other metabolites in a subject after administration of cilostazol are measured, and the concentration ratio of cilostazol or OPC-13015 to the total concentration is calculated, whereby the second cilostazol dose for a specific subject can be determined.

Claims

1. A composition comprising cilostazol or a salt thereof as an active ingredient, an initial dose of the active ingredient is administered to the subject prior to determining a second dose of the active ingredient to be administered to the subject to treat mild cognitive impairment or dementia, or, after administration of the initial dose to the subject, a second dose of the active ingredient is administered to the subject; A treatment for mild cognitive impairment or dementia.

2. The therapeutic agent for mild cognitive impairment or dementia according to claim 1, wherein the amount of cilostazol, OPC-13015, and / or other metabolites present in a sample from the subject is measured after administration of an initial dose of the active ingredient to the subject.

3. 3. The therapeutic agent for mild cognitive impairment or dementia according to claim 2, wherein after an initial dose of the active ingredient is administered to the subject, the abundance ratio of cilostazol or OPC-13015 to the total abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the total abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a sample derived from the subject is calculated.

4. The therapeutic agent for mild cognitive impairment or dementia according to claim 3, wherein the second dose of the active ingredient is determined within a medicamentously acceptable dose range of cilostazol based on the abundance ratio of cilostazol or OPC-13015.

5. The therapeutic agent for mild cognitive impairment or dementia according to claim 4, wherein the second dose of the active ingredient is determined to be a dose greater than the initial dose within a medicamentically acceptable dose range of cilostazol when the abundance ratio of cilostazol in the subject is higher than the reference level, or when the abundance ratio of OPC-13015 in the subject is lower than the reference level, where the abundance ratio of cilostazol or OPC-13015 in a cognitive impairment improvement / maintenance group known to have improved or maintained cognitive impairment is set as a reference level.

6. The therapeutic agent for mild cognitive impairment or dementia according to claim 4 or 5, wherein the second dose of the active ingredient is determined to be a dose higher than the initial dose within a medicamentically acceptable dose range of cilostazol when the abundance ratio of cilostazol in the subject is higher than the reference level, or when the abundance ratio of OPC-13015 in the subject is lower than the reference level, with the abundance ratio of cilostazol or OPC-13015 in a cognitive impairment worsening group known to have worsening cognitive impairment being taken as the reference level.

7. 2. The method of claim 1, wherein the initial dose of the active ingredient is 50 mg twice a day, and the second dose is 100 mg twice a day or 150 mg twice a day.

8. The therapeutic agent for mild cognitive impairment or dementia according to any one of claims 2 to 7, wherein sampling from the subject is performed within 1 to 7 hours after administration of the initial dose of the active ingredient.

9. The therapeutic agent for mild cognitive impairment or dementia according to claim 2 , wherein the sample is plasma.

10. The therapeutic agent for mild cognitive impairment or dementia according to claim 9, wherein the sample is pretreated by a deproteinization method using an organic solvent.

11. The therapeutic agent for mild cognitive impairment or dementia according to any one of claims 2 to 10, wherein the abundance or abundance ratio is measured by a method selected from the group consisting of LC, ELISA, and LC-MS.

12. The therapeutic agent for mild cognitive impairment or dementia according to claim 1, wherein the dementia is Alzheimer's disease.

13. The therapeutic agent for mild cognitive impairment or dementia according to claim 1, wherein the mild cognitive impairment is a decrease in orientation.

14. The therapeutic agent for mild cognitive impairment or dementia according to claim 1 , wherein the agent is an orally administered formulation.

15. The therapeutic agent for mild cognitive impairment or dementia according to any one of claims 1 to 14, wherein the subject has not been diagnosed with intermittent claudication or stroke.

16. A method for determining a second dose of cilostazol for treating mild cognitive impairment or dementia, comprising the following steps 1 to 3:

1. Measuring the amounts of cilostazol and OPC-13015, or in addition thereto, OPC-13213 and / or OPC-13217, in a sample from a subject to whom an initial dose of a composition containing cilostazol or a salt thereof as an active ingredient has been administered; 2. A step of calculating the abundance ratio of cilostazol or OPC-13015 to the total abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the total abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217; 3. Determining a second dose of cilostazol within a pharma- ceutically acceptable dose range of cilostazol based on the abundance ratio.

17. The method according to claim 16, further comprising a step of comparing the abundance ratio of cilostazol or OPC-13015 to the sum of the abundance amounts of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the sum of the abundance amounts of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a cognitive impairment improvement / maintenance group known to have improved or maintained cognitive impairment, with the abundance ratio of cilostazol or the abundance ratio of OPC-13015 in the subject.

18. The method according to claim 16 or 17, further comprising a step of comparing the abundance ratio of cilostazol or OPC-13015 to the sum of the abundance of cilostazol and OPC-13015, or the abundance ratio of OPC-13015 to the sum of the abundance of cilostazol, OPC-13015, and OPC-13213 and / or OPC-13217 in a cognitive impairment worsening group known to have worsening cognitive impairment, with the abundance ratio of cilostazol or the abundance ratio of OPC-13015 in the subject.

19. 17. The method of claim 16, wherein the sample from the subject is sampled within 1 hour to 7 hours after administration of the initial dose of the active ingredient.

20. The method of claim 16 , wherein the sample is plasma.

21. The method according to claim 20 , wherein the sample has been pretreated by a deproteinization method using an organic solvent.

22. The method according to claim 16, wherein the abundance or abundance ratio is measured by a method selected from the group consisting of LC, ELISA, and LC-MS.

23. 17. The method of claim 16, wherein the dementia is Alzheimer's dementia.

24. 17. The method of claim 16, wherein the mild cognitive impairment is reduced orientation.

25. The therapeutic agent for mild cognitive impairment or dementia according to any one of claims 1 to 15; and A system for treating mild cognitive impairment or dementia, comprising an analytical device for measuring the presence of cilostazol, OPC-13015, and / or other metabolites in a sample from the subject after administration of an initial dose of the active ingredient to the subject.

26. The treatment system for mild cognitive impairment or dementia according to claim 25, further comprising a sample pretreatment device.

27. The treatment system for mild cognitive impairment or dementia according to claim 25 or 26, wherein the analytical device is a device selected from the group consisting of LC, LC-MS, LC-MS / MS, and ELISA analytical devices.

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