JPWO2019241503A5

JPWO2019241503A5 -

Info

Publication number: JPWO2019241503A5
Application number: JP2020569002A
Authority: JP
Publication date: 2022-04-22

Claims

A pharmaceutical composition for use in a method of treating, preventing and / or delaying the progression and / or onset of neurodegenerative disease in a required subject, wherein a therapeutically effective amount of aminosterol 1436 or pharmaceutically acceptable thereof. A pharmaceutical composition comprising a salt or derivative.

The neurodegenerative disease is (a) age-related; and / or
(b) Age-related dementia, Alzheimer's disease, Parkinson's disease, Levy body dementia, frontal temperal dementia, vascular dementia, muscular atrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Correlates with one or more pathologies or disorders selected from the group consisting of progressive supranuclear palsy (PSP), Olive Bridge cerebral dementia, and age-related cognitive decline without specific diagnosis from the group. The pharmaceutical composition according to claim 1.

(a) Progression or onset of neurodegenerative disease is delayed, stopped, or reversed, and / or over a defined period of time after administration of the pharmaceutical composition, as measured by medically recognized techniques.
(b) Neurodegeneration is positively affected by administration of the pharmaceutical composition and / or
(c) Neurodegeneration is positively affected by administration of the pharmaceutical composition, and the positive effects and / or progression of neurodegeneration are electroencephalography (EEG), neuroimaging, functional MRI, structural MRI, diffusion tensor. Diagnostic Imaging (DTI), [18F] Fluorodeoxyglucose (FDG) PET, Amyloid Labeling Agent, [18F] F-Dopa PET, Radiotracer Imaging, Volumetric Analysis of Local Tissue Loss, Specificity of Abnormal Protein Deposits Quantitatively or qualitatively measured and / or by one or more techniques selected from the group consisting of diagnostic imaging markers, multimodal diagnostic imaging and biomarker analysis.
(d) Progression or initiation of neurodegenerative disease, when measured by medically recognized techniques, is delayed, stopped, or reversed over a defined period of time after administration of the pharmaceutical composition, and progression or initiation of neurodegenerative disease The start is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. , 85%, 90%, 95%, or 100% delayed, stopped, or reversed, and / or
(e) The pharmaceutical composition according to claim 1 or 2, wherein neurodegeneration correlates with an abnormal pathology of α-synuclein (αS) and / or dopaminergic dysfunction.

Neurodegeneration,
(a) Nerve cell death, intracerebral hemorrhage, subarachnoid hemorrhage, multiple infarct dementia, inflammatory disease, neurological trauma, peripheral neuropathy, multiple neuropathies, metabolic brain disorders, and central nervous system caused by septic shock. Infection; or
(b) Synucleopathy, Alzheimer's disease, Parkinson's disease, dementia with Levy body, multilineage atrophy, Huntington's disease, multiple sclerosis, Parkinsonism, muscular atrophic lateral sclerosis (ALS), schizophrenia, Friedrich ataxia, vascular dementia, spinal temporal muscle atrophy, frontotemporal temporal lobe dementia, progressive nuclear paralysis, age-related degenerative processes, senile dementia, guaderopian parkinsonism, spinal cord Neurodegenerative disease selected from the group consisting of cerebral ataxia, illusion, stroke, traumatic brain injury, Down syndrome, Parkinson's disease, Clave's disease (KD), lysosome state affecting spingoglycolipid metabolism, cerebral palsy, and epilepsy. ;or
(c) Psychological or behavioral disorders; or
(d) Abnormal exercise and obsession behavior, sleep disorders, REM sleep behavior disorders (RBD), depression, major depressive disorders, agitation, anxiety, delirium, irritability, ADHD, psychological blunting, bipolar disorder, depressive disorder Psychological or behavioral disorders selected from the group consisting of suppression, habits, illusions and delusions, forgetfulness, autism; or
(e) Cerebral ischemic disorder or systemic ischemic disorder; or
(f) Cerebral microangiopathy, partial intracerebral ischemia, cardiac arrest or resuscitation / post-survival cerebral ischemia, cerebral ischemia due to intraoperative problems, cerebral ischemia during carotid artery surgery, narrowing of blood supply arteries to the brain Cerebral ischemic disorders selected from the group consisting of chronic cerebral ischemia, cerebral sinus thrombosis or thrombosis, cerebrovascular malformations, diabetic retinopathy;
(g) High blood pressure, high cholesterol, myocardial infarction, heart failure, heart failure, congestive heart failure, myocarditis, peritonitis, peripheral myocarditis, coronary heart disease, angina, congenital heart disease, shock, ischemia of limbs , A general ischemic disorder selected from the group consisting of stenosis of the renal arteries, diabetic retinopathy, thrombosis associated with malaria, artificial heart valve, anemia, hyperspinal hyperfunction syndrome, pulmonary emphysema, pulmonary fibrosis, and pulmonary edema;
The pharmaceutical composition according to any one of claims 1 to 3, which correlates with.

Reversibly slowing the growth, maturation, and / or aging of a subject, including administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of aminosterol 1436 or a pharmaceutically acceptable salt or derivative thereof. Or a pharmaceutical composition that delays and / or prolongs the potential lifespan of the subject.

(a) Slow or delayed growth is compared to subjects of the same age and gender who are not administered a pharmaceutical composition containing a therapeutically effective amount of aminosterol 1436 or a pharmaceutically acceptable salt or derivative thereof. And / or measured by height and / weight;
(b) Subjects administered with the pharmaceutical composition according to the invention are 5% as measured by height and / or body weight compared to subjects of the same age and gender not treated by the method of the invention. 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90 %, 95%, or 100% , growth slowed or delayed; and / or
(c) Delayed maturation is measured by indicating delayed skeletal maturation; and / or
(d) Subjects to whom the pharmaceutical composition was administered were 5%, 10%, 15%, 20%, 25% as measured by skeletal maturity compared to untreated subjects of the same age and gender. , 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% , delayed maturity Will be;
The pharmaceutical composition according to claim 5.

The pharmaceutical composition according to any one of claims 5 to 6, wherein the treatment is administered during an important "growth window" of the subject and optionally the treatment period is before the start of maturation of the subject. Things .

(a) The characteristics of aging affected by the administration of the pharmaceutical composition are selected from the group consisting of muscle endurance, coordination, social behavior and cognitive ability.
(b) Administration of the pharmaceutical composition was 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, compared to untreated subjects of the same gender and age. 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% improve muscle endurance disorders; and / or
(c) Administration of the pharmaceutical composition was 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, compared to untreated subjects of the same gender and age. 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% improve coordination; and / or
(d) Administration of the pharmaceutical composition was 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, compared to untreated subjects of the same gender and age. 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% improve cognitive impairment;
The pharmaceutical composition according to any one of claims 5 to 7.

Treatment of the development of age-related diseases, conditions or health problems in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of aminosterol 1436 or a pharmaceutically acceptable salt or derivative thereof. A prophylactic or delayed pharmaceutical composition .

The age-related disease, condition, or health problem is selected from the group consisting of atherosclerosis and cardiovascular disease, cancer, arteritis, cataracts, osteoporosis, diabetes, hypertension, Alzheimer's disease, arthritis, and osteoporosis. , The pharmaceutical composition according to claim 9.

(a) Aminosterol 1436 or a salt or derivative thereof is a pharmaceutically acceptable quality grade aminosterol 1436 or a salt or derivative thereof; and / or
(b) The pharmaceutical composition is administered via any pharmaceutically acceptable method; and / or
(c) The pharmaceutical composition is administered by intravenous, subcutaneous, subcutaneous, oral, rectal, sublingual, intrathecal, intranasal, or inhalation; and / or
(d) The pharmaceutical composition is administered intranasally; and / or
(e) The pharmaceutical composition is a liquid, capsule, which is formulated in the composition for oral administration and is designed to disintegrate in either the stomach, upper small intestine, or the more distal portion of the intestine. Or tablets; and / or
(f) The pharmaceutical composition is formulated in the composition for intranasal administration and is a nasal spray dry powder or nasal spray liquid; and / or
(g) The pharmaceutical composition is formulated into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, lyophilized formulations, tablets, and capsules; and / or
(h) The pharmaceutical composition is formulated in a dosage form selected from the group consisting of a release controlled formulation, a fast melt formulation, a release delayed formulation, a release prolongation formulation, a pulsatile release formulation, and a mixed formulation of immediate release and controlled release. Be transformed
The pharmaceutical composition according to any one of claims 1 to 10.

(a) The doses of aminosterol 1436 or its derivatives or salts are 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. A group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, and 50 mg / kg. Selected from; and / or
(b) The doses of aminosterol 1436 or its derivatives or salts are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43. , 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68. , 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110 mg / m ² ; and / or
(c) The dose of aminosterol 1436 or its derivative or salt is selected from the group consisting of 10 mg to 400 mg, or 50 mg to 350 mg, or 100 mg to 300 mg, or 100 mg to 200 mg .
The pharmaceutical composition according to any one of claims 1 to 11.

(a) Determine the dose of aminosterol 1436 or a salt or derivative thereof to the subject, where the aminosterol 1436 dose is determined based on the efficacy of the aminosterol 1436 dose in ameliorating or ameliorating the symptoms being assessed. Symptoms here are associated with subject neurodegenerative disease, age-related disease, and / or growth, maturation, and / or aging, and
(b) Subsequent administration of a dose of aminosterol 1436 or a salt or derivative thereof to the subject for a defined period, wherein the method comprises:
(i) Identification of symptoms to be evaluated;
(ii) Identification of the starting dose of aminosterol 1436 or a salt or derivative thereof for a subject; and
(iii) Administer an increasing dose of aminosterol 1436 or a salt or derivative thereof to the subject over a defined period of time until an effective dose is identified, where the effective dose is the dose at which improvement in symptoms is observed. The pharmaceutical composition according to any one of claims 1 to 12, further comprising, and fixing a dose of aminosterol 1436 at that level in a particular subject.

(a) Dose of aminosterol 1436 or a salt or derivative thereof reverses the dysfunction caused by neurodegenerative disease and treats, prevents, ameliorates and / or eliminates the symptoms being evaluated; and / or
(b) Symptom improvement or resolution is measured using clinically recognized scales or tools; and / or
(c) A clinically recognized scale or tool is used to measure improvement or disappearance of symptoms, and the clinically recognized scale or tool is the Unified Parkinson's Disease Scale (UPDRS), Mini Mental State Examination (MMSE). ), Mini Mental Parkinson (MMP), InformantQ uestionnaire on Cognitive Decline in the Elderly (IQCODE), The 7-Minute Screen, Abbreviated Mental Test Score (AMTS), Cambridge Cognitive Examination (CAMCOG), Clock Drawing Inspection (CDT), General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, Memory Impairment Screen (MIS), Montreal Cognitive Assessment (MoCA), Rowland Universal Dementia Assessment (RUDA), Self-A dministered Gerocognitive Examination (SAGE), Short and Sweet Screening Instr ument (SBT), St.Louis Mental Status (SLUMS), Short Portable Mental Status Questionnaire (SPMSQ), Short test of Mental Status (STMS), Time and Change test (T & C), Test Your Memory (TYM) test and Addenbrooke's Selected from the group consisting of Cognitive Examination-Revised (ACER); and / or
(d) Symptom improvement is at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30 when measured using clinically recognized scales or tools. %, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, At least 95%, or at least 100% ;
The pharmaceutical composition according to claim 13.

Aminosterol 1436 or a salt or derivative thereof is orally administered, and
(a) Starting doses range from 1 mg to 175 mg / day ;
(b) The starting oral dose is 25 mg / day ;
(c) The dose of the subject after dose escalation is fixed in the range of 1 mg to 500 mg / day ;
(d) The doses after the dose escalation are 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 365, 370, Fixed to a dose of 475, 480, 485, 490, 495, or 500 mg / day ,
(e) The starting dose of oral aminosterol 1436 is 10, 15, 20, 25, 30, 35, 40, 45, 60, 65, 70, or 75 mg / day .
(f) The dose of aminosterol 1436 or a salt or derivative thereof is increased by 25 mg ;
The pharmaceutical composition according to claim 13 or 14.

Aminosterol 1436 or a salt or derivative thereof is administered intranasally and
(a) Starting doses range from 0.001 mg / day to 3 mg / day ;
(b) The dose to the subject after escalation was fixed in the range of 0.001 mg to 6 mg / day ;
(c) The dose after dose increase is less than the therapeutic dose if administered orally or by injection; and / or
(d) The doses are 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, Increasing in increments of 1.7, 1.8, 1.9, or 2 mg ;
The pharmaceutical composition according to claim 13 or 14.

The dose of aminosterol 1436 or a salt or derivative thereof,
(a) Gradually increased every 3-5 days and / or
(b) Gradually increased every 1-14 days and / or
(c) Gradually increased every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days and / or
(d) Administer 1x / week, 2x / week, biweekly, 1x / month , and / or
(e) A dose containing the starting or fixed dose of aminosterol 1436 or a salt or derivative thereof, once daily, every other day, once a week, twice a week, three times a week, Administer 4 times a week, 5 times a week, 6 times a week, every other week, or every few days, and / or
(f) Administer the dose of Aminosterol 1436 or a salt or derivative thereof, including the starting or fixed dose, for the first specified period of administration, followed by the discontinuation of administration for the second specified period of time. And then resume administration in the event of recurrence of neurodegenerative disease or symptoms of neurodegenerative disease, and / or
(g) The dose containing the starting dose or the fixed dose of aminosterol 1436 or a salt or derivative thereof is gradually decreased after the fixed dose of aminosterol or a salt or derivative thereof is administered to the subject for a specified period. And / or
(h) The dose, including the starting or fixed dose of aminosterol 1436 or a salt or derivative thereof, may be varied by plus or minus the prescribed amount to allow a modest reduction or increase in the fixed dose. And / or
(i) Dosages, including starting or fixed doses of aminosterol 1436 or salts or derivatives thereof, are varied and fixed by adding or subtracting prescribed amounts to allow modest reduction or increase in fixed doses. The doses of aminosterol 1436 are 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15 Increased or decreased by %, 16%, 17%, 18%, 19%, or 20% , and / or
(j) The starting dose of aminosterol 1436 or a salt or derivative thereof is higher and / or if the symptoms being evaluated are severe when measured using a clinically recognized scale or tool.
(k) The starting dose of aminosterol 1436 is based on the baseline score of a cognitive test or tool, where if the baseline score correlates with the assessment of mild neurodegenerative disease, then the baseline score is for severe neurodegenerative disease. The starting dose of aminosterol 1436 is lower than when it correlates with the evaluation; and / or
(l) Subjects experience moderate or mild neurodegenerative disease as determined by clinical scale or test, where the starting dose of oral aminosterol 1436 is 10-75 mg / day ; and / or
(m) Subject experiences severe neurodegenerative disease as determined by clinical scale or test, where the starting dose for oral aminosterol 1436 is greater than 75 mg / day .
The pharmaceutical composition according to any one of claims 13 to 16.

Symptoms
(a) Cognitive impairment as determined by IQ score;
(b) Cognitive impairment as determined by memory or cognitive function tests;
(c) Poor thinking and reasoning;
(d) Confusion;
(e) Poor motor coordination;
(f) Short-term memory loss;
(g) Long-term memory loss;
(h) Loss of identity;
(i) Impaired judgment;
(j) Forgetfulness;
(k) Depression;
(l) Irritability;
(m) Short temper;
(n) Compulsive behavior;
(o) Lethargy and / or lack of motivation;
(p) Emotional imbalance;
(q) Decreased problem-solving ability;
(r) Language disorder;
(s) Decreased reasoning power;
(t) Impairment of decision-making ability;
(u) Lack of concentration;
(v) Communication disorders;
(w) Impairment of ability to carry out daily tasks such as cooking;
(x) Self-care including eating and changing clothes;
(y) Constipation;
(z) Neurodegeneration;
(aa) Sleep problems, sleep disorders and / or sleep disturbances;
(bb) Hypertension;
(cc) hypotension;
(dd) Sexual dysfunction;
(ee) Cardiovascular disease;
(ff) Cardiovascular dysfunction;
(gg) Working memory disorder;
(hh) Gastrointestinal (GI) disorders;
(ii) Attention deficit / hyperactivity disorder;
(jj) Seizures;
(kk) Dysuria;
(ll) Difficulty to chew;
(mm) visual problems; and
(nn) Weakness;
The pharmaceutical composition according to any one of claims 13 to 17, which is selected from the group consisting of.

Symptoms to be evaluated are
(a) Cognitive impairment, determined by IQ score or by memory or cognitive function test, where:
(i) The progression or initiation of CI is delayed and stopped for a defined period of time after administration of a fixed escalating dose of aminosterol 1436 or a salt or derivative thereof, as measured by medically recognized techniques. , Or reversed;
(ii) CI is positively affected by a fixed escalating dose of aminosterol 1436 or a salt or derivative thereof when measured by medically recognized techniques;
(iii) CI is positively affected by a fixed escalating dose of aminosterol 1436 or a salt or derivative thereof when measured by medically recognized techniques, and the positive effects and / or progression of cognitive decline are ADASCog. , Mini-Mental State Exam (MMSE), Mini-cog Exam, Woodcock-Johnson Tests of Cognitive Abilities, Leiter International Performance Scale, Miller Analogies test, Raven's Progressive Matrices, Wonderlic Personnel test, IQ Exam, or Cantab Mobile, Cognigram, Cognivue , Cognision, and computerized tests selected from the Automated Neuropsychological Assessment Metrics Cognitive Performance Test (CPT), measured quantitatively or qualitatively by one or more medically recognized techniques selected from the group consisting of. ,
(iv) 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% of CI progression or onset as measured by medically recognized techniques. , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% delayed, stopped, or reversed;
(b) Depression: Here
(i) The method results in an improvement in the subject's depression when measured by one or more clinically recognized depression assessment scales;
(ii) The method results in an improvement in the subject's depression when measured by one or more clinically recognized depression assessment scales, which are mood, behavior, diet, sleep, vitality, And in physical functions such as sexual activity, and / or in one or more depressive traits selected from the group consisting of episodes of sadness or apathy; and / or
(iii) The method results in an improvement in the subject's depression when measured by one or more clinically recognized depression rating scales, and the improvement experienced by the subject after treatment is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% , optionally patient health questionnaire-9 ( PHQ-9), Beck Depression Questionnaire (BDI), Zung Self-Rating Depression Scale, Epidemiological Research Center Depression Scale (CES-D), and Hamilton Depression Rating Scale (HRSD). One or more depression rating scales recognized in are selected;
(c) Constipation, here:
(i) Treatment of constipation prevents and / or delays the onset and / or progression of neurodegenerative disease;
(ii) A fixed escalating dose of aminosterol 1436 results in defecation of the subject;
(iii) This method results in an increased frequency of defecation in the subject;
(iv) This method results in an increase in the frequency of defecation in the subject, and the increase in the frequency of defecation is defined as follows.
(1) 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% , 85%, 90%, 95%, and 100% increased bowel movements per week; and / or
(2) 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% , 85%, 90%, 95%, or 100%, the rate of decrease in the amount of time between each continuous defecation selected from the group;
(v) As a result of this method, the subject has a defecation frequency recommended by the medical authorities for the subject's age group; and / or
(vi) The starting aminosterol 1436 dose is determined by the severity of constipation:
(1) If the average complete spontaneous defecation volume (CSBM) or spontaneous defecation volume (SBM) is less than once a week, the starting dose of aminosterol 1436 is at least 150 mg ;
(2) If the mean CSBM or SBM is greater than once a week, the starting aminosterol 1436 dose is 75 mg or less;
(d) Sleep problems, sleep disorders or disturbed sleep:
(i) Sleep problems, sleep disorders or disturbed sleep include delayed sleep onset, sleep fragmentation, REM behavior disorders, sleep breathing disorders including sneezing and aspiration, daytime sleepiness, microsleep episodes, narcolepsis, circadian rhythms. Includes dysfunction, REM disorder sleep, or any combination of these;
(ii) Sleep problems, sleep disorders or disturbed sleep include REM behavioral disorders, which include vivid dreams, nightmares, talking or crying to carry out dreams, or hitting arms or legs during sleep. Including;
(iii) Treatment of sleep problems, sleep disorders, or disturbed sleep prevents or delays the onset and / or progression of CI;
(iv) This method results in positive changes in the subject's sleep pattern, where the positive changes are defined as:
(1) The increase in the total amount of sleep obtained is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%. , 70%, 75%, 80%, 85%, 90%, 95%, and 100% , and / or
(2) The rate of decrease in the number of nighttime awakenings is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%. , 70%, 75%, 80%, 85%, 90%, 95%, or 100% .
(v) As a result of this method, the subject obtained the total number of hours of sleep recommended by the medical institution for the subject's age group.
(e) The method according to any one of subsections (a) to (d), wherein the respective specified periods are independently 1 to 10 days, 10 days to 30 days, 30 days. Selected from the group consisting of days to 3 months, 3 months to 6 months, 6 months to 12 months, and over 12 months .
The pharmaceutical composition according to claim 18.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the subject is a human.