JP2013032308A - Pharmaceutical composition for treating/preventing depression - Google Patents
Pharmaceutical composition for treating/preventing depression Download PDFInfo
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- JP2013032308A JP2013032308A JP2011169082A JP2011169082A JP2013032308A JP 2013032308 A JP2013032308 A JP 2013032308A JP 2011169082 A JP2011169082 A JP 2011169082A JP 2011169082 A JP2011169082 A JP 2011169082A JP 2013032308 A JP2013032308 A JP 2013032308A
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- earthworm
- depression
- pharmaceutical composition
- dry powder
- present
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Abstract
Description
本発明は、うつ病を治療または予防するための医薬組成物に関する。本発明はまた、前記医薬組成物を用いてうつ病を治療または予防する方法に関する。 The present invention relates to a pharmaceutical composition for treating or preventing depression. The present invention also relates to a method for treating or preventing depression using the pharmaceutical composition.
東洋諸国では古くからミミズ乾燥物が漢方薬や民間薬として様々な疾患の治療や予防に用いられており、現在知られている代表的な効果効能としては、例えば解熱作用、鎮痛・鎮痙作用、筋肉・気管支弛緩作用、降血圧作用、利尿作用および血栓溶解作用などが挙げられる（非特許文献１）。近年では、それらの効果効能を裏付ける成分の解明も進みつつある。 In the Eastern countries, dried earthworms have long been used as a traditional Chinese medicine and folk medicine for the treatment and prevention of various diseases, and typical known effects such as antipyretic action, analgesic / spasmodic action, muscle, etc. -Bronchial relaxation action, blood pressure lowering action, diuretic action, thrombolytic action, etc. (Non-patent Document 1) In recent years, the elucidation of the component which supports those effect efficacy is also progressing.
現在までに、ミミズに含まれる特有の成分として、強い線容活性を有する酵素であるルンブロキナーゼ（非特許文献２、特許文献１〜３）やフラン化合物（特許文献４）が同定されており、ミミズ乾燥粉末から得られた非酵素分画も強力なプラスミノーゲンアクチベーター産生能を有することが知られている（非特許文献３）。またミミズ乾燥粉末を有効成分として含む医薬、例えば血栓溶解剤（特許文献３）、糖尿病治療剤（特許文献５）、高脂血症剤（特許文献６）、血圧調節剤（特許文献７）および血栓症治療剤（特許文献８）などが開示されている。これらの医薬に有効成分として含まれるミミズ乾燥粉末の製造方法や、それをさらに改良した製造方法が開示されている（特許文献９〜１６）。
一方で、ミミズ乾燥物やミミズ乾燥物の成分がうつ病を治療または予防する可能性については、これまでに何の開示も示唆もなされていない。
To date, lumbrokinase (Non-patent Document 2, Patent Documents 1 to 3) and furan compound (Patent Document 4), which are enzymes having strong volumetric activity, have been identified as unique components contained in earthworms. It is also known that the non-enzymatic fraction obtained from earthworm dry powder also has a strong plasminogen activator-producing ability (Non-patent Document 3). Further, a medicine containing earthworm dry powder as an active ingredient, such as a thrombolytic agent (Patent Document 3), an antidiabetic agent (Patent Document 5), a hyperlipidemia agent (Patent Document 6), a blood pressure regulator (Patent Document 7) and A therapeutic agent for thrombosis (Patent Document 8) and the like are disclosed. The manufacturing method of the earthworm dry powder contained as an active ingredient in these pharmaceuticals, and the manufacturing method which improved it are disclosed (patent documents 9-16).
On the other hand, no disclosure or suggestion has been made so far about the possibility of treating or preventing depression by dried earthworms or components of dried earthworms.
現在、うつ病の治療には三環系抗うつ薬、四環系抗うつ薬、フェニルピペラジン系抗うつ薬、選択的セロトニン再取り込み阻害剤(SSRI)、選択的セロトニン・ノルアドレナリン再取り込み阻害剤(SNRI)、ノルアドレナリン作動性・特異的セロトニン作動性抗うつ薬(NaSSA)などの抗うつ薬が使用されている。うつ病の治療には、これら多くの種類の抗うつ薬の中から個々の患者に適した治療薬を選択し、加えて適切な用量設定を行う必要がある。現在使用されている抗うつ薬は、効果が認められるまでに最低２週間程度、場合によっては更に長い期間が必要とされる。治療効果が認められないかまたは部分的である場合もあり、また、うつ病に対する治療効果が認められる前に副作用が認められる場合や治療効果に加えて副作用を伴う場合が多く存在する。従って、より短期間で高い治療効果が認められ且つ副作用を伴わず安全に使用することができる抗うつ薬の開発が未だ求められている。 Currently, the treatment of depression includes tricyclic antidepressants, tetracyclic antidepressants, phenylpiperazine antidepressants, selective serotonin reuptake inhibitors (SSRI), selective serotonin and noradrenaline reuptake inhibitors ( SNRI) and noradrenergic / specific serotonergic antidepressants (NaSSA) are used. For the treatment of depression, it is necessary to select a therapeutic agent suitable for an individual patient from among these many types of antidepressants and to set an appropriate dose. Currently used antidepressants require a minimum of about two weeks and in some cases a longer period before they are effective. There are cases where the therapeutic effect is not observed or is partial, and there are many cases where a side effect is observed before the therapeutic effect for depression is observed, or there are side effects in addition to the therapeutic effect. Therefore, development of an antidepressant drug that has a high therapeutic effect in a shorter period of time and can be used safely without side effects is still desired.
本発明者は、ミミズ乾燥粉末により頸動脈を含む全身の血流障害が改善するという報告に着目し、うつ病の患者にミミズ乾燥粉末を投与したところ、副作用を伴うことなく短期間でうつ病を治療することができることを見出した。 The present inventor focused on the report that the earthworm dry powder improves systemic blood flow disorders including the carotid artery, and when the earthworm dry powder was administered to a patient with depression, depression occurred in a short period without side effects. Found that can be treated.
すなわち、本発明は、ミミズ乾燥粉末を有効成分として含む、うつ病を治療または予防するための医薬組成物を提供する。本発明の医薬組成物は、うつ病を治療または予防するために、単独で用いることができ、あるいは他の既存の抗うつ薬などと組み合わせても用いることができる。 That is, the present invention provides a pharmaceutical composition for treating or preventing depression, comprising earthworm dry powder as an active ingredient. The pharmaceutical composition of the present invention can be used alone or in combination with other existing antidepressants to treat or prevent depression.
本発明の医薬組成物を用いることにより、従来の治療薬の使用に伴う選択や用量設定の困難性および副作用について考慮することなく、うつ病を安全に治療または予防することができる。 By using the pharmaceutical composition of the present invention, depression can be safely treated or prevented without considering the difficulty and side effects of selection and dose setting associated with the use of conventional therapeutic agents.
本発明の医薬組成物により治療または予防することができる「うつ病」には、「米国精神医学会による精神疾患の診断統計マニュアル：DSM-IV(American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 第4版)」の改訂版であるDSM-IV-TR(2000年発行)の診断基準に基づくと、「気分障害)」に属する「うつ病性障害」が含まれる(高橋三郎 外２名訳、「DSM-IV-TR 精神疾患の分類と診断の手引 新訂版」、株式会社医学書院、2003年8月1日)。前記「うつ病性障害」には「296.2x 大うつ病性障害、単一エピソード」、「296.3x 大うつ病性障害、反復性」、「300.4 気分変調性障害」および「311 特定不能のうつ病性障害」が含まれる。前記「311 特定不能のうつ病性障害」の例としては、月経前不快気分障害、小うつ病性障害、反復性短期抑うつ障害、統合失調症の精神病後うつ病性障害などが挙げられる。 “Depression” that can be treated or prevented by the pharmaceutical composition of the present invention includes “DSM-IV (American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 4th edition). Edition) ”, the“ Depressive Disorders ”belonging to“ mood disorders ”are included based on the diagnostic criteria of DSM-IV-TR (issued in 2000) (2 translations by Saburo Takahashi,“ DSM-IV-TR Classification and Diagnosis Guide for Psychiatric Disorders, Revised Edition, Medical School, Inc., August 1, 2003). The “depressive disorder” includes “296.2x major depressive disorder, single episode”, “296.3x major depressive disorder, repetitive”, “300.4 mood modulation disorder” and “311 unspecified depression”. Pathological disorders ”are included. Examples of the “311 unspecified depressive disorder” include premenstrual dysphoric disorder, minor depressive disorder, repetitive short-term depression disorder, and postpsychotic depressive disorder with schizophrenia.
本発明の医薬組成物により治療または予防することができる「うつ病」には、世界保健機構(WHO)の「疾病と関連保健問題の国際統計分類：ICD-10(International Statistical Classification of Disease and Related Health Problems 第10版)」の診断基準で規定される「F32 うつ病エピソード」、「F33 反復性うつ病性障害」、「F34.1 気分変調症」および「F06.32 器質性うつ病性障害」が含まれる(中根允文 外２名訳、「ICD-10 精神および行動の障害−DCR 研究用診断基準−」、株式会社医学書院、1994年5月15日)。前記「F32 うつ病エピソード」には「F32.0 軽症うつ病エピソード」、「F32.1 中等症うつ病エピソード」、「F32.2 精神病症状を伴わない重症エピソード」、「F32.3 精神病症状を伴う重症うつ病エピソード」、「F32.8 他のうつ病エピソード」および「F32.9 うつ病エピソード、特定不能のもの」が含まれる。前記「F33 反復性うつ病性障害」には、「F33.0 反復性うつ病性障害、現在軽症エピソード」、「F33.1 反復性うつ病性障害、現在中等症エピソード」、「F33.2 反復性うつ病性障害、現在精神病症状を伴わない重症エピソード」、「F33.3 反復性うつ病性障害、現在精神病症状を伴う重症エピソード」、「F33.4 反復性うつ病性障害、現在寛解状態にあるもの」が含まれる。 “Depression” that can be treated or prevented by the pharmaceutical composition of the present invention includes “International Statistical Classification of Disease and Related: ICD-10” of the World Health Organization (WHO). "F32 Depressive Episodes", "F33 Recurrent Depressive Disorder", "F34.1 Dysthymia" and "F06.32 Organic Depressive Disorder" (Nakafumi Nakane et al., 2 translations, "ICD-10 Mental and Behavioral Disorders-DCR Research Diagnostic Criteria", Medical School, May 15, 1994). The `` F32 depression episode '' includes `` F32.0 Mild depression episode '', `` F32.1 moderate depression episode '', `` F32.2 Severe episode without psychosis '', `` F32.3 psychosis symptom '' "Severe Depressive Episodes with", "F32.8 Other Depressive Episodes" and "F32.9 Depressive Episodes, Unspecified". The `` F33 recurrent depressive disorder '' includes `` F33.0 recurrent depressive disorder, currently mild episode '', `` F33.1 recurrent depressive disorder, current moderate episode '', `` F33.2 Recurrent Depressive Disorder, Severe Episodes Without Current Psychiatric Symptoms ”,“ F33.3 Recurrent Depressive Disorder, Severe Episodes With Psychiatric Symptoms ”,“ F33.4 Recurrent Depressive Disorders, Current Remission "Things in state" are included.
本発明の医薬組成物によって治療または予防することができる「うつ病」には、難治性うつ病も含まれる。「難治性うつ病」とは、治療抵抗性うつ病とも呼ばれ、前記DSM-IV-TRまたは前記ICD-10に基づいて規定した「うつ病」の中でも、既存の抗うつ薬を用いた治療では全く治療効果が認められなかった、またはほとんど治療効果が認められなかった病態を有するか、あるいは既存の抗うつ薬を用いた治療で一旦は部分的または全体的に寛解しても服薬の終了により再度発症してしまう反復性の病態を有するものを意味する。
DMS-IV-TRやICD-10以外に臨床現場で前記「うつ病」の診断に用いられる他の診断基準または評価方法としては、例えばモントゴメリー/アスベルグうつ病評価尺度(MADRS)、ハミルトンうつ病評価尺度(HAM-D)、自己評価式抑うつ性尺度(SDS)または光トポグラフィー検査などが挙げられる。
“Depression” that can be treated or prevented by the pharmaceutical composition of the present invention includes intractable depression. “Intractable depression” is also called treatment-resistant depression, and treatment using existing antidepressants among the “depression” defined based on DSM-IV-TR or ICD-10. Treatment was completed, even if the treatment with existing antidepressants was partially or totally ameliorated, with a pathological condition that had no therapeutic effect or little therapeutic effect. Means having a recurrent pathological condition that will reappear.
In addition to DMS-IV-TR and ICD-10, other diagnostic criteria or evaluation methods used in the diagnosis of “depression” in clinical settings include, for example, the Montgomery / Asberg Depression Rating Scale (MADRS), Hamilton Depression Assessment Scale (HAM-D), self-assessment depression scale (SDS) or optical topography test.
本発明において、うつ病を治療することができるとは、上述のうつ病に特徴的な症状の１つ以上について主観的もしくは客観的に軽減または消失が認められることを意味し得る。客観的に認められるとは、臨床現場でうつ病の診断に用いることのできる診断基準、評価尺度または検査の指標によってうつ病の改善の事実が認められることであってもよい。例えば、本発明の医薬組成物の投与により、上述のモントゴメリー/アスベルグうつ病評価尺度(MADRS)、ハミルトンうつ病評価尺度(HAM-D)または自己評価式抑うつ性尺度(SDS)の点数（スコア）が下がった場合、うつ病が治療できた、またはうつ病治療効果があったということができる。あるいは家族、主治医または周囲の人間といった第三者からみて、うつ病に特徴的な症状の１つ以上に軽減や消失などの改善が認められることであってもよい。 In the present invention, being able to treat depression can mean that subjective or objective reduction or disappearance is observed for one or more of the symptoms characteristic of depression described above. Being objectively recognized may mean that the fact of improvement in depression is recognized by diagnostic criteria, rating scales or laboratory indicators that can be used to diagnose depression in the clinical setting. For example, by the administration of the pharmaceutical composition of the present invention, the above-mentioned Montgomery / Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAM-D), or Self-Rating Depression Scale (SDS) Can be said to have been able to treat depression or to be effective in treating depression. Alternatively, it may be that one or more of symptoms characteristic of depression are recognized as improved or reduced, as seen from a third party such as a family member, an attending physician, or a surrounding person.
本発明において、うつ病を予防することができるとは、うつ病の罹患が予測され得る状況で本発明の医薬組成物を投与することにより、うつ病の罹患で予測されうる少なくとも１以上の症状が発症しないか、またはその重症度もしくは進行が抑制されることを意味し得る。うつ病の罹患の予測は、遺伝子検査または光トポグラフィー、CTもしくはMRIなどを用いた検査といった医学的検査の結果に基づくものであっても、環境変化や薬物療法の開始など医学的考察に基づくものであってもよい。 In the present invention, depression can be prevented by administering the pharmaceutical composition of the present invention in a situation where depression can be predicted, and thereby at least one or more symptoms that can be predicted by depression. May not occur, or its severity or progression may be suppressed. Prediction of depression 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 testing or tests using optical topography, CT or MRI It may be a thing.
本発明の医薬組成物に含まれるミミズ乾燥粉末の原料として、天然または養殖の食用ミミズ、例えばアカミミズ(Lumbricus rubellus)、ＬＴミミズ(Lumbricus terrestris)、シマミミズ(Eisenia foetida)、カッショクツリミミズ(Allolobophora caliginosa)、ムラサキツリミミズ(Dendrobaena octaedra)、サクラミミズ(Allolobophora japonica Michaelsen)、ハッタミミズ(Drawida hattamimizu Hatai)、セグロミミズ(Pheretima divergens Michaelsen)、フツウミミズ(Pheretima communissima)、ハタケミミズ(Pheretima agrestis)、シーボルトミミズ(Pheretima sieboldi Horst)、ヒトツモンミミズ(Pheretima hilgendorfi)、イソミミズ(Pontodrilus matsushimensis Iizuka)、イトミミズ(Tubifex hattai Nomura)、ゴトウイトミミズ（ユリミミズ）［Limnodrilus gotoi Hatai＝L.Socialis Stephenson］などを用いることができる。中でもルンブリクス属（Lumbricus）に属するミミズが好ましく、最も好ましくはアカミミズ（Lumbricus rubellus）またはその近縁種である。 As raw materials for earthworm dry powder contained in the pharmaceutical composition of the present invention, natural or cultured edible earthworms such as red earthworm (Lumbricus rubellus), LT earthworm (Lumbricus terrestris), earthworm (Eisenia foetida), brown earthworm (Allolobophora caliginosa) ), Purple earthworm (Dendrobaena octaedra), cherry earthworm (Allolobophora japonica Michaelsen), butterfly earthworm (Drawida hattamimizu Hatai), black earthworm (Pheretima divergens Michaelsen), footwell earthworm (Pheretima communissima), heretis ), Earthworm earthworm (Pheretima hilgendorfi), islet earthworm (Pontodrilus matsushimensis Iizuka), earthworm earthworm (Tubifex hattai Nomura), gotouito earthworm (lily earthworm) [Limnodrilus gotoi Hatai = L. Socialis Stephenson], etc. can be used. Of these, earthworms belonging to the genus Lumbricus are preferable, and red earthworms (Lumbricus rubellus) or related species thereof are most preferable.
本発明の医薬組成物に含まれるミミズ乾燥粉末は、現在市販されている健康食品などに用いられているミミズ乾燥粉末を製造するいずれの方法で製造されたものであってもよい。そのような製造方法の例を挙げると、例えば、ミミズの生体から体皮に付着する汚物、消化管内に残留する消化物、体液などを除去して洗浄した後、ミミズを摩砕してミミズ摩砕物を得るか、またはミミズもしくはミミズ摩砕物をインキュベーションしてミミズ抽出液を得て、得られたミミズ摩砕物またはミミズ抽出液を乾燥させて製造することができる。 The earthworm dry powder contained in the pharmaceutical composition of the present invention may be produced by any method for producing earthworm dry powder used in health foods currently on the market. An example of such a production method is, for example, removing and washing the earthworm's living body, dirt adhering to the body skin, digested matter remaining in the digestive tract, body fluids, etc. A crushed material can be obtained, or an earthworm or earthworm ground can be incubated to obtain an earthworm extract, and the obtained earthworm triturate or earthworm extract can be dried.
ミミズの生体から消化管内に残留する消化物を除去する方法としては、例えば、ミミズを水中に所定時間浸ける等によって消化管内の糞土を吐かせる方法を挙げることができる。また、ミミズの生体から体皮に付着する汚物を除去する方法としては、例えば、ミミズを明所に所定時間（例えば10〜50時間）放置してから体皮に付着する汚物を不織布に吸着させて剥ぎ取る方法を挙げることができる。 As a method for removing digestive substances remaining in the digestive tract from the earthworm's living body, for example, a method in which the earthworm in the digestive tract is spited by immersing the earthworm in water for a predetermined time or the like. In addition, as a method of removing the soil adhering to the body skin from the earthworm's living body, for example, the earthworm is allowed to stand in a light place for a predetermined time (for example, 10 to 50 hours) and then the soil adhering to the body skin is adsorbed to the nonwoven fabric Can be mentioned.
ミミズの体液の除去は、例えば、体皮に付着する汚物および消化管内に残留する消化物を除去した生ミミズをpH2〜5の有機酸水溶液中に所定時間（例えば3〜180分間）浸漬することによって行うことができる。有機酸水溶液中への浸漬は、あらかじめ調製した有機酸水溶液を用いてもよく、生ミミズを有機酸と接触させた後に水で希釈することによって行ってもよい。有機酸としては、例えば酢酸、リンゴ酸、クエン酸、乳酸、マロン酸、コハク酸などがあり、単独で用いても２種以上混合して用いてもよい。特にクエン酸が好ましい。あるいは有機酸として、結晶状ヒドロキシカルボン酸粉末を使用することもできる。結晶状ヒドロキシカルボン酸粉末は、使用条件下で結晶状であればよく、そのヒドロキシ基数またはカルボキシル基数には特に限定されず、モノヒドロキシモノカルボン酸、モノヒドロキシポリカルボン酸、ポリヒドロキシモノカルボン酸、ポリヒドロキシポリカルボン酸のいずれであってもよい。そのようなヒドロキシカルボン酸として、例えばグリコール酸、乳酸、β-ヒドロキシプロピオン酸、α-ヒドロキシ-n-酪酸、β-ヒドロキシ-n-酪酸、α-ヒドロキシ-n-吉草酸、β-ヒドロキシ-n-吉草酸、リンゴ酸、α-メチルリンゴ酸、α-ヒドロキシグルタル酸、β-ヒドロキシグルタル酸、クエン酸などが挙げられ、これらの中でも乳酸、リンゴ酸、クエン酸が好ましい。 To remove earthworm body fluids, for example, immerse raw earthworms, from which dirt attached to the body skin and digestive substance remaining in the digestive tract have been removed, in a pH 2-5 organic acid aqueous solution for a predetermined time (eg, 3 to 180 minutes). Can be done by. The immersion in the organic acid aqueous solution may be carried out by using an organic acid aqueous solution prepared in advance, or by diluting raw earthworms with water after bringing them into contact with the organic acid. Examples of the organic acid include acetic acid, malic acid, citric acid, lactic acid, malonic acid, and succinic acid, which may be used alone or in combination of two or more. Particularly preferred is citric acid. Alternatively, a crystalline hydroxycarboxylic acid powder can be used as the organic acid. The crystalline hydroxycarboxylic acid powder only needs to be crystalline under the conditions of use, and is not particularly limited to the number of hydroxy groups or the number of carboxyl groups. Monohydroxymonocarboxylic acid, monohydroxypolycarboxylic acid, polyhydroxymonocarboxylic acid, Any of polyhydroxypolycarboxylic acids may be used. Examples of such hydroxycarboxylic acids include glycolic acid, lactic acid, β-hydroxypropionic acid, α-hydroxy-n-butyric acid, β-hydroxy-n-butyric acid, α-hydroxy-n-valeric acid, β-hydroxy-n -Valeric acid, malic acid, α-methylmalic acid, α-hydroxyglutaric acid, β-hydroxyglutaric acid, citric acid, and the like. Among these, lactic acid, malic acid, and citric acid are preferable.
洗浄は、例えば水洗などで行うことができる。水洗には純水やマイクロナノバブルを含有する水などを用いてもよい。 The washing can be performed by, for example, washing with water. For washing, pure water or water containing micro-nano bubbles may be used.
このように処理されたミミズを、例えばホモジナイザー、ブレンダー、ホモミキサー、擂潰機または加圧型細胞破壊装置などを用いて摩砕してミミズ摩砕物を得ることができる。摩砕後に濾過することによって、ミミズ摩砕物に含まれるミミズの皮を除去してもよい。得られたミミズ摩砕物にネギ科植物のペーストや抽出物などを添加し混合してインキュベーションしてもよい。インキュベーションは、例えば20℃〜55℃にて5〜170時間行うことができる。そのようなネギ科植物の例としては、ニンニク、タマネギ、ネギ、ラッキョウ、ワケギ、ニラなどが挙げられ、どの部位を用いてもよいが鱗茎の部分が好ましい。
あるいは洗浄したミミズまたは上述のようにして得られたミミズ摩砕物をインキュベーションすることによってミミズ抽出液を滲出させることもできる。インキュベーションは、例えば10℃〜65℃で0.5〜6時間行うことができる。この際、前記ネギ科植物のペーストや抽出物などを共存させてインキュベーションを行うこともできる。
The earthworm treated in this manner can be ground using, for example, a homogenizer, a blender, a homomixer, a crusher, a pressure cell disrupter or the like to obtain a groundworm ground product. You may remove the earthworm skin contained in earthworm ground material by filtering after grinding. You may incubate by mixing and mixing the earthworm plant paste and extract etc. to the obtained earthworm ground material. Incubation can be performed, for example, at 20 to 55 ° C. for 5 to 170 hours. Examples of such leeks include garlic, onion, leeks, raccoon, bamboo shoots, and leek. Any part may be used, but a bulb portion is preferred.
Alternatively, the earthworm extract can be leached by incubating the washed earthworm or the earthworm ground product obtained as described above. Incubation can be performed, for example, at 10 ° C to 65 ° C for 0.5 to 6 hours. In this case, the incubation can also be carried out in the presence of a paste or extract of the leek family.
このようにして得られたミミズ摩砕物またはミミズ抽出液は、凍結乾燥やスプレードライヤーなどの手法を用いて乾燥させることができる。スプレードライヤーで乾燥する場合は、遠心分離や濾過などの方法により、前記摩砕物から濁り成分や不溶物を除去してから乾燥させてもよい。凍結乾燥は、真空下で、脱ガスを同時に行うのが好ましい。凍結乾燥は、例えば、ミミズ摩砕物を−18℃〜−35℃に急冷して20〜240時間凍結させてから、圧力50Pa以下、−60℃〜＋90℃の温度において、数段階的に分けて昇温し、4〜80Paの圧力において、数段階に分け減圧しながら、10〜60時間の範囲で制御して行うのが好ましい。
このようにして得られたミミズ乾燥粉末を、さらに110℃以上130℃未満の温度で加熱処理することもできる。加熱処理の方法は特に限定されず、熱風をかける方法、加熱ジャケットを用いる方法、トレイ等に載せてヒーターで加熱する方法、定温恒温器を使用する方法などによって行うことができる。
The earthworm ground product or the earthworm extract thus obtained can be dried using a technique such as freeze-drying or spray dryer. When drying with a spray dryer, it may be dried after removing turbid components and insoluble matter from the ground product by a method such as centrifugation or filtration. The freeze-drying is preferably performed simultaneously with degassing under vacuum. Freeze-drying is carried out, for example, by rapidly cooling the earthworm ground product to −18 ° C. to −35 ° C. and freezing it for 20 to 240 hours, and then dividing it into several steps at a pressure of 50 Pa or less and −60 ° C. to + 90 ° C. It is preferable that the temperature is raised and the pressure is controlled in the range of 10 to 60 hours while reducing the pressure in several steps at a pressure of 4 to 80 Pa.
The earthworm dry powder thus obtained can be further heat-treated at a temperature of 110 ° C. or higher and lower than 130 ° C. The heat treatment method is not particularly limited, and can be performed by a method of applying hot air, a method of using a heating jacket, a method of heating on a tray or the like, a method of using a constant temperature thermostat, or the like.
また、本発明で用いるミミズ乾燥粉末は、例えば、上記特許文献１０〜１６（特許第4699974号公報、特開2009-249362号公報、特開2011-84483号公報、特開2004-292402号公報、特開2006-96673号公報、特開2009-143845号公報、特開2010-275251号公報）などで開示されている製造方法によって製造されたものであってもよい。 The earthworm dry powder used in the present invention is, for example, the above Patent Documents 10 to 16 (Patent No. 4699974, JP 2009-249362, JP 2011-84483, JP 2004-292402, It may be manufactured by a manufacturing method disclosed in JP-A-2006-96673, JP-A-2009-143845, JP-A-2010-275251) or the like.
本発明の医薬組成物は、有効成分であるミミズ乾燥粉末の製造方法によって特に限定されるものではないが、原料のミミズの生体内に含まれる線容活性阻害物質、有害元素ならびにアンモニアおよび病原性微生物のような有害物質を除去し無害化したミミズ乾燥粉末を用いるのが好ましい。そのようなミミズ乾燥粉末を得る製造方法は、例えば上記特許文献１０〜１２（特許第4699974号公報、特開2009-249362号公報、特開2011-84483号公報）において開示されている。このような製造方法によって得られたミミズ乾燥粉末は、例えばＬＲ末(登録商標)としてワキ製薬株式会社から入手することができる。また、このような製造方法によって得られたミミズ乾燥粉末を含む市販品としては、例えばプロルベイン(登録商標)ＤＲ（株式会社カインKN）などが挙げられる。 The pharmaceutical composition of the present invention is not particularly limited by the method for producing an earthworm dry powder which is an active ingredient, but it includes a tolerant substance, harmful elements, ammonia and pathogenicity contained in the living body of earthworm earthworm. It is preferable to use earthworm dry powder from which harmful substances such as microorganisms have been removed and detoxified. A production method for obtaining such a dried earthworm powder is disclosed in, for example, the above Patent Documents 10 to 12 (Patent No. 4699974, JP-A 2009-249362, and JP-A 2011-84483). The earthworm dry powder obtained by such a production method can be obtained, for example, from Waki Pharmaceutical Co., Ltd. as LR powder (registered trademark). Moreover, as a commercial item containing the earthworm dry powder obtained by such a manufacturing method, prolubein (trademark) DR (Cain KN Co., Ltd.) etc. are mentioned, for example.
本発明の医薬組成物は、成人１日あたりの用量に有効成分としてミミズ乾燥粉末5mg〜1000mgを含むことが好ましく、より好ましくは20mg〜800mg、さらに好ましくは40mg〜600mgのミミズ乾燥粉末を含む。 The pharmaceutical composition of the present invention preferably contains 5 mg to 1000 mg of earthworm dry powder as an active ingredient in an adult daily dose, more preferably 20 mg to 800 mg, and further preferably 40 mg to 600 mg of earthworm dry powder.
本発明の医薬組成物は、経口投与により用いることができる。従って、本発明の医薬組成物は経口投与が可能ないずれの剤形としても用いることができ、そのような剤形としては例えばカプセル剤（ハードカプセルまたはソフトカプセル）、散剤、顆粒剤、錠剤、丸剤、トローチ剤、液剤、エアゾール剤、エリキシル剤およびシロップ剤などを挙げることができる。 The pharmaceutical composition of the present invention can be used by oral administration. Therefore, the pharmaceutical composition of the present invention can be used as any dosage form that can be administered orally. Examples of such dosage forms include capsules (hard capsules or soft capsules), powders, granules, tablets, pills. , Troches, liquids, aerosols, elixirs and syrups.
本発明の医薬組成物は、ミミズ乾燥粉末に加えて、製剤学的および薬理学的に許容される添加物を１つ以上含むこともできる。製剤学的および薬理学的に許容される添加物としては、例えば担体、賦形剤、結合剤、崩壊剤、助剤、溶媒、甘味剤などが挙げられる。そのような添加物の選択や用量設定は、本技術分野における当業者の技術常識の範囲内に含まれる。 The pharmaceutical composition of the present invention may contain one or more pharmaceutically and pharmacologically acceptable additives in addition to the earthworm dry powder. 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.
本発明の医薬組成物は、１日１回〜数回に分けて経口投与することができる。本発明の医薬組成物は、起床直後、食前、食後、食間または就寝前のうちいつ経口投与してもよいが、空腹時、すなわち起床直後、食前、食間または就寝前に経口投与するのが好ましい。
本発明の医薬組成物は、投与開始から最短で２〜３日間で治療上または予防上の効果が認められ得るが、１週間以上継続的に投与するのが好ましく、１ヶ月以上継続的に投与するのがより好ましい。
本発明の医薬組成物は、小児から高齢者まで幅広い年齢の患者に用いることができる。
本発明の医薬組成物の最適な用量および投与計画は、個々の患者の状態、例えば年齢、体重、性別、症状の種類または重症度などに応じて、上述する記載を参考に当業者が適宜決定することができる。そのような決定は、本技術分野における当業者の技術常識の範囲内に含まれる。
The pharmaceutical composition of the present invention can be orally administered once to several times a day. The pharmaceutical composition of the present invention may be administered orally immediately after waking up, before meals, after meals, between meals or before going to bed, but preferably administered orally on an empty stomach, i.e. immediately after getting up, before meals, between meals or before going to bed. .
The pharmaceutical composition of the present invention can have a therapeutic or prophylactic effect within a minimum of 2 to 3 days from the start of administration, but is preferably administered continuously for 1 week or longer, and continuously administered for 1 month or longer. More preferably.
The pharmaceutical composition of the present invention can be used for a wide range of patients from children to the elderly.
The optimal dose and administration schedule of the pharmaceutical composition of the present invention are appropriately determined by those skilled in the art with reference to the above description according to the individual patient's condition, such as age, weight, sex, type of symptom or severity. can do. Such a determination is within the common general knowledge of those skilled in the art.
本発明の医薬組成物は、うつ病を治療または予防するために用いられる１以上の他の医薬と組み合わせて用いることもできる。そのような１以上の他の医薬としては、例えば抗うつ薬、気分安定薬(気分調整薬)、抗精神病薬、抗不安薬、睡眠薬などが挙げられる。本発明の医薬組成物と組み合わせて用いることができる抗うつ薬としては、例えばクロミプラミン、ノリトリプチリン、アミノトリプチリン、アモキサピン、イミプラミン、トリミプラミン、ロフェプラミンおよびドレスピンなどの三環系抗うつ薬、ミアンセリン、マプロチリンおよびセチプチリンなどの四環系抗うつ薬、トラドゾンなどのフェニルピペラジン系抗うつ薬、パロキセチン、セルトラリン、フルボキサミン、フルオキセチン、シタロプラムおよびエスシタロプラムなどの選択的セロトニン再取り込み阻害剤(SSRI)、ミルナシプラン、デュロキセチン、ベンラファキシンおよびネファゾドンなどの選択的セロトニン・ノルアドレナリン再取り込み阻害剤(SNRI)、ならびにミルタザピンなどのノルアドレナリン作動性・特異的セロトニン作動性抗うつ薬(NaSSA)などが挙げられるがこれらに限定されない。前記１以上の他の医薬は、エナンチオマー、ジアステレオマー、それらの薬理学的に許容される塩、前記塩のエナンチオマー、前記塩のジアステレオマー、それらの溶媒和物、それらの活性代謝物またはそれらのプロドラッグなどの形態であってもよい。前記１以上の他の医薬は、本発明の医薬組成物の成分として含まれてもよく、あるいは本発明の医薬組成物とは別の医薬組成物として調剤されているものであってもよい。そのような他の有効成分の選択、用量設定および投与計画などは、本技術分野における当業者の技術常識の範囲内に含まれる。 The pharmaceutical composition of the present invention can also be used in combination with one or more other medicaments used to treat or prevent depression. Examples of such one or more other medicaments include antidepressants, mood stabilizers (mood regulators), antipsychotics, anxiolytics, and sleeping pills. Examples of antidepressants that can be used in combination with the pharmaceutical composition of the present invention include tricyclic antidepressants such as clomipramine, noritriptyline, aminotriptyline, amoxapine, imipramine, trimipramine, lofepramine and dresspin, mianserin, Tetracyclic antidepressants such as maprotiline and cetiptiline, phenylpiperazine antidepressants such as tradozone, selective serotonin reuptake inhibitors (SSRI) such as paroxetine, sertraline, fluvoxamine, fluoxetine, citalopram and escitalopram, milnacipran, Selective serotonin and noradrenaline reuptake inhibitors (SNRI) such as duloxetine, venlafaxine and nefazodone, and noradrenergic and specific serotonin such as mirtazapine Although such agonistic antidepressants (NaSSA) including but not limited to. Said one or more other medicaments are enantiomers, diastereomers, pharmaceutically acceptable salts thereof, enantiomers of said salts, diastereomers of said salts, solvates thereof, active metabolites thereof or These may be in the form of prodrugs. The one or more other medicaments 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 such other active ingredients, dosage setting, administration schedule, and the like are within the common general knowledge of those skilled in the art.
以上説明した本発明の医薬組成物を用いることにより、従来の治療薬の使用に伴う選択や用量設定の困難性および副作用について考慮することなく、うつ病を安全に治療または予防することができる。本発明の効果は、本発明の医薬組成物に有効成分として含まれるミミズ乾燥粉末により得られるものであるが、ミミズ乾燥粉末中に含まれるどのような物質に由来するものであるかは現時点では不明である。当該物質は、既に同定された既知物質である可能性もあるが、未同定の物質である可能性もある。また、当該物質が単独で作用している可能性もあるが、他の成分と相互作用している可能性もある。
本発明の医薬組成物によるうつ病治療効果は最短で２〜３日で表れることから、本発明の医薬組成物の有効成分であるミミズ乾燥粉末について既に報告されている血流改善効果のみで説明できるものとは考えられない。
By using the pharmaceutical composition of the present invention described above, depression can be safely treated or prevented without considering the difficulty and side effects of selection and dose setting associated with the use of conventional therapeutic agents. The effect of the present invention is obtained by the earthworm dry powder contained as an active ingredient in the pharmaceutical composition of the present invention, but what kind of substance is contained in the earthworm dry powder is currently derived from It is unknown. The substance may be a known substance that has already been identified, but may also be an unidentified substance. In addition, the substance may be acting alone, but may be interacting with other components.
Since the therapeutic effect of depression by the pharmaceutical composition of the present invention appears in a minimum of 2 to 3 days, only the blood flow improving effect already reported for the earthworm dry powder which is the active ingredient of the pharmaceutical composition of the present invention will be explained. I can't think of it.
以下の実施例により本発明をさらに説明するが、本発明の範囲はこれら実施例に限定されるものではない。 The following examples further illustrate the present invention, but the scope of the present invention is not limited to these examples.
［ミミズ乾燥粉末の調製例］
水洗により皮ふ表面に付着した汚物を除去した生のアカミミズ(Lumbricus rubellus)30kgを平皿に拡げ、この上にクエン酸250gを均一に振りかけ、15秒後に純粋30リットルを加えて希釈した。水を加えた直後のpHは2.25であり、完全に希釈したときのpHは2.74であった。この希釈したクエン酸中に浸したミミズを20℃にて60分間放置した後、生ミミズを取り出し、水洗して、ホモジナイザーを用いて10℃で摩砕してミミズ摩砕物を得た。このミミズ摩砕物を吸引脱気して摩砕物に含まれるガスを除いた後、瞬間的に−30℃まで急冷して50時間保持することによって凍結させた。凍結したミミズ摩砕物を−30℃で圧力5Paに減圧して10時間保持した後、温度を20℃まで昇温させて、さらに圧力10Paで10時間、次いで40℃で10時間乾燥させ、最後に温度を80℃にして圧力5Paにて5時間保持して真空凍結乾燥させた。
このようにして調製したミミズ乾燥粉末を用いて以下の実施例を行った。
[Preparation example of earthworm dry powder]
30 kg of raw red earthworm (Lumbricus rubellus) from which dirt attached to the skin surface was removed by washing with water was spread on a flat plate, 250 g of citric acid was sprinkled uniformly over this, and after 15 seconds, 30 liters of pure water was added for dilution. The pH immediately after adding water was 2.25, and the pH when fully diluted was 2.74. The earthworm soaked in the diluted citric acid was allowed to stand at 20 ° C. for 60 minutes, and then the raw earthworm was taken out, washed with water, and ground at 10 ° C. using a homogenizer to obtain an earthworm ground product. The earthworm ground product was sucked and degassed to remove the gas contained in the ground product, and then immediately cooled to −30 ° C. and held for 50 hours for freezing. The frozen earthworm grind was reduced to −5 ° C. to a pressure of 5 Pa and held for 10 hours, then the temperature was raised to 20 ° C. and further dried at a pressure of 10 Pa for 10 hours and then at 40 ° C. for 10 hours, The temperature was kept at 80 ° C. and a pressure of 5 Pa for 5 hours, followed by vacuum freeze drying.
The following examples were conducted using the earthworm dry powder thus prepared.
［実施例１］
DSM-IV-TRに基づく診断が「296.2x 大うつ病性障害、単一エピソード」であり、ICD-10に基づく診断が「F32.2 精神病症状をともなわない重症うつ病エピソード」である、44歳会社員の男性の症例である。４年前からうつ病を患って他院で治療をしており抗うつ薬のミルタザピン（リフレックス(登録商標)Meiji Seika ファルマ株式会社）15mg/日および抗不安薬としてロラゼパム（ワイパックス(登録商標)ファイザー株式会社）を服用していたが効果が認められず休職をよぎなくされており、３ヶ月前より本外来で治療を始めた。具体的な症状として抑うつ、不安、思考力・集中力の低下が認められた。最初に抗うつ薬としてフルオキセチン20mg/日を処方したが吐き気などの副作用が認められたためフルオキセチンの処方を中止し、抗不安薬としてエチゾラム（メディピース(登録商標)沢井製薬株式会社）1.5mg/日と気分安定薬としてクロナゼパム（リボトリール(登録商標)中外製薬株式会社）1mg/日とを処方したが症状が改善しなかった。
そこでフルオキセチンに換えてミミズ乾燥物80mg/日を就寝前１回投与したところ、２週間程で治療効果が自覚された。具体的には、抑うつ感および不安が消失し、思考力・集中力が向上した。ミミズ乾燥物を投与する前のMADRS合計スコアは２５点であったが、ミミズ乾燥物投与開始から２週間経過後のMADRS合計スコアは６点にまで下がり、うつ状態の治癒が認められた。本外来での治療開始時は休職中であったが、より良い条件の会社へ転職することもできた。同量のミミズ乾燥物の投与を続けて２ヶ月経過後の現在までにうつ状態の悪化は認められず、いかなる副作用も認められなかった。
これらの所見から、本発明の医薬組成物がうつ病に対して副作用を伴うことなく明確な治療効果を発揮したことが示された。
[Example 1]
The diagnosis based on DSM-IV-TR is `` 296.2x major depressive disorder, single episode '' and the diagnosis based on ICD-10 is `` F32.2 Severe depression episode without psychotic symptoms '', 44 This is a case of a male office worker. Antidepressant mirtazapine (Reflex (registered trademark) Meiji Seika Pharma Co., Ltd.) 15mg / day and Lorazepam (Waipax (registered trademark) as an anxiolytic He was taking Pfizer Inc.) but was unable to take any leave due to lack of effectiveness. Specific symptoms were depression, anxiety, and reduced thinking and concentration. First, fluoxetine 20mg / day was prescribed as an antidepressant, but side effects such as nausea were observed, so the prescription of fluoxetine was discontinued and etizolam (MediPiece (registered trademark) Sawai Pharmaceutical Co., Ltd.) 1.5mg / day as an anxiolytic And 1 mg / day of clonazepam (Rivotril (registered trademark) Chugai Pharmaceutical Co., Ltd.) as a mood stabilizer, but symptoms did not improve.
Therefore, instead of fluoxetine, 80 mg / day of earthworm dried product was administered once before going to bed, and the therapeutic effect was recognized in about 2 weeks. Specifically, feelings of depression and anxiety disappeared, and thinking and concentration improved. The MADRS total score before administration of the earthworm dried product was 25 points, but the MADRS total score after 2 weeks from the start of administration of the earthworm dried product decreased to 6 points, and depression was cured. Although I was on leave at the start of this outpatient treatment, I was able to move to a company with better conditions. No worsening of depression was observed until the present two months after the administration of the same amount of dried earthworm, and 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 depression.
［実施例２］
DSM-IV-TRに基づく診断が「296.2x 大うつ病性障害、単一エピソード」であり、ICD-10に基づく診断が「F32.2 精神病症状をともなわない重症うつ病エピソード」である、33歳会社員の女性の症例である。具体的な症状として、抑うつ感、焦燥感、不安、易刺激性および過食嘔吐が認められた。抗うつ薬としてフルオキセチンを20mg/日で１週間、40mg/日に増量してさらに１週間処方したが、症状の改善がみとめられず、休職せざるを得なかった。
そこで上記処方に加えてミミズ乾燥物80mg/日を就寝前１回投与したところ、２日で治療効果が自覚された。具体的には、抑うつ感、焦燥感、不安および易刺激性が消失した。ミミズ乾燥物を投与する前のMADRS合計スコアは２７点であったが、ミミズ乾燥物投与開始から２週間経過後のMADRS合計スコアは３点にまで下がり、うつ状態の治癒が認められ、復職することができた。同量のミミズ乾燥物の投与を続けて２ヶ月経過後の現在までにうつ状態の悪化は認められず、いかなる副作用も認められなかった。
これらの所見から、本発明の医薬組成物がうつ病に対して副作用を伴うことなく明確な治療効果を発揮したことが示された。
[Example 2]
Diagnosis based on DSM-IV-TR is `` 296.2x major depressive disorder, single episode '' and diagnosis based on ICD-10 is `` F32.2 Severe depression episode without psychotic symptoms '', 33 This is a case of a female office worker. Specific symptoms included depression, agitation, anxiety, irritability, and bulimia vomiting. As an antidepressant, fluoxetine was prescribed at 20 mg / day for 1 week and increased to 40 mg / day for another 1 week. However, improvement in symptoms was not observed, and she was forced to leave.
Therefore, when 80 mg / day of earthworm dried product was administered once before bedtime in addition to the above-mentioned prescription, the therapeutic effect was recognized in 2 days. Specifically, depression, agitation, anxiety and irritability disappeared. The total MADRS score before administration of dried earthworms was 27 points, but the MADRS total score after 2 weeks from the start of administration of dried earthworms decreased to 3 points, healing of depression was observed, and she returned to work I was able to. No worsening of depression was observed until the present two months after the administration of the same amount of dried earthworm, and 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 depression.
［実施例３］
DSM-IV-TRに基づく診断が「296.3x 大うつ病性障害、反復性」であり、ICD-10に基づく診断が「F33.2 反復性うつ病性障害、現在精神病症状をともなわない重症エピソード」である、31歳会社員の女性の症例である。今回の大うつ病エピソードの前に過去１回の大うつ病エピソードが存在し、今回の大うつ病エピソード開始は過去の大うつ病エピソード治癒から約２年半経過後であった。今回の大うつ病エピソードの具体的症状としては抑うつ気分、睡眠障害および疲労感が目立っており、休職せざるを得なかった。前回の大うつ病エピソード時に効果が認められた処方、抗うつ薬としてアモキサピン（アモキサン(登録商標)ファイザー株式会社)10mg/日およびフルボキサミンマレイン酸塩（デプロメール(登録商標) Meiji Seika ファルマ株式会社）25mg/日、睡眠薬としてゾルピデム酒石酸塩（マイスリー(登録商標)アステラス製薬株式会社）5mg/日およびエチゾラム（メディピース(登録商標)沢井製薬株式会社）1mg/日を１週間投与したが症状の改善が認められなかった。この処方にフルオキセチン40mg/日を追加し、さらにアモキサピンを30mg/日まで増量したが、やはり症状の改善が認められなかった。
そこで、上記処方に加えてミミズ乾燥物160mg/日を朝食前80mg、就寝前80mgの２回に分けて投与したところ、２日程でうつ病の治療効果が自覚された。具体的には、睡眠障害が改善して睡眠が深くなって目覚めが良くなり、疲れがとれ、易疲労感が改善し、表情が明るくなって抑うつ気分が消失した。ミミズ乾燥物を投与する前のMADRS合計スコアは２６点であったが、ミミズ乾燥物投与開始から２週間経過時のMADRS合計スコアは８点にまで下がり、うつ状態の治癒が認められた。主観的にも客観的にも、あの時のうつ状態は何だったのだろうと言えるほどの回復を示した。同量のミミズ乾燥物の投与を続けて２ヶ月経過後の現在までにうつ状態の悪化は認められず、いかなる副作用も認められなかった。
これらの所見から、本発明の医薬組成物がうつ病に対して副作用を伴うことなく明確な治療効果を発揮したことが示された。
[Example 3]
Diagnosis based on DSM-IV-TR is “296.3x major depressive disorder, repetitive” and diagnosis based on ICD-10 is “F33.2 Recurrent depressive disorder, present episode with no psychotic symptoms” This is a case of a 31-year-old office worker woman. There was one major depressive episode in the past before this major depressive episode, and the start of this major depressive episode was about two and a half years after the past major depressive episode healing. Depressive mood, sleep disturbance and fatigue were conspicuous as specific symptoms of this major depressive episode, and he had to take leave. Prescriptions that were effective during the last major depressive episode, Amoxapine (Amoxane (registered trademark) Pfizer Inc.) 10 mg / day as antidepressant and Fluvoxamine maleate (Depromer (registered trademark) Meiji Seika Pharma Co., Ltd.) 25 mg Administration of zolpidem tartrate (Mysley (registered trademark) Astellas Pharma Inc.) 5 mg / day and etizolam (Medipece (registered trademark) Sawai Pharmaceutical Co., Ltd.) 1 mg / day as a sleeping pill for 1 week, but symptoms improved I couldn't. Although fluoxetine 40mg / day was added to this formulation and amoxapine was increased to 30mg / day, no improvement in symptoms was observed.
Therefore, in addition to the above prescription, 160 mg / day of earthworm dried product was administered in two doses of 80 mg before breakfast and 80 mg before going to bed, and the therapeutic effect of depression was noticed in about 2 days. Specifically, sleep disturbance improved, sleep became deeper and awakened, tiredness was improved, ease of fatigue was improved, facial expression became brighter and depression was lost. The MADRS total score before administration of the earthworm dried product was 26 points, but the MADRS total score after 2 weeks from the start of administration of the earthworm dried product decreased to 8 points, and depression was cured. Both subjectively and objectively, it showed a recovery that could be said to be what the depression was at that time. No worsening of depression was observed until the present two months after the administration of the same amount of dried earthworm, and 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 depression.
［実施例４］
DSM-IV-TRに基づく診断が「296.2x 大うつ病性障害、単一エピソード」であり、ICD-10に基づく診断が「F32.2 精神病症状をともなわない重症うつ病エピソード」である、23歳大学生の女性の症例である。18歳頃よりうつ状態と過食症に悩んでおり、他院でフルボキサミンマレイン酸塩（ルボックス(登録商標)アボットジャパン株式会社）25mg/日、トラゾドン塩酸塩（デジレル(登録商標)ファイザー株式会社）25mg/日、バルプロ酸ナトリウム徐放剤（デパケン(登録商標)R、協和発酵キリン株式会社）100mg/日を処方されていたが有意な改善が認められず、2年9ヶ月前から本外来で治療を始めた。具体的な症状としては、過食、抑うつ感、易疲労感が認められていた。抗うつ薬としてフルオキセチンを20mg/日から60mg/日まで増量し、加えて気分安定薬としてバルプロ酸ナトリウム徐放剤（デパケン(登録商標)R、協和発酵キリン株式会社）100mg/日またはクロナゼパム（リボトリール(登録商標)中外製薬株式会社）1mg/日を必要に応じて投与していたが、やはり症状の大幅な改善は認められなかった。
そこで上記処方に加えてミミズ乾燥物80mg/日を就寝前１回投与したところ、数日で治療効果が自覚された。具体的には、過食が止み、抑うつ感および易疲労感が消失した。ミミズ乾燥物投与開始から１週間後には、フルオキセチンを40mg/日に減薬することができた。ミミズ乾燥物を投与する前のMADRS合計スコアは２７点であったが、ミミズ乾燥物投与開始から２週間経過後のMADRS合計スコアは５点にまで下がり、うつ状態の治癒が認められた。同量のミミズ乾燥物の投与を続けて２ヶ月経過後の現在までにうつ状態の悪化は認められず、いかなる副作用も認められなかった。
これらの所見から、本発明の医薬組成物がうつ病に対して副作用を伴うことなく明確な治療効果を発揮したことが示された。
[Example 4]
The diagnosis based on DSM-IV-TR is `` 296.2x major depressive disorder, single episode '' and the diagnosis based on ICD-10 is `` F32.2 Severe depression episode without psychotic symptoms '', 23 This is a case of a female university student. I have been suffering from depression and bulimia since around 18 years old. At another hospital, fluvoxamine maleate (Lubox (registered trademark) Abbott Japan Co., Ltd.) 25 mg / day, trazodone hydrochloride (Degirel (registered trademark) Pfizer Inc.) 25 mg / Day, sodium valproate sustained-release agent (Depaken (registered trademark) R, Kyowa Hakko Kirin Co., Ltd.) was prescribed 100 mg / day, but no significant improvement was observed. Started. As specific symptoms, overeating, depression, and fatigue were recognized. Fluoxetine was increased from 20 mg / day to 60 mg / day as an antidepressant, and sodium valproate sustained-release agent (Depaken (registered trademark) R, Kyowa Hakko Kirin Co., Ltd.) 100 mg / day or clonazepam (ribotriol) as a mood stabilizer (Registered trademark) Chugai Pharmaceutical Co., Ltd.) 1 mg / day was administered as needed, but no significant improvement in symptoms was observed.
Therefore, when 80 mg / day of earthworm dried product was administered once before bedtime in addition to the above prescription, the therapeutic effect was recognized within a few days. Specifically, overeating stopped and the feeling of depression and ease of fatigue disappeared. One week after the start of administration of the dried earthworm, fluoxetine could be reduced to 40 mg / day. The MADRS total score before administration of the earthworm dried product was 27 points, but the MADRS total score after 2 weeks from the start of administration of the earthworm dried product was reduced to 5 points, and depression was cured. No worsening of depression was observed until the present two months after the administration of the same amount of dried earthworm, and 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 depression.
［実施例５］
DSM-IV-TRに基づく診断が「F296.2x 大うつ病性障害、単一エピソード」であり、ICD-10に基づく診断が「F32.1 中等症うつ病エピソード」である、46歳公務員の男性の症例である。５年前にうつ病治療のため他院への入院経験があり、退院後も抗不安薬としてブロマゼパム（レキソタン(登録商標)中外製薬株式会社）2mg〜5mg/日、必要に応じて睡眠薬リルマザホン塩酸塩水和物（リスミー(登録商標)塩野義製薬）および抗精神病薬レボメプロマジン（ヒルナミン(登録商標)塩野義製薬株式会社）を服用していたが、職場環境の変化から症状が悪化して２年１１ヶ月前から本外来で治療を始めた。当初の具体的な症状としては、抑うつ感、焦燥、制止、集中力低下および易疲労感が認められた。抗うつ薬としてフルオキセチン20mg〜40mg/日、ベンラファキシン（エフェクサー(登録商標)）150mg/日、抗不安薬としてブロマゼパム（レキソタン(登録商標)中外製薬株式会社）6mg/日の処方で当初に比べては症状の改善が認められていたが、うつ状態の治癒にまでは至らなかった。
そこで上記処方に加えてミミズ乾燥物80mg/日を就寝前１回投与したところ、２日で治療効果が自覚された。具体的には、抑うつ感、焦燥、制止、集中力低下および易疲労感が消失した。ミミズ乾燥物投与開始から１週間後にはブロマゼパムを断薬することができ、さらにミミズ乾燥物投与開始から約１ヶ月後にはフルオキセチンを断薬することができた。ミミズ乾燥物を投与する前のMADRS合計スコアは２３点であったが、ミミズ乾燥物投与開始から２週間経過後のMADRS合計スコアは６点にまで下がり、うつ状態の治癒が認められた。同量のミミズ乾燥物の投与を続けて２ヶ月経過後の現在までにうつ状態の悪化は認められず、いかなる副作用も認められなかった。
これらの所見から、本発明の医薬組成物がうつ病に対して副作用を伴うことなく明確な治療効果を発揮したことが示された。
[Example 5]
A 46-year-old public employee whose diagnosis based on DSM-IV-TR is `` F296.2x major depressive disorder, single episode '' and whose diagnosis based on ICD-10 is `` F32.1 moderate depression episode '' This is a male case. Have been hospitalized at another hospital for treatment of depression 5 years ago, and bromazepam (Lexotan (registered trademark) Chugai Pharmaceutical Co., Ltd.) 2 mg to 5 mg / day as an anxiolytic drug after discharge, sleeping drug rilmazafone hydrochloride as necessary She was taking salt hydrate (Rismy (registered trademark) Shionogi Pharmaceutical Co., Ltd.) and the antipsychotic drug levomepromazine (Hilnamamine (registered trademark) Shionogi Pharmaceutical Co., Ltd.). I started treatment in this outpatient from a month ago. Depressive feeling, agitation, restraint, reduced concentration and ease of fatigue were observed as specific symptoms at the beginning. Fluoxetine 20mg to 40mg / day as an antidepressant, venlafaxine (Effexer (registered trademark)) 150mg / day, bromazepam (Lexotan (registered trademark) Chugai Pharmaceutical Co., Ltd.) 6mg / day as an anxiolytic agent compared to the original In some cases, improvement of symptoms was observed, but the depression was not cured.
Therefore, when 80 mg / day of earthworm dried product was administered once before bedtime in addition to the above-mentioned prescription, the therapeutic effect was recognized in 2 days. Specifically, feelings of depression, agitation, restraint, reduced concentration and ease of fatigue disappeared. One week after the start of administration of the dried earthworm, bromazepam could be withdrawn. Further, about 1 month after the start of administration of the dried earthworm, fluoxetine could be withdrawn. The MADRS total score before administration of the earthworm dried product was 23 points, but the MADRS total score after 2 weeks from the start of administration of the earthworm dried product decreased to 6 points, and the depression was cured. No worsening of depression was observed until the present two months after the administration of the same amount of dried earthworm, and 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 depression.
［実施例６］
DSM-IV-TRに基づく診断が「F296.2x 大うつ病性障害、単一エピソード」であり、ICD-10に基づく診断が「F32.2 精神病症状をともなわない重症うつ病エピソード」である、29歳無職の男性の症例である。約３年半前から本外来に通院しており、具体的な症状としては、抑うつ感、疲労感、思考力の低下、意欲の欠如が認められた。抗うつ薬としてフルオキセチン40mg/日、気分安定薬としてクロナゼパム（ランドセン(登録商標)大日本住友製薬株式会社）を必要に応じて1.5mg〜3mg/日処方していたが、うつ状態の大幅な改善は認められなかった。
そこで上記処方に加えてミミズ乾燥物160mg/日を朝食前80mg、就寝前80mgの２回に分けて投与したところ、７日程でうつ病の治療効果が自覚された。具体的には、疲労感がとれ、思考力の低下が消失し、意欲が回復し、起業準備を始めるまでになった。ミミズ乾燥物投与開始から１ヶ月後にはフルオキセチンを断薬することができた。ミミズ乾燥物を投与する前のMADRS合計スコアは２７点であったが、ミミズ乾燥物投与開始から１週間経過後のMADRS合計スコアは４点にまで下がり、うつ状態の治癒が認められた。同量のミミズ乾燥物の投与を続けて２ヶ月経過後の現在までにうつ状態の悪化は認められず、いかなる副作用も認められなかった。
これらの所見から、本発明の医薬組成物がうつ病に対して副作用を伴うことなく明確な治療効果を発揮したことが示された。
[Example 6]
The diagnosis based on DSM-IV-TR is `` F296.2x major depressive disorder, single episode '', and the diagnosis based on ICD-10 is `` F32.2 Severe depression episode without psychotic symptoms '', This is a case of a 29-year-old unemployed man. He has been in the clinic for about three and a half years. Specific symptoms include depression, fatigue, reduced thinking and lack of motivation. Fluoxetine 40 mg / day as an antidepressant and clonazepam (Landsen (registered trademark) Dainippon Sumitomo Pharma Co., Ltd.) as a mood stabilizer was prescribed 1.5 mg to 3 mg / day as needed, but drastic improvement in depression Was not recognized.
Therefore, in addition to the above prescription, 160 mg / day of earthworm dried product was administered in two doses of 80 mg before breakfast and 80 mg before going to bed, and the therapeutic effect of depression was noticed in about 7 days. Specifically, I felt tired, lost my ability to think, recovered my motivation, and started preparing for entrepreneurship. One month after the start of administration of the dried earthworm, fluoxetine could be stopped. The MADRS total score before administration of the earthworm dried product was 27 points, but the MADRS total score after one week from the start of administration of the earthworm dried product decreased to 4 points, and the depression was cured. No worsening of depression was observed until the present two months after the administration of the same amount of dried earthworm, and 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 depression.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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