WO2009093671A1 - Antidepressant/antianxiety agent - Google Patents

Antidepressant/antianxiety agent Download PDF

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Publication number
WO2009093671A1
WO2009093671A1 PCT/JP2009/051027 JP2009051027W WO2009093671A1 WO 2009093671 A1 WO2009093671 A1 WO 2009093671A1 JP 2009051027 W JP2009051027 W JP 2009051027W WO 2009093671 A1 WO2009093671 A1 WO 2009093671A1
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Prior art keywords
ile
leu
peptide
anxiety
active ingredient
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PCT/JP2009/051027
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French (fr)
Japanese (ja)
Inventor
Atsumi Nitta
Yoko Hibi
Toshitaka Nabeshima
Koji Morishita
Takeshi Ikeda
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Kyowa Hakko Bio Co., Ltd.
National University Corporation Nagoya University
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Publication of WO2009093671A1 publication Critical patent/WO2009093671A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid

Definitions

  • the present invention relates to an antidepressant and anxiolytic agent effective in suppressing and improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
  • Tricyclic antidepressants such as imipramine were widely used as treatments for depression, but these have strong unpleasant side effects due to anticholinergic effects such as dry mouth, blurred vision, urinary retention, and constipation. It is known.
  • selective serotonin reuptake inhibitors with reduced side effects and serotonin and noradrenaline reuptake inhibitors have been put on the market, and the options for drug treatment for depression are expanding.
  • side effects such as sexual dysfunction and gastrointestinal disorders have been pointed out, and it is not suitable for long-term use or preventive use of the elderly. Therefore, a new type of antidepressant that has no side effects and high safety is desired.
  • benzodiazepine-based drugs are widely used as anxiolytic drugs, but when taken over a long period of time, side effects such as tolerance, mental and physical dependence may occur. Alternatively, even when taken in a small amount or for a short period of time, side effects such as drowsiness, reduced behavioral ability, and ataxia may occur, and there is a need to develop a highly safe anxiolytic agent that has no side effects.
  • Non-Patent Document 1 Non-Patent Document 1
  • BDNF brain-derived neurophic factor
  • Non-patent Document 2 glial cell line-derived neurophic factor
  • Akt Akt involved in the regulation of GDNF production
  • JP-A-2005-41834 WO / 2006/090555 Nitta A. et al., Folia Pharmacologica Japonica, 122: 81-83 (2003) Nitta A et al .. J Neurosci. Res., 78: 250-258 (2004)
  • An object of the present invention is to provide a novel antidepressant and anxiolytic agent effective in suppressing or improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
  • the present inventors have found that the dipeptide Leu-Ile, which has significantly different physical properties and chemical structures from conventional representative antidepressants or anxiolytic agents, such as depression and anxiety.
  • the present inventors have found that it is effective in suppressing and improving psychiatric symptoms, and have completed the present invention.
  • the present invention has been obtained from the above knowledge and has the following configuration.
  • An antidepressant comprising a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
  • An anxiolytic agent comprising a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
  • a method for preventing or treating depression or anxiety comprising the step of administering to a living body a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient.
  • peptides are expressed according to a conventional notation so that the left end is the amino terminus and the right end is the carboxyl terminus.
  • the amino acid residue is L-form
  • the indication that it is L-form is omitted.
  • the present invention provides a novel antidepressant and anxiolytic agent effective in suppressing or improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
  • 6 is a graph showing measurement results of immobility time by a forced swimming test of Test Example 1. It is a graph which shows the measurement result of the open arm stay time by the elevated plus maze test of Test example 2. 6 is a graph showing the results of the number of new neurons in the hippocampal dentate gyrus of Test Example 3.
  • examples of the peptide consisting of Leu and Ile include Leu-Ile and Ile-Leu, but Leu-Ile is preferably used.
  • a peptide consisting of Leu and Ile or a modified form thereof is a part of the basic structure (dipeptide) consisting of Leu and Ile (may be a plurality of positions) with other atomic groups or the like.
  • a compound having a structure different from the basic structure is shown at least in part by modification such as substitution or addition of another molecule.
  • a peptide obtained by substituting at least one of Leu and Ile in a dipeptide with a D-form or DL-form is also included in a peptide comprising Leu and Ile or a modified form thereof.
  • a peptide derivative in which a part of the side chain of Leu or Ile is substituted with another atom or atomic group can be mentioned.
  • Other atoms or atomic groups herein include a hydroxyl group, halogen (fluorine, chlorine, bromine, iodine, etc.), alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, etc.), hydroxyalkyl group ( Examples thereof include hydroxymethyl group, hydroxyethyl group, etc., alkoxy groups (methoxy group, ethoxy group, etc.), acyl groups (formyl group, acetyl group, malonyl group, benzoyl group, etc.) and the like.
  • the modified peptide of the present invention includes those in which the functional group of Leu or Ile is protected by an appropriate protecting group.
  • an acyl group, an alkyl group, a monosaccharide, an oligosaccharide, a polysaccharide and the like can be used.
  • Such a protecting group is linked by an amide bond, an ester bond, a urethane bond, a urea bond, or the like according to the peptide site to which the protecting group is bound, the kind of the protecting group to be used, or the like.
  • modified peptide of the present invention one modified by addition of a sugar chain can be mentioned.
  • various peptide derivatives classified into alkylamine, alkylamide, sulfinyl, sulfonylamide, halide, amide, aminoalcohol, ester, aminoaldehyde, etc. by replacing the N-terminal or C-terminal with other atoms etc. Included in the modified peptides of the invention.
  • a peptide derivative constituted by combining the various modification methods described above may be used as the modified peptide of the present invention.
  • the peptide of Leu and Ile according to the present invention or a modified form thereof includes a salt of the peptide, a salt of the modified peptide or a hydrate thereof.
  • the salt of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and is a salt (inorganic acid salt) with hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, boric acid or the like, formic acid, acetic acid, lactic acid, fumaric acid Examples thereof include salts (organic acid salts) with maleic acid, tartaric acid, citric acid and the like. These salts can be prepared by conventional means.
  • dietary supplements include oral preparations that have the same shape as pharmaceuticals but do not belong to pharmaceuticals under the Pharmaceutical Affairs Law, or those obtained by adding the active ingredient of the present invention to foods.
  • the present invention corresponds to a pharmaceutical composition or a dietary supplement nutrition composition containing a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
  • the pharmaceutical preparation means a carrier usually used as a pharmaceutical preparation base for the active ingredient of the present invention, such as an excipient, a disintegrant, a lubricant, a buffering agent, a binder, an emulsifier, a suspending agent, and a soothing agent.
  • a carrier usually used as a pharmaceutical preparation base for the active ingredient of the present invention, such as an excipient, a disintegrant, a lubricant, a buffering agent, a binder, an emulsifier, a suspending agent, and a soothing agent.
  • an excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • starch carboxymethylcellulose, calcium carbonate and the like
  • Phosphate, citrate, acetate, etc. can be used as the buffer.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • binder pullulan, gum arabic, gelatin, starch or the like can be used.
  • lubricant magnesium stearate, methylcellulose, or magnesium silicate can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • stabilizer propylene glycol, diethylin sulfite, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • the dietary supplement oral preparation in the present invention is a carrier that is usually used as a base for a nutritional food preparation for the active ingredient of the present invention, such as an excipient, a disintegrant, an emulsifier, a stabilizer, a lubricant, a buffer, a fragrance.
  • the dosage form includes tablets, powders, fine granules, granules, and capsules.
  • Examples of dietary supplements obtained by adding the active ingredient of the present invention to foods include nutritional drinks, soft drinks, jelly, and the like produced by the conventional method using the active ingredient of the present invention.
  • a peptide comprising Leu and Ile can be produced by a known peptide synthesis method (for example, solid phase synthesis method, liquid phase synthesis method). However, when the peptide of the present invention exists in nature, it can also be prepared by operations such as extraction and purification. Examples of sources for obtaining the peptide of the present invention include animal cells (including humans), plant cells, body fluids (blood, urine, etc.).
  • a modified form of a peptide consisting of Leu and Ile can be produced by a conventional method as described above.
  • compositions or oral dietary supplement preparations containing modified peptides of Leu and Ile as active ingredients should be produced according to conventional methods using the obtained modified peptides of Leu and Ile as the main active ingredients. Can do.
  • other pharmaceutically acceptable ingredients for example, carriers, excipients, disintegrants, buffers, emulsifiers, binders, lubricants, suspending agents, soothing agents, stabilizers, Preservatives, preservatives, physiological saline, and the like
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
  • gum arabic sodium alginate, tragacanth and the like
  • binder pullulan, gum arabic, gelatin, starch or the like
  • lubricant magnesium stearate, methylcellulose, or magnesium silicate can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • propylene glycol, diethylin sulfite, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • desired dosage forms such as tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and suppositories can be produced by conventional methods.
  • modified foods of peptides consisting of Leu and Ile can be added to produce nutritional foods such as nutritional drinks, soft drinks, and jelly by conventional methods.
  • the antidepressant and anxiolytic agent comprising the thus obtained Leu and Ile peptide of the present invention or a modified product thereof as an active ingredient is administered orally or parenterally (intravenous, intraarterial, (Subcutaneous, intramuscular, intraperitoneal injection, etc.).
  • the content of active ingredients (peptides, etc.) in the drug of the present invention generally varies depending on the dosage form, but in the case of liquid preparations such as injections, it is about 0.001% to about 10% by weight, preferably 0.01% to about 3% by weight. Particularly preferably, it is 0.1% by weight to about 1% by weight. In the case of a solid preparation such as a tablet, 0.1% by weight to about 90% by weight, preferably 1% by weight to about 50% by weight, particularly preferably 3% by weight to about 1% by weight. 30% by weight.
  • the treatment method or prevention method of the present invention includes a step of administering to a living body a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient.
  • the administration route is not particularly limited, and examples thereof include oral, intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, and transmucosal.
  • the dose of the drug varies depending on symptoms, patient age, sex, weight, and the like, but those skilled in the art can appropriately set an appropriate dose.
  • the amount of active ingredient per day for an adult is about 0.1 ⁇ g to about 3000 kg, preferably about 0.1 mg to about
  • the dose can be set to 2000 mg, particularly preferably about 0.1 mg to about 1000 mg.
  • the administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted.
  • a method for preventing depression (anxiety) and anxiety (anxiety symptoms) by administering a preparation comprising a peptide consisting of Leu and Ile or a modified form thereof as an active ingredient is the expression of symptoms of depression and anxiety
  • non-adult adults take prophylactic preparations containing a peptide consisting of Leu and Ile or a modified form thereof as an active ingredient.
  • a method of treating depression and anxiety by administering a preparation comprising a peptide comprising Ile or a modified form thereof as an active ingredient is a method for suppressing or preventing progression of depression and anxiety in a patient who has developed symptoms of depression or anxiety Indicates administration to improve. In setting the administration schedule, it is possible to take into account the patient's medical condition and the duration of the drug effect.
  • depression or “depression” according to the present invention is a kind of mood disorder, depressed mood, decreased motivation, loss of interest and joy, reduced concentration and attention, self-evaluation and reduced confidence It means psychiatric symptoms or diseases characterized by guilt and worthlessness, pessimism about the future, suicidal ideation, sleep disorders, and anorexia. In clinical settings, it is often treated as depression that has a certain degree of severity in the DSM diagnostic criteria, which is “other than bereavement reaction, lasts every day for more than 2 weeks and presents functional impairment of life”. However, in the present invention, without being bound by such diagnostic criteria, depression associated with transient psychological stress (adaptation disorder, acute stress disorder, PTSD, etc.), schizophrenia, panic disorder, etc. It is intended to broadly encompass diseases or symptoms associated with depression, such as depression and endogenous depression as symptoms of other diseases.
  • anxiety or “anxiety symptom” is a psychiatric symptom or disease whose main symptom is anxiety (a kind of emotion that occurs when the self cannot cope with fear without a clear target). It means general and may manifest as physical symptoms such as sweating, palpitation, tachycardia, chest pain, headache, diarrhea as well as behavioral and psychological disorders.
  • the “anxiety” includes phobic anxiety disorder (square fear, social phobia (social anxiety disorder), interpersonal phobia), panic disorder, irritable bowel syndrome, generalized anxiety disorder, mixedness Anxiety is a major symptom, such as anxiety-depressive disorder, obsessive-compulsive disorder, severe stress response and adjustment disorder (PTSD, acute stress disorder, adjustment disorder), general physical anxiety disorder, substance-induced anxiety disorder, unspecified anxiety disorder It is intended to encompass a wide range of diseases or symptoms.
  • the antidepressant action and anxiolytic action of the present invention can be confirmed by a forced swimming test method using a mouse and an elevated plus maze test, as described below.
  • the forced swimming test method is the most widely used method for evaluating antidepressants in animals, and clinically effective antidepressants are known to shorten immobility time (Porsortet al. Nature 266, 730-732, 1977).
  • the elevated plus maze test is commonly used as an anxiolytic evaluation method. When anxiety is reduced by the administration of anxiolytics, the time spent on a runway with no walls (open arm) is extended. (Pellow et al., Pharmacol, Biochem, Behav., 24, 525-529, 1986).
  • Leu-Ile 750 ⁇ mol / Kg was orally administered to the Leu-Ile administration group using an oral sonde. Forced swimming and dosing were performed for 2 weeks. Statistical analysis was performed by analysis of variance (determined that there was a significant difference at a significance level of less than 5%), and the antidepressant action of Leu-Ile was measured.
  • Figure 1 shows the result of the immobility time.
  • the immobility time was significantly shortened on the 14th day compared to the control group. From these results, it was revealed that Leu-Ile has an antidepressant action.
  • Brodeoxyuridine (BrdU) 75 mg / Kg was intraperitoneally administered three times every 3 hours on the last day. The remaining 1 group was not loaded with forced swimming, and BrdU was administered at the same timing as the other 2 groups (forced swimming unloaded group).
  • the results of the number of new neurons in the hippocampal dentate gyrus are shown in FIG.
  • the control group showed a significant decrease in the number of BrdU positive cells compared to the forced swimming no-load group.
  • the Leu-Ile administration group showed a significant increase in the number of BrdU positive cells compared to the control group. From these results, it was revealed that Leu-Ile promotes the neurogenesis of neurons.
  • Example 1 Tablets Tablets having the following composition are prepared by a conventional method.
  • the present invention can be used in the pharmaceutical and food fields as a pharmaceutical composition and a nutritional composition for dietary supplements for the purpose of preventing or treating depression or anxiety.

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Abstract

Disclosed is a novel antidepressant and antianxiety agent which is effective for the prevention or amelioration of a mental condition induced by stress or the like, particularly a depression or anxiety condition. The antidepressant and antianxiety agent comprises a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.

Description

抗うつ・抗不安剤Antidepressant / Anxiolytic
　本発明は、ストレスなどに起因する精神症状、特にうつ、不安症状の抑制や改善に有効な抗うつおよび抗不安剤に関する。 The present invention relates to an antidepressant and anxiolytic agent effective in suppressing and improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
　近年のストレス社会を反映して、うつ病もしくは不安症になる人が年々増加しており、大きな社会問題となっている。うつ病の治療薬としては、イミプラミンを代表とする三環系抗うつ剤が広く用いられていたが、これらは口渇、かすみ目、尿閉、便秘など、抗コリン作用による不快な副作用が強いことが知られている。最近では副作用の軽減された選択的セロトニン再取り込み阻害剤や、セロトニン・ノルアドレナリン再取り込み阻害剤が上市され、うつ病に対する薬物治療の選択肢が広がっている。しかしながら依然として、性機能障害や消化器障害といった副作用の発現が指摘されており、高齢者の長期間の服用、予防的な服用などには適していない。そのため副作用がなく、安全性の高い新しいタイプの抗うつ剤が望まれている。 Reflecting the recent stress society, the number of people who become depressed or anxious is increasing year by year, which is a big social problem. Tricyclic antidepressants such as imipramine were widely used as treatments for depression, but these have strong unpleasant side effects due to anticholinergic effects such as dry mouth, blurred vision, urinary retention, and constipation. It is known. Recently, selective serotonin reuptake inhibitors with reduced side effects and serotonin and noradrenaline reuptake inhibitors have been put on the market, and the options for drug treatment for depression are expanding. However, side effects such as sexual dysfunction and gastrointestinal disorders have been pointed out, and it is not suitable for long-term use or preventive use of the elderly. Therefore, a new type of antidepressant that has no side effects and high safety is desired.
　一方で不安症の治療薬としては、ベンゾジアゼピン系の薬剤が広く用いられているが、長期間に渡って服用した場合、耐性や精神及び身体依存などの副作用が引き起されることがある。或いは少量もしくは短期間の服用でも、眠気、行動力低下、運動失調などの副作用の発生が起こることもあり、副作用がなく、安全性の高い抗不安剤の開発が必要とされている。 On the other hand, benzodiazepine-based drugs are widely used as anxiolytic drugs, but when taken over a long period of time, side effects such as tolerance, mental and physical dependence may occur. Alternatively, even when taken in a small amount or for a short period of time, side effects such as drowsiness, reduced behavioral ability, and ataxia may occur, and there is a need to develop a highly safe anxiolytic agent that has no side effects.
　ジペプチドであるLeu-Ileには、薬物依存症に対する治療効果があること（特許文献１、非特許文献１）、脳内線条体でbrain-derived neurophic factor(BDNF)およびglial cell line-derived neurophic factor(GDNF)の産生を増やし、ドーパミン作動性神経の細胞死を抑制する作用（非特許文献２）、GDNFの産生調節に関与するAktの活性化作用が知られているが（特許文献２）、抗うつもしくは抗不安作用を有することは知られていない。
特開２００５－４１８３４ WO/2006/090555 Nitta A.et al., Folia Pharmacologica Japonica, 122:81-83 (2003) Nitta A et al..J Neurosci. Res., 78:250-258 (2004) Leu-Ile, a dipeptide, has a therapeutic effect on drug dependence (Patent Document 1, Non-Patent Document 1), brain-derived neurophic factor (BDNF) and glial cell line-derived neurophic factor in the cerebral striatum The action of increasing the production of (GDNF) and suppressing cell death of dopaminergic nerves (Non-patent Document 2) and the activation action of Akt involved in the regulation of GDNF production are known (Patent Document 2). It is not known to have antidepressant or anxiolytic effects.
JP-A-2005-41834 WO / 2006/090555 Nitta A. et al., Folia Pharmacologica Japonica, 122: 81-83 (2003) Nitta A et al .. J Neurosci. Res., 78: 250-258 (2004)
　本発明は、ストレスなどに起因する精神症状、特にうつ、不安症状の抑制や改善に有効な、新規の抗うつおよび抗不安剤を提供することを目的とする。 An object of the present invention is to provide a novel antidepressant and anxiolytic agent effective in suppressing or improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
　本発明者らは、上記課題を解決するために鋭意検討した結果、従来の代表的な抗うつ剤あるいは抗不安剤とは物性、化学構造が著しく異なるジペプチドLeu-Ileに、うつや不安などの精神症状の抑制や改善に効果があることを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that the dipeptide Leu-Ile, which has significantly different physical properties and chemical structures from conventional representative antidepressants or anxiolytic agents, such as depression and anxiety. The present inventors have found that it is effective in suppressing and improving psychiatric symptoms, and have completed the present invention.
　本発明は、上記知見により得られたものであって以下の構成を有する。 The present invention has been obtained from the above knowledge and has the following configuration.
（１）LeuおよびIleからなるペプチドまたはその修飾体を有効成分とする抗うつ剤。 (1) An antidepressant comprising a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
（２）LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする（１）の抗うつ剤。 (2) The antidepressant according to (1), wherein the peptide comprising Leu and Ile is Leu-Ile.
（３）Leu-Ileを有効成分とする（１）の抗うつ剤。 (3) The antidepressant according to (1) comprising Leu-Ile as an active ingredient.
（４）LeuおよびIleからなるペプチドまたはその修飾体を有効成分とする抗不安剤。 (4) An anxiolytic agent comprising a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
（５）LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする（４）の抗不安剤。 (5) The anxiolytic agent according to (4), wherein the peptide comprising Leu and Ile is Leu-Ile.
（６）Leu-Ileを有効成分とする（４）の抗不安剤。 (6) The anxiolytic agent according to (4), comprising Leu-Ile as an active ingredient.
（７）LeuおよびIleからなるペプチドまたはその修飾体を有効成分として含む製剤を生体に投与するステップを含む、うつ病または不安症の予防方法または治療方法。 (7) A method for preventing or treating depression or anxiety, comprising the step of administering to a living body a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient.
（８）LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする（７）の予防方法または治療方法。 (8) The preventive or therapeutic method according to (7), wherein the peptide comprising Leu and Ile is Leu-Ile.
（９）製剤がLeu-Ileを有効成分とする、（７）の予防方法または治療方法。 (9) The preventive or therapeutic method according to (7), wherein the preparation contains Leu-Ile as an active ingredient.
（１０）うつ病または不安症を予防または治療するための医薬の製造における、LeuおよびIleからなるペプチドまたはその修飾体の使用。 (10) Use of a peptide comprising Leu and Ile or a modified form thereof in the manufacture of a medicament for preventing or treating depression or anxiety.
（１１）LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする（１０）の使用。 (11) Use of (10), wherein the peptide comprising Leu and Ile is Leu-Ile.
（１２）LeuおよびIleからなるペプチドまたはその修飾体がLeu-Ileである、（１０）の使用。 (12) Use of (10), wherein the peptide consisting of Leu and Ile or a modified form thereof is Leu-Ile.
　なお、本明細書では慣例の表記法に従い左端がアミノ末端、右端がカルボキシル末端となるようにペプチドを表記する。また、アミノ酸残基がL体である場合には、L体である旨の表示を省略する。 In the present specification, peptides are expressed according to a conventional notation so that the left end is the amino terminus and the right end is the carboxyl terminus. When the amino acid residue is L-form, the indication that it is L-form is omitted.
　本発明により、ストレスなどに起因する精神症状、特にうつ、不安症状の抑制や改善に有効な、新規の抗うつおよび抗不安剤が提供される。 The present invention provides a novel antidepressant and anxiolytic agent effective in suppressing or improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
試験例１の強制遊泳試験による不動時間の測定結果を示すグラフである。6 is a graph showing measurement results of immobility time by a forced swimming test of Test Example 1. 試験例２の高架式十字迷路試験によるオープンアーム滞在時間の測定結果を示すグラフである。It is a graph which shows the measurement result of the open arm stay time by the elevated plus maze test of Test example 2. 試験例３の海馬歯状回の新生神経細胞数の結果を示すグラフである。6 is a graph showing the results of the number of new neurons in the hippocampal dentate gyrus of Test Example 3.
　本明細書は、本願の優先権の基礎である特願２００８－０１３６３０号の明細書、特許請求の範囲および図面に記載された内容を包含する。 This specification includes the contents described in the description, claims, and drawings of Japanese Patent Application No. 2008-013630, which is the basis of the priority of the present application.
　本発明において、LeuおよびIleからなるペプチドとは、Leu-IleおよびIle-Leuが挙げられるがLeu-Ileを用いることが好ましい。 In the present invention, examples of the peptide consisting of Leu and Ile include Leu-Ile and Ile-Leu, but Leu-Ile is preferably used.
　本発明において、LeuおよびIleからなるペプチドまたはその修飾体とは、LeuとIleからなる基本構造（ジペプチド）に対して、その一部（複数箇所であってもよい）を他の原子団等で置換すること、或いは他の分子を付加すること等の修飾を施すことによって、少なくとも一部において前記基本構造と相違する構造の化合物を示す。更に、ジペプチド中のLeuおよびIleの少なくとも一つをD体またはDL体に置換したものもLeuおよびIleからなるペプチドまたはその修飾体に含まれる。 In the present invention, a peptide consisting of Leu and Ile or a modified form thereof is a part of the basic structure (dipeptide) consisting of Leu and Ile (may be a plurality of positions) with other atomic groups or the like. A compound having a structure different from the basic structure is shown at least in part by modification such as substitution or addition of another molecule. Further, a peptide obtained by substituting at least one of Leu and Ile in a dipeptide with a D-form or DL-form is also included in a peptide comprising Leu and Ile or a modified form thereof.
　本発明における修飾体の代表例としては、LeuまたはIleの側鎖の一部が他の原子または原子団で置換されたペプチド誘導体を挙げることができる。ここでの他の原子または原子団としては、ヒドロキシル基、ハロゲン（フッ素、塩素、臭素、ヨウ素等）、アルキル基（メチル基、エチル基、ｎ－プロピル基、イソプロピル基等）、ヒドロキシアルキル基（ヒドロキシメチル基、ヒドロキシエチル基等）、アルコキシ基（メトキシ基、エトキシ基等）、アシル基（ホルミル基、アセチル基、マロニル基、ベンゾイル基等）等を例示することができる。 As a typical example of the modified form in the present invention, a peptide derivative in which a part of the side chain of Leu or Ile is substituted with another atom or atomic group can be mentioned. Other atoms or atomic groups herein include a hydroxyl group, halogen (fluorine, chlorine, bromine, iodine, etc.), alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, etc.), hydroxyalkyl group ( Examples thereof include hydroxymethyl group, hydroxyethyl group, etc., alkoxy groups (methoxy group, ethoxy group, etc.), acyl groups (formyl group, acetyl group, malonyl group, benzoyl group, etc.) and the like.
　本発明のペプチド修飾体には、LeuまたはIleの官能基が適当な保護基によって保護されているものも含まれる。このような目的に使用される保護基としては、アシル基、アルキル基、単糖、オリゴ糖、多糖等を用いることができる。このような保護基は、保護基を結合させるペプチド部位や使用する保護基の種類などに応じて、アミド結合、エステル結合、ウレタン結合、尿素結合等によって連結される。 The modified peptide of the present invention includes those in which the functional group of Leu or Ile is protected by an appropriate protecting group. As the protecting group used for such a purpose, an acyl group, an alkyl group, a monosaccharide, an oligosaccharide, a polysaccharide and the like can be used. Such a protecting group is linked by an amide bond, an ester bond, a urethane bond, a urea bond, or the like according to the peptide site to which the protecting group is bound, the kind of the protecting group to be used, or the like.
　本発明のペプチド修飾体の更なる例としては、糖鎖の付加による修飾が施されているものを挙げることができる。また、Ｎ末端またはＣ末端が他の原子等で置換されることによってアルキルアミン、アルキルアミド、スルフィニル、スルフォニルアミド、ハライド、アミド、アミノアルコール、エステル、アミノアルデヒド等に分類される各種ペプチド誘導体も本発明のペプチド修飾体に含まれる。 As a further example of the modified peptide of the present invention, one modified by addition of a sugar chain can be mentioned. In addition, various peptide derivatives classified into alkylamine, alkylamide, sulfinyl, sulfonylamide, halide, amide, aminoalcohol, ester, aminoaldehyde, etc. by replacing the N-terminal or C-terminal with other atoms etc. Included in the modified peptides of the invention.
　尚、以上で説明した各種の修飾方法を組み合わせることによって構成されるペプチド誘導体を本発明のペプチド修飾体としてもよい。 A peptide derivative constituted by combining the various modification methods described above may be used as the modified peptide of the present invention.
　本発明のLeuおよびIleからなるペプチドまたはその修飾体には、上記ペプチドの塩また上記ペプチド修飾体の塩またはその水和物も含まれる。本発明の塩は薬学的に許容可能な限りその種類は特に限定されず、塩酸、リン酸、硫酸、硝酸、ホウ酸等との塩（無機酸塩）や、ギ酸、酢酸、乳酸、フマル酸、マレイン酸、酒石酸、クエン酸等との塩（有機酸塩）をその例として挙げることができる。これらの塩の調製は慣用手段によって行なうことができる。 The peptide of Leu and Ile according to the present invention or a modified form thereof includes a salt of the peptide, a salt of the modified peptide or a hydrate thereof. The salt of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and is a salt (inorganic acid salt) with hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, boric acid or the like, formic acid, acetic acid, lactic acid, fumaric acid Examples thereof include salts (organic acid salts) with maleic acid, tartaric acid, citric acid and the like. These salts can be prepared by conventional means.
　本発明における抗うつおよび抗不安剤としては、医薬製剤またはダイエタリーサプリメントが挙げられる。ダイエタリーサプリメントとしては、医薬品と同様の形状を有するが薬事法上医薬品に属さない経口投与製剤、または本発明の有効成分を食品に添加したものが挙げられる。 As the antidepressant and anxiolytic agent in the present invention, pharmaceutical preparations or dietary supplements may be mentioned. Examples of dietary supplements include oral preparations that have the same shape as pharmaceuticals but do not belong to pharmaceuticals under the Pharmaceutical Affairs Law, or those obtained by adding the active ingredient of the present invention to foods.
　即ち本発明はLeuおよびIleからなるペプチドまたはその修飾体を有効成分とする医薬組成物またはダイエタリーサプリメント用栄養組成物に該当する。 That is, the present invention corresponds to a pharmaceutical composition or a dietary supplement nutrition composition containing a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
　本発明において医薬製剤とは、本発明の有効成分に医薬品製剤基剤として通常用いられる担体、例えば賦形剤、崩壊剤、滑沢剤、緩衝剤、結合剤、乳化剤、懸濁剤、無痛化剤、安定剤、保存剤、防腐剤、生理食塩水等を加えたものを表し、剤型としては錠剤、散剤、細粒剤、顆粒剤、カプセル剤、シロップ剤、注射剤、外用剤、および座剤等が挙げられる。賦形剤としては乳糖、デンプン、ソルビトール、D-マンニトール、白糖等を用いることができる。崩壊剤としてはデンプン、カルボキシメチルセルロース、炭酸カルシウム等を用いることができる。緩衝剤としてはリン酸塩、クエン酸塩、酢酸塩等を用いることができる。乳化剤としてはアラビアゴム、アルギン酸ナトリウム、トラガント等を用いることができる。結合剤としては、プルラン、アラビアゴム、ゼラチン、デンプン等を用いることができる。滑沢剤としてはステアリン酸マグネシウム、メチルセルロース、ケイ酸マグネシウムを用いることができる。懸濁剤としてはモノステアリン酸グリセリン、モノステアリン酸アルミニウム、メチルセルロース、カルボキシメチルセルロース、ヒドロキシメチルセルロース、ラウリル硫酸ナトリウム等を用いることができる。無痛化剤としてはベンジルアルコール、クロロブタノール、ソルビトール等を用いることができる。安定剤としてはプロピレングリコール、ジエチリン亜硫酸塩、アスコルビン酸等を用いることができる。保存剤としてはフェノール、塩化ベンザルコニウム、ベンジルアルコール、クロロブタノール、メチルパラベン等を用いることができる。防腐剤としては塩化ベンザルコニウム、パラオキシ安息香酸、クロロブタノール等と用いることができる。 In the present invention, the pharmaceutical preparation means a carrier usually used as a pharmaceutical preparation base for the active ingredient of the present invention, such as an excipient, a disintegrant, a lubricant, a buffering agent, a binder, an emulsifier, a suspending agent, and a soothing agent. Represents additives, stabilizers, preservatives, preservatives, physiological saline, etc., and dosage forms include tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and Suppositories and the like can be mentioned. As the excipient, lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used. As the disintegrant, starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer. As the emulsifier, gum arabic, sodium alginate, tragacanth and the like can be used. As the binder, pullulan, gum arabic, gelatin, starch or the like can be used. As the lubricant, magnesium stearate, methylcellulose, or magnesium silicate can be used. As the suspending agent, glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used. As the soothing agent, benzyl alcohol, chlorobutanol, sorbitol and the like can be used. As the stabilizer, propylene glycol, diethylin sulfite, ascorbic acid or the like can be used. As preservatives, phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used. As preservatives, benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
　本発明における、ダイエタリーサプリメント経口製剤とは、本発明の有効成分に栄養食品製剤基剤として通常用いられる担体、例えば賦形剤、崩壊剤、乳化剤、安定剤、滑沢剤、緩衝剤、香料等を加えたものを表し、剤型としては錠剤、散剤、細粒剤、顆粒剤、カプセル剤が挙げられる。 The dietary supplement oral preparation in the present invention is a carrier that is usually used as a base for a nutritional food preparation for the active ingredient of the present invention, such as an excipient, a disintegrant, an emulsifier, a stabilizer, a lubricant, a buffer, a fragrance. The dosage form includes tablets, powders, fine granules, granules, and capsules.
　本発明の有効成分を食品に添加したダイエタリーサプリメントとは、本発明の有効成分を用いて常法により製造した、栄養飲料、清涼飲料、ゼリー等が挙げられる。 Examples of dietary supplements obtained by adding the active ingredient of the present invention to foods include nutritional drinks, soft drinks, jelly, and the like produced by the conventional method using the active ingredient of the present invention.
　LeuおよびIleからなるペプチドは、公知のペプチド合成法（例えば固相合成法、液相合成法）によって製造することができる。但し、本発明のペプチド等が天然に存在する場合には、抽出、精製などの操作によってそれを調製することもできる。本発明のペプチド等の取得源としては例えば、動物細胞（ヒトを含む）、植物細胞、体液（血液、尿等）等が考えられる。 A peptide comprising Leu and Ile can be produced by a known peptide synthesis method (for example, solid phase synthesis method, liquid phase synthesis method). However, when the peptide of the present invention exists in nature, it can also be prepared by operations such as extraction and purification. Examples of sources for obtaining the peptide of the present invention include animal cells (including humans), plant cells, body fluids (blood, urine, etc.).
　更に微生物、酵素等を用いたジペプチドの効率の良い生産方法が知られており（WO2004/058960）、上記公報に開示された製法に従いLeu－Ileからなるペプチドを効率的に製造することができる。 Furthermore, an efficient production method of dipeptides using microorganisms, enzymes and the like is known (WO2004 / 058960), and peptides composed of Leu-Ile can be efficiently produced according to the production method disclosed in the above publication.
　更にLeuおよびIleからなるペプチドの修飾体は前述のとおり常法により製造することができる。 Furthermore, a modified form of a peptide consisting of Leu and Ile can be produced by a conventional method as described above.
　LeuおよびIleからなるペプチドの修飾体を有効成分とする医薬製剤もしくは経口ダイエタリーサプリメント製剤は、得られたLeuおよびIleからなるペプチドの修飾体を主活性成分として用いて、常法に従い製造することができる。 Pharmaceutical preparations or oral dietary supplement preparations containing modified peptides of Leu and Ile as active ingredients should be produced according to conventional methods using the obtained modified peptides of Leu and Ile as the main active ingredients. Can do.
　製剤化する場合には、製剤上許容される他の成分（例えば、担体、賦形剤、崩壊剤、緩衝剤、乳化剤、結合剤、滑沢剤、懸濁剤、無痛化剤、安定剤、保存剤、防腐剤、生理食塩水など）をLeuおよびIleからなるペプチドの修飾体に含有させて所望の製剤を製造することができる。賦形剤としては乳糖、デンプン、ソルビトール、D-マンニトール、白糖等を用いることができる。崩壊剤としてはデンプン、カルボキシメチルセルロース、炭酸カルシウム等を用いることができる。緩衝剤としてはリン酸塩、クエン酸塩、酢酸塩等を用いることができる。乳化剤としてはアラビアゴム、アルギン酸ナトリウム、トラガント等を用いることができる。結合剤としては、プルラン、アラビアゴム、ゼラチン、デンプン等を用いることができる。滑沢剤としてはステアリン酸マグネシウム、メチルセルロース、ケイ酸マグネシウムを用いることができる。懸濁剤としてはモノステアリン酸グリセリン、モノステアリン酸アルミニウム、メチルセルロース、カルボキシメチルセルロース、ヒドロキシメチルセルロース、ラウリル硫酸ナトリウム等を用いることができる。無痛化剤としてはベンジルアルコール、クロロブタノール、ソルビトール等を用いることができる。安定剤としてはプロピレングリコール、ジエチリン亜硫酸塩、アスコルビン酸等を用いることができる。保存剤としてはフェノール、塩化ベンザルコニウム、ベンジルアルコール、クロロブタノール、メチルパラベン等を用いることができる。防腐剤としては塩化ベンザルコニウム、パラオキシ安息香酸、クロロブタノール等と用いることができる。 In the case of formulation, other pharmaceutically acceptable ingredients (for example, carriers, excipients, disintegrants, buffers, emulsifiers, binders, lubricants, suspending agents, soothing agents, stabilizers, Preservatives, preservatives, physiological saline, and the like) can be contained in modified peptides of Leu and Ile to produce a desired preparation. As the excipient, lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used. As the disintegrant, starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer. As the emulsifier, gum arabic, sodium alginate, tragacanth and the like can be used. As the binder, pullulan, gum arabic, gelatin, starch or the like can be used. As the lubricant, magnesium stearate, methylcellulose, or magnesium silicate can be used. As the suspending agent, glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used. As the soothing agent, benzyl alcohol, chlorobutanol, sorbitol and the like can be used. As the stabilizer, propylene glycol, diethylin sulfite, ascorbic acid or the like can be used. As preservatives, phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used. As preservatives, benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
　これらの製剤基剤を用いて常法により錠剤、散剤、細粒剤、顆粒剤、カプセル剤、シロップ剤、注射剤、外用剤、および座剤等所望の剤型を製造することができる。 Using these preparation bases, desired dosage forms such as tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and suppositories can be produced by conventional methods.
　またLeuおよびIleからなるペプチドの修飾体を添加して、常法により栄養飲料、清涼飲料、ゼリー等、栄養食品を製造することができる。 Moreover, modified foods of peptides consisting of Leu and Ile can be added to produce nutritional foods such as nutritional drinks, soft drinks, and jelly by conventional methods.
　このように製剤化した本発明のLeuおよびIleからなるペプチドまたはその修飾体を有効成分とする抗うつおよび抗不安剤は、その形態に応じて経口投与または非経口投与（静脈内、動脈内、皮下、筋肉、腹腔内注射など）によって患者に適用され得る。本発明の薬剤中における有効成分（ペプチド等）の含量は一般に剤型によって異なるが、注射剤等液体製剤の場合は約0.001重量％～約10重量％、好ましくは0.01重量％～約3重量％、とりわけ好ましくは0.1重量％～約1重量％であり、錠剤等固形剤の場合は0.1重量％～約90重量％、好ましくは1重量％～約50重量％、とりわけ好ましくは3重量％～約30重量％である。 The antidepressant and anxiolytic agent comprising the thus obtained Leu and Ile peptide of the present invention or a modified product thereof as an active ingredient is administered orally or parenterally (intravenous, intraarterial, (Subcutaneous, intramuscular, intraperitoneal injection, etc.). The content of active ingredients (peptides, etc.) in the drug of the present invention generally varies depending on the dosage form, but in the case of liquid preparations such as injections, it is about 0.001% to about 10% by weight, preferably 0.01% to about 3% by weight. Particularly preferably, it is 0.1% by weight to about 1% by weight. In the case of a solid preparation such as a tablet, 0.1% by weight to about 90% by weight, preferably 1% by weight to about 50% by weight, particularly preferably 3% by weight to about 1% by weight. 30% by weight.
　本発明により、LeuおよびIleからなるペプチドまたはその修飾体を有効成分とする製剤を投与する、うつ病（うつ）および不安症（不安症状）の予防方法または治療方法が提供される。本発明の治療方法または予防方法は、LeuおよびIleからなるペプチドまたはその修飾体を有効成分として含む製剤を生体に投与するステップを含む。投与経路は特に限定されず例えば経口、静脈内、皮内、皮下、筋肉内、腹腔内、経皮、経粘膜などを挙げることができる。薬剤の投与量は症状、患者の年齢、性別、および体重などによって異なるが、当業者であれば適宜適当な投与量を設定することが可能である。例えば、Leu-Ileを有効成分として含む製剤を使用する場合には、成人（体重約60 kg）を対象として一日当たりの有効成分量が約0.1μg～約3000 mg、好ましくは約0.1mg～約2000 mg、とりわけ好ましくは約0.1mg～約1000 mg、となるよう投与量を設定することができる。投与スケジュールとしては例えば一日一回～数回、二日に一回、或いは三日に一回などを採用できる。 According to the present invention, there is provided a method for preventing or treating depression (depression) and anxiety (anxiety symptoms), wherein a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient is administered. The treatment method or prevention method of the present invention includes a step of administering to a living body a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient. The administration route is not particularly limited, and examples thereof include oral, intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, and transmucosal. The dose of the drug varies depending on symptoms, patient age, sex, weight, and the like, but those skilled in the art can appropriately set an appropriate dose. For example, when a preparation containing Leu-Ile as an active ingredient is used, the amount of active ingredient per day for an adult (body weight of about 60 kg) is about 0.1 μg to about 3000 kg, preferably about 0.1 mg to about The dose can be set to 2000 mg, particularly preferably about 0.1 mg to about 1000 mg. As the administration schedule, for example, once to several times a day, once every two days, or once every three days can be adopted.
　本発明において、LeuおよびIleからなるペプチドまたはその修飾体を有効成分とする製剤を投与するうつ病（うつ）および不安症（不安症状）の予防方法とは、うつ病および不安症の症状は発現していない成人が、ストレスによりうつ病および不安症の症状が発現するのを防ぐために、予防的にLeuおよびIleからなるペプチドまたはその修飾体を有効成分とする製剤を服用することを示し、LeuおよびIleからなるペプチドまたはその修飾体を有効成分とする製剤を投与するうつ病および不安症の治療方法とは、うつ病および不安症の症状を発現した患者に対して、それらの進行を抑制または改善するために投与することを示す。投与スケジュールの設定においては、患者の病状や薬剤の効果持続時間などを考慮することができる。 In the present invention, a method for preventing depression (anxiety) and anxiety (anxiety symptoms) by administering a preparation comprising a peptide consisting of Leu and Ile or a modified form thereof as an active ingredient is the expression of symptoms of depression and anxiety In order to prevent the development of symptoms of depression and anxiety by stress, non-adult adults take prophylactic preparations containing a peptide consisting of Leu and Ile or a modified form thereof as an active ingredient. And a method of treating depression and anxiety by administering a preparation comprising a peptide comprising Ile or a modified form thereof as an active ingredient is a method for suppressing or preventing progression of depression and anxiety in a patient who has developed symptoms of depression or anxiety Indicates administration to improve. In setting the administration schedule, it is possible to take into account the patient's medical condition and the duration of the drug effect.
　なお、本発明にかかる「うつ病」あるいは「うつ」とは、気分障害の一種であり、抑うつ気分、意欲低下、興味と喜びの喪失、集中力と注意力の減退、自己評価と自信の低下、罪責感と無価値感、将来への悲観、自殺念慮、睡眠障害、食欲不振などを特徴とする精神症状あるいは疾患を意味する。臨床場面では、DSMの診断基準で「死別反応以外のもので、2週間以上にわたり毎日続き、生活の機能障害を呈している」ある程度の重症のものをうつ病として扱うことが多い。しかしながら、本発明においてはそのような診断基準に拘束されることなく、一過性の心理的ストレス（適応障害、急性ストレス障害、PTSDなど）に付随するうつ状態、統合失調症・パニック障害など、他の疾患の症状としてのうつ状態、内因性うつ病等、うつ状態を伴う疾患あるいは症状を広く包含するものとする。 In addition, “depression” or “depression” according to the present invention is a kind of mood disorder, depressed mood, decreased motivation, loss of interest and joy, reduced concentration and attention, self-evaluation and reduced confidence It means psychiatric symptoms or diseases characterized by guilt and worthlessness, pessimism about the future, suicidal ideation, sleep disorders, and anorexia. In clinical settings, it is often treated as depression that has a certain degree of severity in the DSM diagnostic criteria, which is “other than bereavement reaction, lasts every day for more than 2 weeks and presents functional impairment of life”. However, in the present invention, without being bound by such diagnostic criteria, depression associated with transient psychological stress (adaptation disorder, acute stress disorder, PTSD, etc.), schizophrenia, panic disorder, etc. It is intended to broadly encompass diseases or symptoms associated with depression, such as depression and endogenous depression as symptoms of other diseases.
　また、本発明にかかる「不安症」あるいは「不安症状」とは、不安（明確な対象を持たない恐怖に対して自己が対処できない時に発生する感情の一種）を主症状とする精神症状あるいは疾患全般を意味し、行動や心理的障害だけでなく、発汗、動悸、頻脈、胸痛、頭痛、下痢などといった身体症状として現れることもある。よって、本発明にかかる「不安症」には、恐怖症性不安障害（広場恐怖、社会恐怖（社会不安障害）、対人恐怖症）、パニック障害、過敏性腸症候群、全般性不安障害、混合性不安抑うつ障害、強迫性障害、重度ストレス反応および適応障害（PTSD、急性ストレス障害、適応障害）、一般身体疾患による不安障害、物質誘発性不安障害、特定不能の不安障害など、不安を主症状とする疾患あるいは症状を広く包含するものとする。 The “anxiety” or “anxiety symptom” according to the present invention is a psychiatric symptom or disease whose main symptom is anxiety (a kind of emotion that occurs when the self cannot cope with fear without a clear target). It means general and may manifest as physical symptoms such as sweating, palpitation, tachycardia, chest pain, headache, diarrhea as well as behavioral and psychological disorders. Therefore, the “anxiety” according to the present invention includes phobic anxiety disorder (square fear, social phobia (social anxiety disorder), interpersonal phobia), panic disorder, irritable bowel syndrome, generalized anxiety disorder, mixedness Anxiety is a major symptom, such as anxiety-depressive disorder, obsessive-compulsive disorder, severe stress response and adjustment disorder (PTSD, acute stress disorder, adjustment disorder), general physical anxiety disorder, substance-induced anxiety disorder, unspecified anxiety disorder It is intended to encompass a wide range of diseases or symptoms.
　本発明の抗うつ作用および抗不安作用は、それぞれ以下に記載するように、マウスを用いた強制水泳試験法、および高架式十字迷路試験により確認することができる。強制水泳試験法は、抗うつ剤の動物での評価法のうち、最も広く用いられており、臨床的に有効な抗うつ剤は不動時間を短縮することが知られている（Porsortet al. Nature. 266, 730-732, 1977）。また高架式十字迷路試験は、抗不安剤の評価法として一般的に用いられており、抗不安剤の投与により不安が低減されると、壁のない走路（オープンアーム）に滞在する時間が延長されることが知られている（Pellow et al. Pharmacol Biochem Behav. 24, 525-529, 1986）。 The antidepressant action and anxiolytic action of the present invention can be confirmed by a forced swimming test method using a mouse and an elevated plus maze test, as described below. The forced swimming test method is the most widely used method for evaluating antidepressants in animals, and clinically effective antidepressants are known to shorten immobility time (Porsortet al. Nature 266, 730-732, 1977). The elevated plus maze test is commonly used as an anxiolytic evaluation method. When anxiety is reduced by the administration of anxiolytics, the time spent on a runway with no walls (open arm) is extended. (Pellow et al., Pharmacol, Biochem, Behav., 24, 525-529, 1986).
　以下に、本発明の実施例、Leu-Ileの抗うつ作用、および抗不安作用を調べた試験例を示す。 The following are examples of the present invention and test examples in which Leu-Ile's antidepressant action and anxiolytic action were examined.
[試験例１]　抗うつ作用の評価
　ICR系マウス（体重２０－２２ｇ(７-１０週齢)、日本ＳＬＣ（静岡）より購入）を２群（ｎ=１２-１５）に分け、１日１回６分間、水温２５℃、深さ１５ｃｍの円筒状水槽内で遊泳させ、６分間のうち最初の1分間を除いた5分間の観察時間中に泳いだ時間を、赤外線検出装置によって測定した。この数値を観察時間３００秒から引いた値を無動時間として、各実験群で比較した。１日１回の強制水泳直後に、コントロール群には 注射用水を、Leu-Ile投与群にはLeu-Ile 750μmol/Kgを、経口ゾンデを用いて経口投与した。２週間にわたり強制水泳および投与を行った。分散分析による統計解析を行い（有意水準５％未満で有意差ありと判定した）、Leu-Ileの抗うつ作用を測定した。 [Test Example 1] Evaluation of antidepressant action ICR mice (body weight 20-22 g (7-10 weeks old), purchased from Japan SLC (Shizuoka)) were divided into 2 groups (n = 12-15) per day. Swim in a cylindrical water tank with a water temperature of 25 ° C. and a depth of 15 cm for 6 minutes, and the swim time during the observation period of 5 minutes excluding the first one of the 6 minutes was measured by an infrared detector. The value obtained by subtracting this value from the observation time of 300 seconds was set as the immobility time, and the comparison was made in each experimental group. Immediately after forced swimming once a day, water for injection was orally administered to the control group and Leu-Ile 750 μmol / Kg was orally administered to the Leu-Ile administration group using an oral sonde. Forced swimming and dosing were performed for 2 weeks. Statistical analysis was performed by analysis of variance (determined that there was a significant difference at a significance level of less than 5%), and the antidepressant action of Leu-Ile was measured.
　無動時間の結果を図１に示した。Leu-Ile投与群はコントロール群に比べ、14日目には無動時間が有意に短縮された。これらのことからLeu-Ileは抗うつ作用を有することが明らかとなった。 Figure 1 shows the result of the immobility time. In the Leu-Ile administration group, the immobility time was significantly shortened on the 14th day compared to the control group. From these results, it was revealed that Leu-Ile has an antidepressant action.
[試験例２]　抗不安作用の評価
　ICR系マウス（体重２０－２２ｇ(７－１０週齢)、日本ＳＬＣ（静岡）より購入）を５群（ｎ＝１５）に分け、生理食塩水もしくはLeu-Ile（1.5、15、150 μmol/Kg）を、１日１回１４日間にわたり皮下投与した。最終投与から２４時間後に、マウスを地面から３０ｃｍの高さにおいた十字迷路におき、６分間の観察時間中にオープンアームに出てきた時間を測定し、各実験群で比較した。分散分析による統計解析を行い（有意水準５％未満で有意差ありと判定した）、Leu-Ileの抗不安作用を測定した。 [Test Example 2] Evaluation of anti-anxiety action ICR mice (body weight 20-22 g (7-10 weeks old), purchased from Japan SLC (Shizuoka)) were divided into 5 groups (n = 15) and either saline or Leu -Ile (1.5, 15, 150 μmol / Kg) was administered subcutaneously once a day for 14 days. Twenty-four hours after the final administration, the mice were placed in a cross maze at a height of 30 cm from the ground, and the time of coming out to the open arm during the observation period of 6 minutes was measured and compared in each experimental group. Statistical analysis was performed by analysis of variance (determined that there was a significant difference at a significance level of less than 5%), and the anxiolytic effect of Leu-Ile was measured.
　オープンアーム滞在時間の結果を図２に示した。図２によれば、Leu-Ile投与群はコントロール群に比べ、用量依存的にオープンアーム滞在時間が有意に延長した。このことからLeu-Ileには抗不安作用を有することが明らかとなった。 The result of the open arm stay time is shown in FIG. According to FIG. 2, the open arm residence time was significantly extended in the Leu-Ile administration group in a dose-dependent manner as compared to the control group. This revealed that Leu-Ile has an anxiolytic effect.
　最近の研究から、成体においても海馬の歯状回では、神経細胞の新生が盛んに起こっており（Gouldet al. J Neurosci. 22, 619-623, 2002）、神経細胞新生の低下は、うつ病や不安症と密接に関連することが示唆されている（Santarelliet al. Science. 301, 805-809, 2003）。そこでLeu-Ileの作用メカニズムとして、以下に海馬の神経細胞新生促進作用を評価した試験例を示す。 Recent studies have shown that neuronal neogenesis is actively occurring in the dentate gyrus of the hippocampus even in adults (Gouldet al. J Neurosci. 22, 619-623, 2002). It has been suggested that it is closely related to anxiety (Santarelliet al. Science. 301, 805-809, 2003). Thus, as an action mechanism of Leu-Ile, a test example in which the action of promoting hippocampal neurogenesis is evaluated is shown below.
[試験例３]　神経細胞新生促進作用の評価
　ICR系マウス（体重20-22ｇ(7-10週齢)、日本ＳＬＣ（静岡）より購入）を３群（n=12-15）に分け、そのうち２群（コントロール群、Leu-Ile投与群）には、１日１回２週間にわたり、水温２５℃、深さ１５ｃｍの円筒状水槽内で、６分間遊泳させた。１日１回の強制水泳直後に、コントロール群には 注射用水を、Leu-Ile投与群にはLeu-Ile 750μmol/Kgを、経口ゾンデを用いて経口投与した。最終日に３時間ごとに計３回、ブロモデオキシウリジン（ＢｒｄＵ）75 mg/Kgを腹腔内に投与した。残り１群には強制水泳を負荷せず、他の２群と同じタイミングでＢｒｄＵを投与した（強制水泳無負荷群）。 [Test Example 3] Evaluation of neuronal cell formation promoting action ICR mice (body weight 20-22g (7-10 weeks old), purchased from Japan SLC (Shizuoka)) were divided into 3 groups (n = 12-15), of which Two groups (control group, Leu-Ile administration group) were allowed to swim for 6 minutes in a cylindrical water tank having a water temperature of 25 ° C. and a depth of 15 cm once a day for 2 weeks. Immediately after forced swimming once a day, water for injection was orally administered to the control group and Leu-Ile 750 μmol / Kg was orally administered to the Leu-Ile administration group using an oral sonde. Brodeoxyuridine (BrdU) 75 mg / Kg was intraperitoneally administered three times every 3 hours on the last day. The remaining 1 group was not loaded with forced swimming, and BrdU was administered at the same timing as the other 2 groups (forced swimming unloaded group).
　ＢｒｄＵの最終投与から２４時間後に、これらの動物に麻酔薬を投与し、４％パラホルムアルデヒド（ＰＦＡ）溶液で灌流固定した後、脳を取り出した。脳は４℃にて一晩同じＰＦＡ溶液で後固定し、30%シュークロース溶液に入れ替えて、沈むまで4℃で浸漬・置換させた後、コンパウンド（Tissue Tek O.C.T. Compound（SAKURA FINETEC社））で包埋した。 Twenty-four hours after the final administration of BrdU, these animals were administered anesthesia, perfusion-fixed with 4% paraformaldehyde (PFA) solution, and the brains were removed. The brain is postfixed overnight at 4 ° C with the same PFA solution, replaced with a 30% sucrose solution, immersed and replaced at 4 ° C until it sinks, and then compounded (Tissue Tek OCT Compound (SAKURA FINETEC)) Embedded.
　包埋された脳から、海馬を含む厚さ３０μmの連続した凍結切片を作製し、５枚ごとに計８枚の切片を取り出し、抗ＢｒｄＵ抗体で免疫染色を行った（BrdU Detection Kit、Roche社）。各切片の海馬歯状回のＢｒｄＵ陽性細胞を数え、Leu-Ileの神経細胞新生促進作用を評価した。分散分析による統計解析を行い、有意水準５％未満で有意差ありと判定した。 30 μm-thick continuous frozen sections including the hippocampus were prepared from the embedded brain, and a total of 8 sections were taken out every 5 sheets, and immunostained with anti-BrdU antibody (BrdU Detection Kit, Roche) ). The number of BrdU positive cells in the hippocampal dentate gyrus of each section was counted, and the effect of Leu-Ile on promoting neurogenesis was evaluated. Statistical analysis by analysis of variance was performed, and it was determined that there was a significant difference at a significance level of less than 5%.
　海馬歯状回の新生神経細胞数の結果を図３に示した。コントロール群は強制水泳無負荷群に比べて、有意にＢｒｄＵ陽性細胞数の低下が認められた。一方でLeu-Ile投与群はコントロール群に比べ、ＢｒｄＵ陽性細胞数の有意な増加が認められた。これらのことからLeu-Ileは神経細胞の新生を促進することが明らかとなった。 The results of the number of new neurons in the hippocampal dentate gyrus are shown in FIG. The control group showed a significant decrease in the number of BrdU positive cells compared to the forced swimming no-load group. On the other hand, the Leu-Ile administration group showed a significant increase in the number of BrdU positive cells compared to the control group. From these results, it was revealed that Leu-Ile promotes the neurogenesis of neurons.
[実施例１]　錠剤
　常法により、次の組成からなる錠剤を調製する。 [Example 1] Tablets Tablets having the following composition are prepared by a conventional method.
処方：　　　　　　　　　　　　　 
Leu-Ile 25mg
ラクトース 138.4 mg
馬鈴薯デンプン 30 mg
ヒドロキシプロピルセルロース 6 mg
ステアリン酸マグネシウム 0.6 mg　
計200 mg
[実施例２]　注射剤
　常法により、次の組成からなる注射剤を調製する。 Formula:
Leu-Ile 25mg
Lactose 138.4 mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
200 mg total
[Example 2] Injection An injection having the following composition is prepared by a conventional method.
処方：　　　　　　　　　　 
Leu-Ile 2 mg
D-マンニトール 10 mg
塩酸水溶液 適量
水酸化ナトリウム水溶液 適量
注射用蒸留水適量　　　　　
計2.00 mL
[実施例３]　ダイエタリーサプリメント錠剤
　常法により、次の組成からなるダイエタリーサプリメント錠剤を調製する。 Formula:
Leu-Ile 2 mg
D-mannitol 10 mg
Hydrochloric acid aqueous solution appropriate amount Sodium hydroxide aqueous solution appropriate amount
Suitable amount of distilled water for injection
2.00 mL total
[Example 3] Dietary supplement tablet A dietary supplement tablet having the following composition is prepared by a conventional method.
処方：　　　　　　　　　　　　　　　　　　
Leu-Ile 20mg
エリスリトール 245 mg
カルボキシメチルセルロースカルシウム 5 mg
香料 10 mg
ショ糖脂肪酸エステル20 mg　　　　　　　　
計300 mg Formula:
Leu-Ile 20mg
Erythritol 245 mg
Carboxymethylcellulose calcium 5 mg
Fragrance 10 mg
Sucrose fatty acid ester 20 mg
300 mg total
　本発明は、うつ病または不安症の予防・治療を目的とした医薬組成物やダイエタリーサプリメント用栄養組成物として、医薬、食品分野において利用可能である。 The present invention can be used in the pharmaceutical and food fields as a pharmaceutical composition and a nutritional composition for dietary supplements for the purpose of preventing or treating depression or anxiety.
　本明細書中で引用した全ての刊行物、特許および特許出願をそのまま参考として本明細書中にとり入れるものとする。 All publications, patents and patent applications cited in this specification shall be incorporated into this specification as they are.

Claims (12)

  1. 　LeuおよびIleからなるペプチドまたはその修飾体を有効成分とする抗うつ剤。 An antidepressant containing a peptide consisting of Leu and Ile or a modified product thereof as an active ingredient.
  2. 　LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする請求項１記載の抗うつ剤。 The antidepressant according to claim 1, wherein the peptide comprising Leu and Ile is Leu-Ile.
  3. 　Leu-Ileを有効成分とする請求項１記載の抗うつ剤。 The antidepressant according to claim 1, comprising Leu-Ile as an active ingredient.
  4. 　LeuおよびIleからなるペプチドまたはその修飾体を有効成分とする抗不安剤。 An anxiolytic agent comprising a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
  5. 　LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする請求項４記載の抗不安剤。 The anxiolytic agent according to claim 4, wherein the peptide comprising Leu and Ile is Leu-Ile.
  6. 　Leu-Ileを有効成分とする請求項４記載の抗不安剤。 The anxiolytic agent according to claim 4, comprising Leu-Ile as an active ingredient.
  7. 　LeuおよびIleからなるペプチドまたはその修飾体を有効成分として含む製剤を生体に投与するステップを含む、うつ病または不安症の予防方法または治療方法。 A method for preventing or treating depression or anxiety, comprising the step of administering to a living body a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient.
  8. 　LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする請求項７記載の予防方法または治療方法。 The preventive or therapeutic method according to claim 7, wherein the peptide comprising Leu and Ile is Leu-Ile.
  9. 　製剤がLeu-Ileを有効成分とする、請求項７記載の予防方法または治療方法。 The preventive or therapeutic method according to claim 7, wherein the preparation comprises Leu-Ile as an active ingredient.
  10. 　うつ病または不安症を予防または治療するための医薬の製造における、LeuおよびIleからなるペプチドまたはその修飾体の使用。 Use of a peptide consisting of Leu and Ile or a modified form thereof in the manufacture of a medicament for preventing or treating depression or anxiety.
  11. 　LeuおよびIleからなるペプチドがLeu-Ileであることを特徴とする請求項１０記載の使用。 The use according to claim 10, wherein the peptide consisting of Leu and Ile is Leu-Ile.
  12. 　LeuおよびIleからなるペプチドまたはその修飾体がLeu-Ileである、請求項１０記載の使用。 The use according to claim 10, wherein the peptide consisting of Leu and Ile or a modified form thereof is Leu-Ile.
PCT/JP2009/051027 2008-01-24 2009-01-23 Antidepressant/antianxiety agent WO2009093671A1 (en)

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