WO2012090676A1

WO2012090676A1 - Novel medicinal composition and utilization of same

Info

Publication number: WO2012090676A1
Application number: PCT/JP2011/078522
Authority: WO
Inventors: 和夫酒井
Original assignee: Sakai Kazuo
Priority date: 2010-12-26
Filing date: 2011-12-09
Publication date: 2012-07-05
Also published as: JPWO2012090676A1; JP5807018B2

Abstract

The purpose of the present invention is to safely treat or prevent, without difficulties in drug selection or dose design and without side effects, developmental disorder, schizophrenia, mood disorder, eating disorder, a mental disease following cerebrovascular disorder or a mental disease following head trauma, and to potentiate the effect of a therapeutic for cognitive impairment or an antidepressant. A medicinal composition according to the present invention, which comprises, as the active ingredient, at least one compound selected from the group consisting of ferulic acid, an ester thereof, a pharmacologically acceptable salt of the same and a pharmacologically acceptable solvate of the same, can be used, either alone or in combination with an active ingredient of a therapeutic for the aforesaid diseases or disorders, for treating the diseases or disorders.

Description

Novel pharmaceutical composition and use thereof

The present invention relates to a pharmaceutical composition for treating or preventing developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after head trauma. The invention also relates to the use of said pharmaceutical composition for treating or preventing developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after head trauma.
Furthermore, the present invention relates to a pharmaceutical composition and its use for enhancing the effect of a dementia therapeutic agent or an antidepressant.

Ferulic acid is a compound that exists mainly as an ester or glycoside of ferulic acid in the cell walls of plants and seeds such as rice, wheat, vegetables and citrus. These have been shown to have antibacterial action, antioxidant action, UV absorption action, anticancer action, etc., and are useful as additives in various products such as cosmetics and foods and in pharmaceutical compositions. Applications as components are also disclosed (specifications of Non-Patent Document 1 and Patent Documents 1 to 6).

JP-A-62-120312 JP-A 64-13017 JP-A-2-167291 Japanese Unexamined Patent Publication No. 63-283552 JP 61-204196 Japanese Unexamined Patent Publication No. 1-186835

Developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders, or mental disorders after head trauma are often difficult to identify and have a wide range of symptoms. However, there is a drawback in that there is no therapeutic agent, or even if a therapeutic agent is present, its effect is limited or selection and dose setting are very difficult. Even drugs with therapeutic effects often have side effects on the gastrointestinal / digestive system and others. The mental illness or psychiatric disorder is very often affected in combination, but there is virtually no drug capable of treating the combined illness alone, and there are contraindications between multiple therapeutic agents used in combination. Interaction must also be considered.

Thus, safely treat developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after head trauma without the difficulty and side effects of selection and dose setting There is still a need for medicinal products that can be prevented. There is also a need for pharmaceuticals that can treat or prevent the combined morbidity of these diseases or disorders, alone or in combination with other active ingredients.

Also, since the effects of existing therapeutic agents for dementia are limited, there is a need for a means of treatment or prevention that can show a further effect of improving cognitive function.

The pharmaceutical composition of the present invention effectively uses at least one compound selected from the group consisting of ferulic acid, its ester, their pharmacologically acceptable salt and their pharmacologically acceptable solvate. It is for treating or preventing a developmental disorder, schizophrenia, mood disorder, eating disorder, mental illness after cerebrovascular disorder or mental illness after head injury.

In the pharmaceutical composition of the present invention, the active ingredient may be ferulic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof.

The pharmaceutical composition of the present invention may be in a dosage form for oral administration.

In the pharmaceutical composition of the present invention, the daily dose of the active ingredient for adults may be 5 mg to 600 mg in terms of ferulic acid.

In addition, the pharmaceutical composition of the present invention may be for treating or preventing developmental disorders. In this case, the pharmaceutical composition of the present invention may be used for improving intelligence against intellectual impairment in developmental disorders, or may be used for improving athletic ability against motor impairment associated with developmental disorders.

Also, the pharmaceutical composition of the present invention may be for treating or preventing schizophrenia.

Also, the pharmaceutical composition of the present invention may be for treating or preventing mood disorders.

Moreover, the pharmaceutical composition of the present invention may be for treating or preventing eating disorders.

Further, the pharmaceutical composition of the present invention may be for treating or preventing a mental illness after cerebrovascular disorder.

Further, the pharmaceutical composition of the present invention may be for treating or preventing a mental illness after head injury.

In addition, the pharmaceutical composition of the present invention is another active ingredient for treating or preventing developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after head injury. It may be used in combination with.

Moreover, the pharmaceutical composition of the present invention may be used in combination with a dementia therapeutic agent.

Moreover, the pharmaceutical composition of the present invention may be used in combination with an antidepressant.

Pharmaceutical composition of the present invention comprising at least one compound selected from the group consisting of ferulic acid, its ester, their pharmacologically acceptable salt and their pharmacologically acceptable solvate as an active ingredient A product for treating or preventing developmental disorder, schizophrenia, mood disorder, eating disorder, mental illness after cerebrovascular disorder or mental illness after head injury, or a therapeutic agent for said disease or disorder It can be used in combination with the active ingredient.

In addition, the pharmaceutical composition of the present invention can be combined with an active ingredient of the dementia therapeutic agent or antidepressant in order to enhance the effect of the dementia therapeutic agent or antidepressant.

By using the pharmaceutical composition of the present invention, developmental disorder, schizophrenia, mood disorder, eating disorder, cerebrovascular without worrying about the difficulty and side effects of selection and dose setting associated with the use of conventional therapeutic agents A mental illness after a disorder or a mental illness after a head injury can be safely treated or prevented without side effects. Complex morbidity of the disease or disorder can also be treated or prevented by the single use of the pharmaceutical composition of the present invention. Furthermore, the effect of the therapeutic agent for the disease or disorder can be enhanced by combining with the pharmaceutical composition of the present invention.

Also, by combining the pharmaceutical composition of the present invention, the effect of a dementia therapeutic agent or an antidepressant can be enhanced.

In one embodiment, the pharmaceutical composition of the present invention can treat or prevent developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after head trauma. . Here, developmental disorder, schizophrenia, mood disorder, eating disorder, mental illness after cerebrovascular disorder or mental illness after head injury are roughly classified as developmental disorder, schizophrenia, mood. Meaning having at least one symptom characteristic of a disease or disorder classified as a disorder, eating disorder, mental disorder after cerebrovascular disorder or mental disorder after head injury. Such diseases or disorders are described in general medical books such as Merck Manual and 18th Edition (Merck Sharp and Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA). Are listed. Alternatively, it may be diagnosed or evaluated using any of the diagnostic criteria or evaluation methods normally used for such diseases or disorders in clinical practice. Such diagnostic criteria or evaluation methods are comprehensive, such as DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision: American Psychiatric Association) and “International Statistical Classification of Diseases and Related Health Issues”. (International classification of diseases) 10th revision (ICD-10: International Statistical classification of disease and Related Health Problems 10 th revision: WHO) be one of the also good, or individual of the disease name or the name of the fault and the like The disease or disorder will be described in detail below, but the disease names and disorder names shown below are listed for illustrative purposes, and the scope of the present invention is limited to these. is not.

In the present invention, “developmental disorder” includes, for example, attention deficit / hyperactivity disorder (AD / HD), autism spectrum disorder, learning disorder (LD), mental retardation, etc. (Merck Manual 18th edition). Also included are those with the following names of diseases or disorders classified as “usually diagnosed first in early childhood, childhood, or adolescence” as defined by DSM-IV-TR: mental retardation, Learning disabilities, motor disabilities, communication disabilities, pervasive developmental disabilities (autistic disorders, lettuce disorders, childhood disintegrative disorders, Asperger's disorders, unspecified pervasive developmental disorders (including atypical autism)), attention Defects and disruptive behavioral disorders, early childhood or early childhood nursing and eating disorders, tic disorders, excretion disorders, and other disorders in early childhood, childhood, or adolescence. Or it is classified as “mental retardation [intellectual disability]”, “disorder of psychological development” or “behavioral and emotional disorders that usually occur in childhood and adolescence, unspecified mental disorders” as defined by ICD-10 The following names are also included: mild mental retardation [intellectual disability], moderate [moderate] mental retardation [intellectual disability], severe mental retardation [intellectual disability], most severe mental Delay [intellectual disability], other mental retardation [intellectual disability], unspecified mental retardation [intellectual disability], specific developmental disorder of speech and language, specific developmental disability of academic ability, specific development of motor function Disorders, mixed-specific developmental disorders, pervasive developmental disorders (related to childhood autism, atypical autism, Rett syndrome, other childhood disintegration disorders, mental retardation [intellectual disabilities] and stereotypic movement Hyperkinetic disorder, Asperger syndrome, other pervasive developmental disorder, pervasive developmental disorder (unspecified)), etc. Psychological developmental disorder, unspecified psychological developmental disorder, hyperactivity disorder, behavioral disorder, mixed behavioral and emotional disorder, emotional disorder that develops specifically in childhood, specific to childhood and adolescence Disorders of social function, tic disorders, other behavioral and emotional disorders that usually develop in childhood and adolescence, mental disorders, etc. Other diagnostic criteria or evaluation methods used for diagnosis of developmental disorders in clinical settings include, for example, Wexler intelligence test (WAIS-R adult intelligence test, WISC-III, WPPSI), Binner intelligence test, infant mental development diagnosis Law.

The classification of developmental disorders can be broadly divided into
(1) low intelligence group,
(2) A group with normal to excellent intelligence but poor development of neural circuits in the brain, resulting in various symptoms,
Exists. Developmental disorders are a broad concept, and a single patient often has several disorders. Specifically, the development of cognitive and memory skills, sociality, emotional and behavioral control, motor skills, and language skills (understanding and expression) are clearly stagnant.

The pharmaceutical composition of the present invention has the effect of improving intelligence against the group (1) with low intelligence in developmental disorders, as shown in Examples below. That is, the pharmaceutical composition of the present invention is also useful as an intelligence improving agent for improving intelligence impairment in developmental disorders.

Moreover, the pharmaceutical composition of the present invention has an effect of improving athletic ability against movement disorders associated with developmental disorders (particularly coordination movement disorders), as shown in Examples below. That is, the pharmaceutical composition of the present invention is also useful as an athletic ability improving agent for improving athletic ability disorders associated with developmental disorders.

It is also known that people with developmental disabilities are likely to be absent from school or delinquency before puberty, and after entering the society, depression is likely to develop due to adaptation disorders. People with developmental disabilities have low stress tolerance and fail to adapt and become depressed if they have to deal with complex relationships and work in the workplace. Antidepressants are less effective for people with developmental disabilities and depression, and once they take a leave, they can hardly return to work. There is a developmental disorder behind the depression behind the extremely difficult reinstatement of those who take a leave due to depression, which is likely to prevent antidepressants from working. The pharmaceutical composition of the present invention is effective in improving developmental disorders behind depression, and as a result, is effective in treating depression itself. That is, the pharmaceutical composition of the present invention is also useful as a therapeutic agent for depression associated with developmental disorders.

Here, “depression” refers to those described in DSM IV IV TR (mood disorders, depression clinically diagnosed by specialists (eg psychiatrists, psychoanalysts, psychologists, and therapists). , As well as depressions that cannot be diagnosed clinically by mental health professionals, but can still be severe and long-term). Depression clinically diagnosed as a non-limiting example includes dementia, acute depression, schizophrenia, and other clinical depressive disorders classified in DSM IV STR.

The pharmaceutical composition of the present invention can enhance the effect of treating the depression of the active ingredient by combining with the active ingredient of the antidepressant. The active ingredient that can be combined with the pharmaceutical composition of the present invention is not particularly limited as long as it is used for the treatment of depression. Examples of antidepressants include tricyclic antidepressants such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, and imipramine, selective serotonin reuptake inhibitors such as citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, phenelzine And monoamine oxidase (MAO) inhibitors such as tranylcypromine and serotonin / noradrenaline reuptake inhibitors (SNRI) such as milnacipran and duloxetine. The active ingredient of the antidepressant may be included as a component of the pharmaceutical composition of the present invention, or may be formulated as a pharmaceutical composition different from the pharmaceutical composition of the present invention. Selection of an active ingredient of such an antidepressant, dosage setting, administration schedule, and the like are within the common general knowledge of those skilled in the art.

In the present invention, “schizophrenia” includes schizophrenia and related disorders such as short-term psychotic disorder, delusional disorder, schizophrenic emotional disorder and schizophrenia-like disorder (Merck Manual 18th edition). Or the names of the following diseases or disorders classified as “schizophrenia and other psychotic disorders” as defined by DSM-IV-TR: Schizophrenia, other psychotic disorders (schizophrenia) Symptomatic disorder, ataxic emotional disorder, delusional disorder, short-term psychotic disorder, shared psychotic disorder (two-person psychosis), ... [indicating general physical disease] ... psychotic disorder, substance-induced psychotic Disorder, unspecified psychotic disorder). Or the names of the following diseases or disorders classified as “schizophrenia, schizophrenic disorder and delusional disorder” as defined by ICD-10: Schizophrenia, schizophrenic disorder, persistent Delusional disorder, acute transient psychotic disorder, sensitive delusional disorder, schizophrenic emotional disorder, other non-organized psychotic disorders, unspecified non-organized psychosis. Examples of other diagnostic criteria or evaluation methods used for diagnosis of schizophrenia in clinical settings include the positive / negative symptom evaluation scale (PANSS).

In the present invention, “mood disorder” includes depressive disorder, bipolar disorder, mood circulatory disorder, etc. (Merck Manual 18th edition). Also includes those with the following disease or disorder names classified as “mood disorders” as defined by DSM-IV-TR: Depressive disorders, bipolar disorders and other mood disorders. Also includes the following disease names or disorder names classified as “mood (emotional) disorders” as defined by ICD-10: manic episodes, bipolar emotional disorder [manic depression], depression episodes, recurrent Sexual depressive disorder, persistent mood (emotion) disorder, other mood (emotion) disorder, unspecified mood (emotion) disorder. Other diagnostic criteria or evaluation methods used to diagnose mood disorders in the clinical setting include, for example, the Montgomery / Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAM-D), and the self-rated depression scale. (SDS).

In the present invention, “eating disorders” includes anorexia nervosa, bulimia nervosa, and dysphagia (Merck Manual 18th edition). Also includes those with the following disease or disorder names classified as “eating disorders” as defined by DSM-IV-TR: Anorexia nervosa, bulimia nervosa, unspecified eating disorders . Or the following disease names or disorders classified as “eating disorders” belonging to “behavioral syndromes related to physiological disorders and physical factors” defined by ICD-10: Anorexia nervosa Dysphagia, atypical anorexia nervosa, bulimia nervosa, atypical bulimia bulimia, bulimia associated with other psychological disorders, vomiting associated with other psychological disorders, Other eating disorders, eating disorders / unspecified.

In the present invention, the “mental disorder after cerebrovascular disorder” includes all mental disorders that occur after cerebrovascular disorder. The cerebrovascular disorders include all disorders that occur in the cerebral blood vessels such as ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. The mental illness after cerebrovascular disorder of the present invention includes the following disease names or disorder names classified as "psychiatric disorders due to general physical diseases" defined by DSM-IV-TR: Delirium due to disorder, dementia due to cerebrovascular disorder, amnestic disorder due to cerebrovascular disorder, psychotic disorder due to cerebrovascular disorder, mood disorder due to cerebrovascular disorder, anxiety disorder due to cerebrovascular disorder, sexual dysfunction due to cerebrovascular disorder, brain Sleep disorder due to vascular disorder, tension disorder due to cerebrovascular disorder, personality change due to cerebrovascular disorder, unspecified mental illness due to cerebrovascular disorder. Or “Other mental disorders due to brain damage, brain dysfunction and physical disease” or “Personality and behavior due to brain disease, brain damage and brain dysfunction” belonging to “Organic psychiatric disorders including symptomatic” as defined by ICD-10 The following diseases or disorders with the name “disorders” are also included: organic hallucinations, organic tension symptoms, organic paranoia [schizophrenia-like] disorders, organic mood [emotions] Disability, organic anxiety disorder, organic dissociation disorder, organic emotional instability [powerlessness] disorder, mild cognitive impairment, other specific mental disorders due to brain dysfunction, unspecified mental disorders due to brain dysfunction, Organic personality disorder, other organic personality and behavioral disorders due to brain dysfunction, unspecified organic personality and behavioral disorders due to brain dysfunction.

In the present invention, “mental illness after head injury” includes all mental illnesses that occur after head injury. The head trauma may be an open injury or a closed injury. If it is a mental illness that occurs after head injury, it does not matter whether a causal relationship with head injury is clearly shown. Mental diseases after head trauma according to the present invention include those having the following disease names or disorders classified as “psychological diseases caused by general physical diseases” as defined by DSM-IV-TR: Delirium due to trauma, dementia due to head trauma, amnestic disorder due to head trauma, psychotic disorder due to head trauma, mood disorder due to head trauma, anxiety disorder due to head trauma, sexual dysfunction due to head trauma, head Sleep disorder due to head injury, tension disorder due to head injury, personality change due to head injury, unspecified mental illness due to head injury. Or “Other mental disorders due to brain damage, brain dysfunction and physical disease” or “Personality and behavior due to brain disease, brain damage and brain dysfunction” belonging to “Organic psychiatric disorders including symptomatic” as defined by ICD-10 The following diseases or disorders with the name “disorders” are also included: organic hallucinations, organic tension symptoms, organic paranoia [schizophrenia-like] disorders, organic mood [emotions] Disability, organic anxiety disorder, organic dissociation disorder, organic emotional instability [powerlessness] disorder, mild cognitive impairment, brain injury and brain dysfunction Unspecified psychiatric disorder, organic personality disorder, other organic personality and behavioral disorders due to brain damage and brain dysfunction, unspecified organic personality due to brain damage and brain dysfunction Failure of the pre-action.

In another aspect, the pharmaceutical composition of the present invention can enhance the dementia therapeutic effect of the active ingredient by combining with the active ingredient of the dementia therapeutic agent. The active ingredient that can be combined with the pharmaceutical composition of the present invention is not particularly limited as long as it is used for the treatment of dementia. For example, it may be an active ingredient contained in a therapeutic agent for Alzheimer-type dementia, such as donepezil hydrochloride, and an active ingredient contained in a cerebral circulation improving drug such as ifenprodil tartrate, ibudilast and nicergoline, or the brain It may be an active ingredient contained in the metabolism improving drug, such as amantadine hydrochloride. The active ingredient of the therapeutic agent for dementia may be contained as a component of the pharmaceutical composition of the present invention, or may be formulated as a pharmaceutical composition different from the pharmaceutical composition of the present invention. Good. Selection of an active ingredient, dosage setting, administration schedule, and the like of such a dementia therapeutic agent are included within the common general knowledge of those skilled in the art.

In the present invention, “dementia” includes Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, HIV-related dementia, etc. (Merck Manual 18th edition). Or include the following disease or disorder names classified as “dementia” belonging to “delirium, dementia, amnestic disorder, and other cognitive disorders” as defined by DSM-IV-TR: Alzheimer Type dementia, vascular dementia, and other common diseases. Or it includes those with the following disease names or disorders classified as “organized mental disorders including symptomatic” as defined by ICD-10: Alzheimer's disease type dementia, vascular dementia, etc. Dementia of other diseases, unspecified dementia. Examples of diagnostic criteria or evaluation methods used to diagnose dementia in clinical settings include the revised Hasegawa Simple Intelligence Evaluation Scale (HDS-R).

In the present invention, therapeutically “effective” or “effective” means that subjective or objective alleviation or disappearance of one or more symptoms characteristic of the target mental disease or disorder is recognized. Can mean that. Objectively recognized may be that the fact of improvement of the disease or disorder is recognized by an index of a diagnostic standard or evaluation scale that can be used for diagnosis of the target disease or disorder in a clinical setting, or a family member In addition, one or more of the symptoms characteristic of the disease or disorder as seen from the third party such as the attending physician or a surrounding person may be recognized as an improvement such as reduction or disappearance.

In the present invention, “effective” or “effective” in terms of prevention means that the disease or disorder is administered by administering the pharmaceutical composition of the present invention in a situation where the subject can be predicted to suffer from the disease or disorder. It may mean that at least one or more symptoms that can be predicted by the onset of the disease do not develop, or that its severity or progression is suppressed. Prediction of the disease or disorder is based on medical considerations such as changes in the environment and onset of drug therapy, even if it is based on the results of medical tests such as genetic tests or tests such as CT or MRI. Also good.

The pharmaceutical composition of the present invention is at least one selected from the group consisting of ferulic acid, an ester thereof, a pharmacologically acceptable salt thereof, and a pharmacologically acceptable solvate thereof as an active ingredient. Contains one compound. The ester of ferulic acid of the present invention includes a monoester or diester obtained by esterifying one or both of the hydroxyl group and carboxyl group of ferulic acid with an aliphatic or aromatic alcohol or an aliphatic or aromatic carboxylic acid. The pharmacologically acceptable salts of ferulic acid and its esters may be those usually used in this technical field, for example, inorganic salts such as hydrochloride, sulfate, carbonate, etc., maleate, fumaric acid Organic salts such as salts and sulfonates may be used. Such pharmacologically acceptable solvates include those usually used in this technical field, such as solvates with water, alcohols or ethers. Any compound selected from the group consisting of ferulic acid, esters thereof, pharmacologically acceptable salts thereof and pharmacologically acceptable solvates thereof can be used, among which ferulic acid, Their pharmacologically acceptable salts or their pharmacologically acceptable solvates are preferred. At least one compound selected from the group consisting of ferulic acid, its esters, their pharmacologically acceptable salts and their pharmacologically acceptable solvates is extracted from any plant or seed -It may be purified or chemically synthesized. Those extracted and purified from plants are preferably those derived from rice bran, and examples of ferulic acid derived from rice bran include Feldex (trademark) manufactured by Tsukino Food Industry Co., Ltd. (Japanese Patent Publication No. 7-78032). Issue gazette). As a chemical synthesis method, for example, a method using a condensation reaction of vanillin and malonic acid is known (Journal of American Chemical Society, 74, 5346 (1952)).

The pharmaceutical composition of the present invention can be used by any administration method, but oral administration is particularly preferable among them.

The pharmaceutical composition of the present invention can be used in any dosage form, but can be administered orally, for example, powder, granule, capsule (hard capsule or soft capsule), tablet, pill, troche, liquid Particularly preferred are aerosols, elixirs and syrups.

The pharmaceutical composition of the present invention is added to at least one compound selected from the group consisting of ferulic acid, its ester, their pharmacologically acceptable salt, and their pharmacologically acceptable solvate. And one or more pharmaceutically and pharmacologically acceptable additives. Examples of pharmaceutically and pharmacologically acceptable additives include carriers, excipients, binders, disintegrants, auxiliaries, solvents, sweeteners and the like. Selection of such additives and dose setting are included within the common general knowledge of those skilled in the art.

The pharmaceutical composition of the present invention is preferably formulated so that the daily dose for adults is 5 mg to 600 mg in terms of ferulic acid. More preferably, the daily dose is 30 mg to 400 mg in terms of ferulic acid, and most preferably the daily dose is 50 mg to 250 mg in terms of ferulic acid.

The pharmaceutical composition of the present invention may be administered any time of the day, but is preferably administered once in the morning or twice in the morning and night.

The pharmaceutical composition of the present invention may have therapeutic or prophylactic effects when administered for 2 to 3 days, but is preferably administered repeatedly for 1 week or longer.

The optimal dosage and administration schedule of the pharmaceutical composition of the present invention should be appropriately determined by those skilled in the art according to the individual patient's condition, such as age, weight, sex, type or severity of disease or disorder, symptoms, etc. Can do. Such a determination is within the common general knowledge of those skilled in the art.

In addition, the pharmaceutical composition of the present invention can be used to treat or prevent developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after brain trauma. It can also be used in combination with the active ingredient. The other active ingredient is particularly an active ingredient used for treating or preventing developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after brain trauma. It is not limited. The other active ingredient may be contained as a component of the pharmaceutical composition of the present invention, or may be formulated as a pharmaceutical composition different from the pharmaceutical composition of the present invention. Selection of such other active ingredients, dosage setting, administration schedule, and the like are within the common general knowledge of those skilled in the art.

The following examples further illustrate the present invention, but the scope of the present invention is not limited to these examples.

[Example 1: Case 1 of developmental disorder]
A 20-year-old woman diagnosed with attention deficit / hyperactivity disorder (AD / HD). As specific symptoms, it was difficult to concentrate on study and work, concentration was easy to be interrupted, and a decline in results due to careless mistakes was observed. When I was a high school student, I was treated with methylphenidate hydrochloride, Ritalin® and Concerta®. The administration of Ritalin improved the academic performance by reducing careless mistakes, but had limited effects and side effects, such as sudden collapse and further depression after a certain amount of over-concentration. Even with the administration of concerta, careless mistakes decreased and academic performance improved, but the duration of overconcentration was longer than Ritalin, but this time it accumulated fatigue and became depressed, with the same limited effects as Ritalin. Side effects were noted. No drug treatment was given for about 2 years and 3 months after the age of 18 and the use of the concerta was not allowed due to age restrictions.

Therefore, ferulic acid 50 mg / day was orally administered once in the morning. From day 3 after the start of administration, improvement of attention deficit / hyperactivity disorder (AD / HD) was noticed. Specifically, my concentration improved moderately, and I was able to calm down and work on my studies and work. You can now prioritize things and improve your work setup and judgment. Unlike Ritalin and Concerta, there was no overconcentration and no side effects such as depression. The good condition continues about 2 months after the administration of the same amount of ferulic acid. In addition, no other side effects were observed.

From these findings, it was shown that the pharmaceutical composition of the present invention exerted a clear therapeutic effect with no side effects alone for developmental disorders.

[Example 2: Case 2 of developmental disorder]
This is a case of a 22-year-old woman. Symptoms of developmental disabilities such as intellectual disability, learning disability, attention deficit / hyperactivity disorder (AD / HD) derived from Williams syndrome were observed. The intelligence index measured by the Binai intelligence test was about 40. There was also a rebellious attitude towards the surrounding human beings due to the symptoms of developmental disabilities.

Therefore, ferulic acid 50 mg / day was orally administered once in the morning. From the third day after the start of administration, symptoms of developmental disorders were improved subjectively and objectively. Specifically, the organization of information in my head became smooth, and my judgment and prediction were improved. Along with that, the rebellious attitude decreased drastically and consent increased, and it became more emotionally calm. The good condition continues about one and a half months after the administration of the same amount of ferulic acid. In addition, no side effects were observed.

From these findings, it was shown that the pharmaceutical composition of the present invention exerted a clear therapeutic effect with no side effects on complex developmental disorders alone.

[Example 3: Case 3 of developmental disorder]
This is a case of a 17-year-old man. Symptoms of developmental disabilities such as mild intellectual disability, learning disability, attention deficit / hyperactivity disorder (AD / HD) derived from severe neonatal asphyxia were observed. In particular, there were symptoms such as poor recognition of time and inability to act systematically, and slow response in conversation.

Therefore, ferulic acid 50 mg / day was orally administered once in the morning. From one week after the start of administration, symptoms of developmental disorders were improved both subjectively and objectively. Specifically, the ability to recognize time has improved, and it has become possible to act systematically. In addition, improvement in judgment and prediction was seen, and the speed of response in conversation was also improved. The good condition continues about one and a half months after the administration of the same amount of ferulic acid. In addition, no side effects were observed.

[Example 4: Case 1 of Schizophrenia]
This is a case of a 49-year-old man. He developed schizophrenia at the age of 21 and has been hospitalized 7 times so far, and has been undergoing treatment at this outpatient clinic for about 4 years and 5 months. Various therapeutic drugs used for schizophrenia have been administered up to the maximum dose before the start of this outpatient treatment, and the positive symptoms disappeared, but strong negative symptoms were continuously observed. Therefore, although ABILIFY (registered trademark), that is, aripiprazole (Otsuka Pharmaceutical Co., Ltd.) was administered at an increased dose up to 30 mg / day (maximum dose), the negative symptoms did not improve. Subsequently, Lonacene (registered trademark), that is, blonanserin (Dainippon Sumitomo Pharma Co., Ltd.) was changed to 24 mg / day (maximum dose), but negative symptoms were not improved. Specific negative symptoms were conspicuous detours, decreased motivation and inactivity.

Therefore, in addition to ABILIFY 12 mg / day, 180 mg / day of ferulic acid was orally administered once in the morning. Within one week from the start of administration, improvement in negative symptoms was observed both subjectively (subjectively) and objectively (objectively). According to the positive and negative symptom rating scale (PANSS) for schizophrenia, the negative scale was 36 before ferulic acid administration, but the negative symptom improved until the negative scale reached 16 after ferulic acid administration. did. Specifically, Shiki became clear, motivated and motivated to work and activities such as going to Hello Work. Two months after the administration of the same amount of ferulic acid continues to be in good condition for negative symptoms, and no positive symptoms appear. In addition, no side effects were observed. Men's families also feel that their condition has improved the most since taking ferulic acid since the man developed schizophrenia.

From these findings, it was shown that the pharmaceutical composition of the present invention exerted a clear therapeutic effect on schizophrenia without side effects.

[Example 5: Case 2 of schizophrenia]
This is a case of a 37-year-old woman. She was diagnosed with schizophrenia at the age of 23 and has been hospitalized twice. The treatment started at this outpatient for 2 and a half years ago, and the positive symptoms have disappeared. However, the negative symptoms continued, the badness of the thoughts was conspicuous, and almost no abstract thinking was possible. The conversation with a third party could only be answered in a crisp style and could only last for 1-2 minutes. Atypical antipsychotics existing in Japan, specifically Seroquel (registered trademark), that is, quetiapine fumarate (Astellas Pharma Inc.) 300 mg / day, aripiprazole 30 mg / day, Rispadal (registered trademark), that is, risperidone ( Jansen Pharma Co.) 6 mg / day or Zyprexa (registered trademark), or olanzapine (Japan Eli Lilly Co., Ltd.) 10 mg / day, did not improve the negative symptoms. Next, Rispadaru 4mg / day, Abilify 12mg / day, Wintermin (registered trademark), that is, chlorpromazine hydrochloride (Shionogi Pharmaceutical Co., Ltd.) 25mg / day, and Depas (registered trademark), ie, etizolam (Mitsubishi Tanabe Pharma Corporation) 2mg / day, However, negative symptoms did not improve.

Therefore, in addition to these four therapeutic agents, 100 mg / day of ferulic acid was orally administered once in the morning. Improvement of negative symptoms was observed within one week from the start of administration. According to the positive and negative symptom rating scale (PANSS) for schizophrenia, the negative symptom was 34 points before ferulic acid administration, but the negative symptom improved until the negative scale reached 16 points after ferulic acid administration did. Specifically, it was animated to make a mistake, and improved motivation was recognized. You can also think abstractly, and you can continue to talk with third parties. Two months after the administration of the same amount of ferulic acid continues to be in good condition for negative symptoms, and no positive symptoms appear. In addition, no side effects were observed.

[Example 6: Case 1 of mood disorder]
This is a case of a 38-year-old housewife. He had been depressed for 3 months before visiting a psychiatric outpatient clinic. As specific symptoms, chest compression, mood depression, anxiety and insomnia were conspicuous, and the patient was diagnosed with major depressive disorder. The Montgomery / Asberg Depression Rating Scale (MADRS) at the psychiatric visit was 24 points. Prozac (registered trademark), that is, fluoxetine hydrochloride (Eli Lilly and Company) 60 mg / day was administered, and MADRS improved to 18 points in about 10 months. During the following 2 months, Prozac was used with 40 mg / day and Ribotril 1.5 mg / day for observation, but depression continued.

Therefore, in addition to 40 mg / day Prozac, 150 mg / day of ferulic acid was orally administered once in the morning. Three days after the start of administration, improvement of depressive symptoms was noted. Specifically, a feeling of chest compression, a reduction in mood, a reduction in anxiety, an improvement in sleep and an increase in motivation were observed. Two weeks after the start of ferulic acid administration, depression improved until MADRS reached 8 points. Thereafter, Prozac was reduced to half (20 mg / day) and at the same time, administration of the same amount of ferulic acid was continued. In addition, no side effects were observed. There was no change in the environment since the onset of major depression.

From these findings, it was shown that the pharmaceutical composition of the present invention exerted a clear therapeutic effect on mood disorders without side effects. *

[Example 7: Case 2 of mood disorder]
A case of a 34-year-old office worker general woman. Decreased attention, concentration, motivation, increased work mistakes, decreased memory, sleep disturbance, thought of death, and visited a psychiatric outpatient, and DSM-IV-TR Diagnosed. There were other unexplained headaches and abdominal pain. Prozac was started at 20 mg / day and increased to 60 mg / day. Sleep disorders and anxiolytics such as MediPiece (registered trademark) or Etizolam (Sawai Pharmaceutical Co., Ltd.) 0.5 mg / day, Myslee (registered trademark) or zolpidem tartrate (Astellas Pharma Inc.) 10 mg / day, Quazepam 15 mg / Day, Lexotan (registered trademark), ie Bromazepam (Eisai Co., Ltd.) 2mg / day, Ribotolyl (registered trademark), clonazepam (Chugai Pharmaceutical Co., Ltd.) 1mg / day, if necessary, Abilify 3ml / time However, the condition did not improve. In the meantime, she had been depressed for about 3 years and 7 months from the start of treatment.

Therefore, in addition to 60 mg / day of Prozac and the above-mentioned sleep disorder therapeutic agents, ferulic acid 150 mg / day was orally administered once in the morning. The MADRS at the start of ferulic acid administration was 26 points. On the second day after administration of ferulic acid, improvement in depression was recognized. Two weeks after the start of administration, the thinking speed, judgment and motivation improved significantly, and the depression improved until MADRS reached 8. Neither the person nor his family was surprised by the sudden recovery, and no side effects were observed.

From these findings, it was shown that the pharmaceutical composition of the present invention exhibited a clear therapeutic effect with no side effects on mood disorders.

[Example 8: Case of mood disorder and dementia]
This is a case of a 68-year-old housewife. He had a depressive disorder for about 10 years, and had dementia. For this reason, Aricept (registered trademark), that is, a combination of a plurality of therapeutic agents including donepezil hydrochloride (Eisai Co., Ltd.) has been used for many years, but no improvement was observed in depression and dementia.

Therefore, ferulic acid 50 mg / day was orally administered once in the morning in addition to the plurality of therapeutic agents administered so far. There was a clear improvement in depression one month after the start of administration. Specifically, memory impairment improved, and abstract thinking and judgment were improved. Motor functions such as walking function were also improved. Also, conversations increased and became brighter and more active. Continued administration of the same amount of ferulic acid, and two months later, good condition for improvement of depression continues. In addition, no side effects were observed.

From these findings, it was clearly shown that the pharmaceutical composition of the present invention enhanced the therapeutic effect and the effect of the therapeutic agent for dementia without causing side effects on the combined morbidity of mood disorders and dementia.

[Example 9: Case 1 of dementia]
This is a case of a 74-year-old woman. Memory impairment began about half a year ago, and after five months, memory impairment worsened until he was unable to return home. She was diagnosed with Alzheimer's dementia after MRI examination. At this time, no findings of vascular dementia were observed. At this time, the evaluation by the revised Hasegawa simplified intelligence evaluation scale (HDS-R) was 12 points. Aricept 3 mg / day was administered for 2 weeks, then increased to 5 mg / day and administered for another month, but no improvement in memory impairment was observed.

Therefore, in addition to Aricept 5 mg / day, 200 mg of ferulic acid per day was orally administered once in the morning. Short-term memory was improved within one week from the start of administration. After two weeks, I can always go home after going out every day. The evaluation by the revised Hasegawa simplified intelligence evaluation scale after the administration of ferulic acid was 20 points, and the symptom was clearly improved.
Two months after the administration of the same amount of ferulic acid continued to be in good condition, and the degree of memory impairment was restored to the same level as that of healthy individuals. In addition, no side effects were observed.

From these findings, it was clearly shown that the pharmaceutical composition of the present invention enhanced the effect of the therapeutic agent for dementia without causing side effects.

[Example 10: Case 2 of dementia]
This is a case of a 79-year-old man. There was a sign of dementia a year ago, and the rate of progression of dementia increased 6 months ago. Three months later, my memory impairment became so severe that it interfered with my daily life. Specifically, both short-term memory impairments, such as not remembering having breakfast, that is, the ability to remember, and long-term memory impairments, such as the absence of the names of sons and daughters, were recognized. At this time, the evaluation by the revised Hasegawa simplified intelligence evaluation scale was 16 points. Donepezil hydrochloride (Aricept (registered trademark), Eisai Co., Ltd.) was administered at 3 mg / day for 2 weeks, then increased to 5 mg / day and administered for another month, but no improvement in symptoms was observed.

Therefore, when oral administration of ferulic acid 200 mg once a day in addition to 5 mg / day of donepezil hydrochloride was performed once in the morning, short-term memory was improved from the fifth day of administration. The evaluation by the revised Hasegawa simplified intelligence evaluation scale after administration of ferulic acid was 22 points, and the symptom was clearly improved. After the administration of the same amount of ferulic acid, a good condition continued for a month and a half, and the degree of memory impairment recovered to the same level as that of a healthy person. In addition, no side effects were observed.

[Example 11: Case 4 of developmental disorder]
This is a case of a 53-year-old woman. It is a developmental disorder that does not involve mental retardation. Specifically, the difference between what you can do and what you can't do is extreme, you can't do two or more things (the same is true in life), and you often forget. He complained of symptoms such as difficulty in grasping the flow of time, difficulty in explaining something, things difficult to keep in memory, compiling materials, and sometimes comprehending sentences. Because of these symptoms, I have never worked in the same workplace for a long time. The patient was diagnosed with developmental disability with attention deficit / hyperactivity disorder (AD / HD) and learning disabilities.

Therefore, when ferulic acid was administered at a dose of 50 mg a day, no side effects appeared, the effect appeared in 2 to 3 days, and after 7 days all of the problem symptoms improved, and he felt that he was an ordinary person for the first time. Finally, 100 mg of ferulic acid was taken daily. After that, he entered a vocational training school, was able to finish successfully, succeeded in finding employment, and worked full-time.

[Example 12: Case 5 of developmental disorder]
This is a case of a 10-year-old man. One year ago, the age of intelligence was 4.0 years. It was very clumsy, low in reading and expression, and could not enter the group. The patient was diagnosed with a developmental disorder combined with mental retardation, learning disabilities, motor disabilities (coordination disorders), and communication disorders.

Therefore, when 50 mg of ferulic acid was administered daily, jumping rope that could not be performed at all was able to be performed 30 times in a week after taking it. Two weeks later, it became possible to play a role in the play. While continuing to administer ferulic acid, I became motivated in learning. I was able to swim, which I couldn't do, and even participated in music concerts. After two months, the paintings have become more complex, and after ten months, language comprehension has improved significantly. One year later, the intelligence test improved the intelligence age to 7.5 years, confirming the effect of increasing intelligence. Previous drugs had side effects, but ferulic acid has seen significant improvement without side effects and is currently living in school.

From these findings, it was shown that the pharmaceutical composition of the present invention exerted a clear therapeutic effect with no side effects on complex developmental disorders alone. In particular, it was confirmed that an improvement effect of intelligence, motor ability, and communication can be obtained for developmental disabilities combined with mental retardation, coordination movement disorder, and communication disorder.

[Example 13: Case 6 of developmental disorder]
This is a case of a 37-year-old man. A year after I got married, I noticed that my wife couldn't exchange emotions with her husband, that something was wrong with my daily life, and that many small accidents happened. She also went to psychiatry. The person seemed unable to understand his wife. As a result of evaluating the mental state, Asperger's syndrome was diagnosed.

Therefore, when 75 mg of ferulic acid was administered daily, the wife reported that the interaction in the conversation between the couple improved significantly at the visit two weeks later. In addition, the unnaturalness of daily life has improved and there has been no inattention. There were no side effects.

[Example 14: Case 7 of developmental disorder]
This is a case of a 38-year-old male office worker who had a developmental disorder in the background of depression. I was in charge of accounting at the company. When I became the accounting manager of my personal circle, a part of the accounting became unclear and I was reprimanded as the person's responsibility. Even with the maximum dose of various antidepressants, only some improvement was seen.
The room was cluttered with circle accounting slips, receipts, etc., and could not be cleaned up or processed. After 6 months of antidepressant treatment and leave, depression improved to some extent, but reinstatement was impossible. A close examination of the person's mental condition prior to leave indicated the presence of developmental disabilities.

Therefore, in addition to the antidepressant used at that time, ferulic acid was started at 50 mg per day and 150 mg per day one month later, and after 2 weeks, the depression improved. He returned to work two months later and has been working for a year since then. In addition, the dose of antidepressants has been significantly reduced.

From these findings, it was clearly shown that the pharmaceutical composition of the present invention enhanced the therapeutic effect and the effect of an antidepressant without side effects on the combined morbidity of depression and the developmental disorder behind it. .

As described above, the embodiments of the present invention have been described in detail for the purpose of illustration, but the present invention is not limited to the above-described embodiments, and various modifications are possible. This international application claims priority based on Japanese Patent Application No. 2010-289036 filed on Dec. 26, 2010, the entire contents of which are incorporated herein by reference.

Claims

Developmental disorders and integration comprising as an active ingredient at least one compound selected from the group consisting of ferulic acid, its esters, their pharmacologically acceptable salts and their pharmacologically acceptable solvates A pharmaceutical composition for treating or preventing mental disorders after ataxia, mood disorders, eating disorders, cerebrovascular disorders, or mental disorders after head trauma.
The pharmaceutical composition according to claim 1, wherein the active ingredient is ferulic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof.
The pharmaceutical composition according to claim 1, which is a dosage form for oral administration.
The pharmaceutical composition according to claim 1, wherein the daily dose of the active ingredient for adults is 5 mg to 600 mg in terms of ferulic acid.
The pharmaceutical composition according to claim 1, for treating or preventing developmental disorders.
The pharmaceutical composition according to claim 5, which is used for improving intelligence against intellectual impairment in developmental disorders.
6. The pharmaceutical composition according to claim 5, which is used for improving athletic ability for athletic ability disorder associated with developmental disorder.
The pharmaceutical composition according to claim 1, for treating or preventing schizophrenia.
The pharmaceutical composition according to claim 1, for treating or preventing mood disorders.
The pharmaceutical composition according to claim 1 for treating or preventing eating disorders.
The pharmaceutical composition according to claim 1, for treating or preventing a mental illness after cerebrovascular disorder.
The pharmaceutical composition according to claim 1, for treating or preventing a mental illness after head injury.
2. Used in combination with other active ingredients for treating or preventing developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after head trauma Pharmaceutical composition.
The pharmaceutical composition according to claim 1, which is used in combination with a therapeutic agent for dementia.
The pharmaceutical composition according to claim 1, which is used in combination with an antidepressant.
Ferulic acid, its esters, their pharmacologically acceptable for treating or preventing developmental disorders, schizophrenia, mood disorders, eating disorders, mental disorders after cerebrovascular disorders or mental disorders after head trauma Use of a pharmaceutical composition comprising as an active ingredient at least one compound selected from the group consisting of a salt thereof and a pharmacologically acceptable solvate thereof.
At least one selected from the group consisting of ferulic acid, esters thereof, pharmacologically acceptable salts thereof and pharmacologically acceptable solvates thereof for enhancing the effect of a therapeutic agent for dementia Use of a pharmaceutical composition comprising one compound as an active ingredient.
At least one selected from the group consisting of ferulic acid, its esters, their pharmacologically acceptable salts and their pharmacologically acceptable solvates for improving intelligence impairment in developmental disorders Use of a pharmaceutical composition comprising a compound as an active ingredient.
At least selected from the group consisting of ferulic acid, its esters, their pharmacologically acceptable salts and their pharmacologically acceptable solvates for improving motor impairment associated with developmental disorders Use of a pharmaceutical composition comprising one compound as an active ingredient.
At least one selected from the group consisting of ferulic acid, its esters, their pharmacologically acceptable salts and their pharmacologically acceptable solvates for enhancing the effect of antidepressants Use of a pharmaceutical composition comprising a compound as an active ingredient.