WO2005072721A1 - Medicinal composition for preventing or treating neural disorders accompanying topical lowering in brian blood flow - Google Patents
Medicinal composition for preventing or treating neural disorders accompanying topical lowering in brian blood flow Download PDFInfo
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- WO2005072721A1 WO2005072721A1 PCT/JP2005/000973 JP2005000973W WO2005072721A1 WO 2005072721 A1 WO2005072721 A1 WO 2005072721A1 JP 2005000973 W JP2005000973 W JP 2005000973W WO 2005072721 A1 WO2005072721 A1 WO 2005072721A1
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- blood flow
- cerebral blood
- nervous system
- encephalopathy
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating a nervous system disorder associated with a decrease in local cerebral blood flow.
- the causative diseases are various, but the decrease in local cerebral blood flow is classified into thrombotic, embolic, and hemodynamic. Simultaneously, oxygen deficiency, decrease in substrate supply, and accumulation of metabolites occur. It is considered to be a progressive condition.
- the type of nervous system disorder varies depending on the underlying disease and the degree of decreased blood flow.However, not only serious disorders but also relatively mild disorders impair the Q ⁇ L of patients. Treatment is important. Furthermore, it is important to prevent the occurrence of nervous system disorders beforehand, and it is also characterized as a disorder that requires an immediate effect on the therapeutic effect.
- Relatively mild nervous system disorders include, for example, reduced age-related cognition or memory, reduced cognitive and concentration, lack of mental clarity and clarity, mental vitality and short-term Patients with memory and learning problems are also important treatment targets.
- Hepatic encephalopathy is a neuropsychiatric symptom centered on impaired consciousness caused by severe liver damage such as fulminant hepatitis and cirrhosis. It has been considered that neuropsychiatric symptoms in hepatic encephalopathy are scarce or non-existent before the onset of hepatic encephalopathy and the onset of overt encephalopathy.
- hepatic encephalopathy In recent years, acute and quantitative psychoneurological tests in liver cirrhosis that are not clinically recognized as hepatic encephalopathy, such as overt hepatic encephalopathy, in which the symptoms are clear, have shown The existence of a condition with abnormalities has been clarified, and this is called occult hepatic encephalopathy. Of occult hepatic encephalopathy Although unified diagnostic criteria and psychoneurological testing methods are not used for diagnosis, a comprehensive diagnosis of abnormalities is performed by performing a neuropsychiatric function test (symbol tracking test, etc.) and a neurological test (electroencephalogram, etc.). (See Non-Patent Document 1).
- transition rate of occult hepatic encephalopathy to overt encephalopathy has not been clarified yet, but has been reported to be about 40%, which is expected to be a very high transition rate. Therefore, it is considered that a drug having an effect of reducing the rate of transfer of occult hepatic encephalopathy to overt encephalopathy is highly useful.
- vasodilators and the like have given certain effects, but are carefully administered to the above patients in consideration of side effects. In such cases, considerable care must be taken in selecting drugs, determining their dosage, and determining the duration of administration in accordance with the underlying disease of the patient.
- the drug may be administered prophylactically, but in many cases the drug is discontinued due to side effects.
- neuronal cell death such as a neuroprotective drug is expected.
- Many therapeutic methods have been proposed, including low-molecular-weight compounds that prevent the disease and agents that improve brain cell metabolism.However, neurological disorders caused by localized hypoperfusion in the brain can be treated clinically as soon as possible without side effects. We have not yet found a drug that works.
- branched-chain amino acid (BCAA) preparation containing isoleucine oral isin and palin as an active ingredient for the purpose of improving hypoalbuminemia in patients with cirrhosis, etc.
- React registered trademark manufactured by Ajinomoto Co. Trademark
- nutritional effects such as nitrogen balance, improvement of hypoalbuminemia, and increase of muscle protein have been studied and reported. The following reports are available for effects other than nutritional effects.
- Patent Document 1 discloses that as the life expectancy is extended, cerebral damage caused by ischemia or oxygen deprivation is part of the cause, and typical examples include cerebral ischemic stroke and senile dementia. As an example, L-isoleucine has been described as an agent for treating this.
- Patent Document 1 measures the time from the intraperitoneal administration of L-mouthlet isine to the cessation of respiration of a mouse with an arterial connection. The results show that the intraperitoneal administration of L-bit isine is effective for prolonging the survival time under cerebral ischemia or oxygen deprivation. However, Patent Document 1 does not disclose the effect of L-mouth isine administration on a nervous system disorder associated with a decrease in local cerebral blood flow.
- Patent Document 2 discloses that recovery of intellectual function is observed by allowing a senile dementia patient to take a branched-chain amino acid for 3 months, conducting a simple intellectual function test, and continuing to take a branched-chain amino acid. It is described that the effect of improving the metabolism of brain cells was considered to have been achieved. However, it was described that the effect of intellectual function tests when simply using branched-chain amino acids was effective, suggesting the usefulness of dementia in test patients due to abnormalities in brain cell metabolism. It is useful for patients with nervous system impairment due to decreased blood flow, and is useful for patients other than dementia patients, for example, nervous system impairment due to regional cerebral blood flow decrease based on hepatic encephalopathy due to liver disease. There is no description.
- Patent Document 3 proposes a therapeutic drug for ischemic encephalopathy by using a combination of an amino acid selected from isoleucine, leucine, and arginine with dalcos.
- Experimental data show that arcuate nucleus damage is reduced by single administration. From these results, typical nutrients such as arginine and glucose can suppress or reduce abnormal elevation of glutamic acid in the brain due to cerebral ischemia, and prevent and treat encephalopathy represented by arcuate nucleus disorder It is described.
- no experiment has been conducted to determine whether isoleucine and leucine exert the same effect as arginine, and it is effective in improving neurological symptoms by improving dysfunction of arcuate nuclei in the brain. It is not described whether or not there is, and cerebral ischemia itself, that is, both experimental data and explanations suggesting that it improves nervous system disorders associated with regional cerebral blood flow reduction, is described.
- Non-Patent Document 1 describes that there is a condition diagnosed as occult hepatic encephalopathy as a pre-stage of hepatic overt encephalopathy.
- hepatic encephalopathy (trade name: Morihepamine (registered trademark), Ajinomoto) containing multiple amino acids such as branched-chain amino acids (BCAA) and arginine for patients with cirrhosis.
- BCAA branched-chain amino acids
- arginine arginine
- Patent Document 1 JP-A-11-180823 (8-3 lines from the bottom right of page 148, 2 lines of bottom right from page 151)
- Patent Document 2 JP-A-2-172915 (lower left column of page 96, line 76 from the bottom)
- Patent Literature 3 Patent Registration No. 2814529 (page (3), column 6, line 9-14)
- Non-Patent Document 1 Akinobu Kato, "Kipobi-knee” Vol. 47, No. 1, July 2003, pp. 63-73, 2003
- Non-Patent Document 2 Motoo Iwasa, Liver, Vol. 43, Suppl. (3), November 5, 2002, Published by The Japanese Society of Hepatology, 34th Annual Meeting of the Japanese Society of Hepatology, A271, Liver S6-4 Disclosure of the Invention
- An object of the present invention is to provide a novel pharmaceutical composition containing a branched-chain amino acid for improving a decrease in local cerebral blood flow and treating or preventing a nervous system disorder.
- the present invention comprises isoleucine, leucine and palin as active ingredients, and the mass ratio thereof is 1: 1.9-2.2: 1.1-1.3.
- the present invention relates to a pharmaceutical composition for use in the prevention or treatment of neuropathy associated with a decrease in local cerebral blood flow.
- the dose of the active ingredient in the pharmaceutical composition of the present invention at one time is preferably 1.0 to 50 g.
- the pharmaceutical composition of the present invention is effective for the prophylactic treatment of nervous system disorders of the central nervous system.
- the pharmaceutical composition of the present invention improves cerebral blood flow reduction at one or more of the thalamus, cingulate, or parietal.
- the pharmaceutical composition of the present invention is effective for preventing and treating a nervous system disorder caused by occult hepatic encephalopathy.
- a particularly useful use of the pharmaceutical composition of the present invention is to prevent the transition from occult hepatic encephalopathy to overt encephalopathy. The invention's effect
- local cerebral blood flow decrease can be improved by simple administration such as oral or enteral administration, and nervous system disorders associated with the local cerebral blood flow decrease can be prevented. Or treatment is possible. In particular, it is useful for preventing the transition from occult hepatic encephalopathy to overt encephalopathy.
- FIG. 1 shows the results of examining changes in cerebral blood flow before and after BCAA granule administration using SPM analysis of SPECT images.
- FIG. 2 is a diagram showing the results of examining changes in cerebral blood flow before and after administration of corn starch granules using SPM analysis of SPECT images.
- the present inventors examined the effects of oral administration of a composition containing a branched-chain amino acid as an active ingredient on regional cerebral blood flow by analyzing cerebral blood flow SPECT images. As a result, they found that the composition had an effect of improving regional cerebral blood flow disorders observed by analysis of cerebral blood flow SPECT images, specifically, an effect of increasing cerebral blood flow in the thalamus, cingulate gyrus and parietal. It has been found that this makes it possible to prevent or treat nervous system disorders associated with a decrease in local cerebral blood flow.
- the present inventors have also found that the pharmaceutical composition of the present invention reduces the rate of subclinical hepatic encephalopathy transition to overt hepatic encephalopathy.
- the diencephalon can be distinguished between the layers of the upper thalamus, the thalamus, and the hypothalamus stacked on top of each other.
- the thalamus can be further distinguished into dorsal and ventral thalamus.
- the dorsal thalamus terminates the sensory and sensory tracts (skin perception, taste, sight, hearing, and vestibular tract) and is in communication with the cerebral cortex.
- the ventral thalamus is a continuation of the midbrain tectum, and this area is considered the motor area of the diencephalon. Motor impairment and painful attacks are treated with stereotaxic thalamus surgery.
- the thalamocortical tract which is a specific part of the thalamus, the state changes from an excitement state to a calm state, and at the same time, general indifference and flatness of personality. Is seen.
- language disorders are caused by thalamic pillow disorders.
- impairment of the thalamus affects sensory organs, including movement and vision.
- the cingulate gyrus (peripheral gyrus) surrounds the corpus callosum, is located at the margin of the corpus callosum, is separated from the dentate gyrus by the hippocampal sulcus on the caudal side, and is located on the rostral side with the paraventricular gyrus It ends in Hiroshino.
- the cingulate cortex affects the hypothalamus and the plant nervous system.
- the limbic system, such as the cingulate plays an important role in regulating basic life processes such as food intake, digestion and reproduction.
- the sensory tract ends at the parietal (parietal lobe), which is called the somatosensory cortex, and consists of the first, second, and third areas. In the second area, the positions and movements of the limbs are recorded. When the crown is broken, the disorder of symbolic thinking occurs. In other words, since the ability to understand letters and numbers is lost, it becomes impossible to read, write, count and calculate, and the three-dimensional concept of space is broken.
- the present invention can prevent and treat various nervous system disorders by ameliorating a decrease in local cerebral blood flow in the thalamus, cingulate and parietal.
- the prophylactic or therapeutic agent of the present invention can be suitably used in patients whose nervous system disorder is occult hepatic encephalopathy.
- the pharmaceutical composition for prevention or treatment of the present invention preferably contains isoleucine, leucine, and valine as active ingredients and contains a pharmaceutically acceptable substance for a pharmaceutical preparation.
- any of L-, D- and DL-isomers can be used, but if they exist in nature, the viewpoint is that From L-body preferred.
- the amount of the drug of the present invention (the drug used for the treatment, prevention, etc. of the disease abnormality intended in the present invention) is determined. Since the above calculation range is determined as an active ingredient, the amount to be ingested or administered for another purpose, for example, from the necessity of a normal diet or for the treatment of another disease, is determined. For branched-chain amino acids, it is not necessary to include this in the calculation.
- the pharmaceutical composition of the present invention is administered orally.
- the dose varies depending on the condition, age, and administration method of the patient to be administered, but is usually about 0.1-30.0 g of isoleucine, 30.0 g of leucine O.lg-30.0 g, and 0.1-30.0 g of parin per day. is there.
- a general adult preferably about 0.5 10.0 g of isoleucine, 0.5 10.0 g of leucine, and 0.5 10.0 g of valine per day, more preferably about 1.0-5.0 g of isoleucine 1.0-5.0 g, leucine 2.0-8.0 g, and parin 1.0 per day is there.
- the dose per administration should be 20 g or less per administration. Is more preferably 10 g or less.
- the pharmaceutical composition of the present invention can be prepared by a conventional method. It may also contain various pharmacologically acceptable substances for preparations (as auxiliaries and the like). Pharmaceutical substances can be appropriately selected according to the dosage form of the pharmaceutical preparation.Examples include excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, lubricants, lubricants, and flavoring agents. , Sweeteners, solubilizers and the like.
- substances for preparation include magnesium carbonate, titanium dioxide, ratatose, mannitol and other saccharides, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents.
- sterile water and monohydric or polyhydric alcohols, such as glycerol for example, sterile water and monohydric or polyhydric alcohols, such as glycerol.
- the drug substance contains at least one selected from flavoring agents, flavoring agents, excipients, and coating agents without impairing the gastrointestinal absorption of the active ingredient. ,.
- an easily absorbable preparation is prepared so that the prophylactic or therapeutic agent of the present invention can absorb an effective amount of an effective ingredient for improving local cerebral blood flow reduction within one hour by gastrointestinal tract absorption.
- the preparation can be suitably selected.
- the active ingredient intended in the present invention preferably a mixture of L-isoleucine, L-one-isine and L-valine, is contained at the above-mentioned preferred ratio, and the desired pharmacological activity is obtained. If indicated, they are included in the pharmaceutical composition of the present invention.
- each or all of the individual amino acids used as the active ingredient can be used in the form of a salt.
- the pharmaceutical composition of the present invention may be in the form of various pharmaceutical preparations known or to be developed as described above, for example, as described above, for example, oral administration, intraperitoneal administration, transdermal administration, intravenous administration, inhalation, It can be prepared into various administration forms such as a co-administration.
- oral administration intraperitoneal administration
- transdermal administration intravenous administration
- inhalation It can be prepared into various administration forms such as a co-administration.
- known or future-developed methods can be appropriately adopted.
- compositions include, for example, appropriate solid or liquid preparation forms, for example, granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, milks Suspensions, drops, solutions for injection, preparations that prolong the release of the active substance, and the like can be mentioned.
- appropriate solid or liquid preparation forms for example, granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, milks Suspensions, drops, solutions for injection, preparations that prolong the release of the active substance, and the like can be mentioned.
- the drug of the present invention in the preparation form exemplified above should contain the above-mentioned components in an effective amount for exhibiting a medicinal effect.
- a formulation useful as one form of the pharmaceutical composition of the present invention which contains isoleucine (952 mg), L-leucine (1904 mg), and L-valine (1144 mg) and is an orally administrable granule. It is.
- BCAA granule administration group 10 patients (6 males, 4 females, 8 had no history of overt hepatic encephalopathy 2 cases had repeated encephalopathy
- cornstarch was orally administered in the same amount as the branched-chain amino acid preparation (cornstarch group), and the same analysis as in the BCAA granule administration group was performed.
- Cornstarch group 9 cases (6 men and 3 women, 8 cases have no history of overt hepatic encephalopathy)
- the patient was rested and in a supine position 26 minutes before taking the drug, injected with 1.5 ml of 99mTc-ethyl cysteinate dimer (ECD), and used the Toshiba SPECT device GCA-9300A / DI to prepare the base before administration of both drugs. I took a line SPECT. Subsequently, 60 minutes after the administration of both drugs, 1.5 ml of ECD was again administered, and SPECT was performed.
- ECD 99mTc-ethyl cysteinate dimer
- Branched-chain amino acids act directly on the central nervous system and are useful in patients with occult hepatic encephalopathy. It proved useful.
- Example 1 brand name: Rebact (R) ) Granules, manufactured by Ajinomoto Co. 9.48 g was orally administered for 2 to 42 months.
- the increase in local cerebral blood flow due to the administration of the branched-chain amino acid shown in Example 1 is one of the improvement factors, and it can be evaluated that the onset of overt encephalopathy is prevented.
- local cerebral blood flow decrease can be improved by simple administration such as oral or enteral administration, and nervous system disorders associated with the local cerebral blood flow decrease can be prevented. Or treatment is possible. In particular, it is useful for preventing the transition from occult hepatic encephalopathy to overt encephalopathy.
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Abstract
A medicinal composition for preventing or treating neural disorders accompanying a topical lowering in brain blood flow, in particular, for preventing the progress from potential hepatic encephalopathy into evident potential hepatic encephalopathy, which comprises isoleucine, leucine and valine as the active ingredients and elevates topical brain blood flow.
Description
明 細 書 Specification
局所脳血流低下に伴う神経系障害の予防または治療のための医薬組成 物 Pharmaceutical composition for preventing or treating nervous system disorders associated with reduced local cerebral blood flow
技術分野 Technical field
[0001] 本発明は、局所脳血流低下に伴う神経系障害の予防または治療のための医薬組 成物に関する。 The present invention relates to a pharmaceutical composition for preventing or treating a nervous system disorder associated with a decrease in local cerebral blood flow.
背景技術 Background art
[0002] 近年、高齢化社会の進展とともに、種々の脳血管疾患が増加している。また、劇症 肝炎や肝硬変等の重篤な肝疾患によって生じる意識障害を中心とする神経系障害 も増加している。 [0002] In recent years, various cerebrovascular diseases are increasing with the progress of an aging society. In addition, nervous system disorders, especially consciousness disorders caused by severe liver diseases such as fulminant hepatitis and cirrhosis, are increasing.
[0003] 一般に、原因となる疾患は様々であるが、局所脳血流の低下は、血栓性、塞栓性、 血行動態性に分類され、酸素不足、基質供給の減少、代謝産物の蓄積が同時に進 行する病態と考えられる。原因となる疾患や血流低下の程度により神経系障害の種 類と程度は異なるが、重篤な障害はもとより、比較的軽症であっても、患者の Q〇Lを 損なうため、その予防および治療が重要となる。さらに、神経系障害の発生を未然に 予防することが重要で、治療効果に即効性を要求される障害であることも特徴として とらえられてレ、る。 [0003] In general, the causative diseases are various, but the decrease in local cerebral blood flow is classified into thrombotic, embolic, and hemodynamic. Simultaneously, oxygen deficiency, decrease in substrate supply, and accumulation of metabolites occur. It is considered to be a progressive condition. The type of nervous system disorder varies depending on the underlying disease and the degree of decreased blood flow.However, not only serious disorders but also relatively mild disorders impair the Q〇L of patients. Treatment is important. Furthermore, it is important to prevent the occurrence of nervous system disorders beforehand, and it is also characterized as a disorder that requires an immediate effect on the therapeutic effect.
[0004] 比較的軽症の神経系障害としては、例えば年齢に関する認識または記憶の低下、 認識能力および集中力の低下が挙げられ、精神的明瞭性や鮮明度を欠き、精神的 活力や短期間の記憶、学習に問題のある患者も治療の対象として重要である。 [0004] Relatively mild nervous system disorders include, for example, reduced age-related cognition or memory, reduced cognitive and concentration, lack of mental clarity and clarity, mental vitality and short-term Patients with memory and learning problems are also important treatment targets.
[0005] 神経系障害の一つに例えば肝性脳症がある。肝性脳症は、劇症肝炎や肝硬変な どの重篤な肝障害が原因で生ずる意識障害を中心とする精神神経症状である。肝 性脳症における精神神経症状は、肝性脳症の発症しなレゝ状態ゃ顕性脳症の発現前 には、乏しいか全く見られないと考えられてきた。し力 近年、顕性の肝性脳症のよう に精神神経症状が明らかでなぐ臨床的に肝性脳症とは認められない肝硬変におい て鋭敏で定量的な精神神経機能検査を行うと精神神経機能の異常が指摘される病 態の存在が明らかとなり、これを潜在性肝性脳症と呼んでいる。潜在性肝性脳症の
診断には統一した診断基準や精神神経学検査法はなレ、が、精神神経機能検査 (記 号追跡試験他）および神経学検査 (脳波他)などを施行して異常を総合的に診断す る方法が試みられてレ、る（非特許文献 1参照）。潜在性肝性脳症の顕性脳症への移 行率はまだ明確にされてはないが、約 40%と報告がされており、非常に高い移行率 と予想される。したがって、潜在性肝性脳症の顕性脳症への移行率を下げる効果を 有する医薬の有用性は高いと考えられる。 [0005] One of the nervous system disorders is, for example, hepatic encephalopathy. Hepatic encephalopathy is a neuropsychiatric symptom centered on impaired consciousness caused by severe liver damage such as fulminant hepatitis and cirrhosis. It has been considered that neuropsychiatric symptoms in hepatic encephalopathy are scarce or non-existent before the onset of hepatic encephalopathy and the onset of overt encephalopathy. In recent years, acute and quantitative psychoneurological tests in liver cirrhosis that are not clinically recognized as hepatic encephalopathy, such as overt hepatic encephalopathy, in which the symptoms are clear, have shown The existence of a condition with abnormalities has been clarified, and this is called occult hepatic encephalopathy. Of occult hepatic encephalopathy Although unified diagnostic criteria and psychoneurological testing methods are not used for diagnosis, a comprehensive diagnosis of abnormalities is performed by performing a neuropsychiatric function test (symbol tracking test, etc.) and a neurological test (electroencephalogram, etc.). (See Non-Patent Document 1). The transition rate of occult hepatic encephalopathy to overt encephalopathy has not been clarified yet, but has been reported to be about 40%, which is expected to be a very high transition rate. Therefore, it is considered that a drug having an effect of reducing the rate of transfer of occult hepatic encephalopathy to overt encephalopathy is highly useful.
[0006] 神経系障害の治療薬として、血管拡張剤等は一定の効果を挙げているが、副作用 を考慮して慎重に前述の患者に投与される。その場合、患者の基礎疾患に対応した 薬剤の選択と投与量、投与期間の決定には相当の注意が必要である。また、予防的 に前記薬剤が投与されることもあるが、副作用の発現で投与を中断する症例も多くあ る。 [0006] As therapeutic agents for nervous system disorders, vasodilators and the like have given certain effects, but are carefully administered to the above patients in consideration of side effects. In such cases, considerable care must be taken in selecting drugs, determining their dosage, and determining the duration of administration in accordance with the underlying disease of the patient. The drug may be administered prophylactically, but in many cases the drug is discontinued due to side effects.
[0007] 局所脳血流の低下を改善し、副作用が少なぐすみやかな治療効果の発現または 予防的効果が期待できる薬剤の提供が期待されているなか、神経保護薬等のニュー ロン細胞死を防止する低分子化合物、脳細胞代謝改善剤等多くの薬剤による治療 方法が提案されているが、脳内における局部的な血流低下に伴い発症する神経障 害を副作用なぐまた速やかに臨床的に効果を奏する薬剤を見出すには至っていな レ、。 [0007] In the hope of providing a drug that can improve the local cerebral blood flow and achieve a rapid therapeutic effect with few side effects or a prophylactic effect, neuronal cell death such as a neuroprotective drug is expected. Many therapeutic methods have been proposed, including low-molecular-weight compounds that prevent the disease and agents that improve brain cell metabolism.However, neurological disorders caused by localized hypoperfusion in the brain can be treated clinically as soon as possible without side effects. We have not yet found a drug that works.
[0008] 肝硬変患者の低アルブミン血症の改善の改善等を目的とする、イソロイシン、口イシ ン及びパリンを有効成分とする分岐鎖アミノ酸 (BCAA)製剤として、味の素社製のリ 一バクト (登録商標)等が使用されている。この分枝鎖アミノ酸製剤の肝硬変症に対 する有用性に関しては、窒素平衡や低アルブミン血症の改善、筋蛋白質量の増加な ど、主に栄養学的効果が検討および報告されてきたが、栄養学的効果以外の効果 については、以下のような報告がある。 [0008] As a branched-chain amino acid (BCAA) preparation containing isoleucine, oral isin and palin as an active ingredient for the purpose of improving hypoalbuminemia in patients with cirrhosis, etc., React (registered trademark) manufactured by Ajinomoto Co. Trademark) etc. are used. With regard to the usefulness of this branched-chain amino acid preparation for cirrhosis, nutritional effects such as nitrogen balance, improvement of hypoalbuminemia, and increase of muscle protein have been studied and reported. The following reports are available for effects other than nutritional effects.
[0009] 特許文献 1には、平均寿命の延長に伴って、虚血または酸素欠乏を要因の一部と する脳障害が増加し、その代表的な例は脳虚血性発作および老人性痴呆であるとし て、これを処置する薬剤として L一イソロイシンが記載されてレ、る。 [0009] Patent Document 1 discloses that as the life expectancy is extended, cerebral damage caused by ischemia or oxygen deprivation is part of the cause, and typical examples include cerebral ischemic stroke and senile dementia. As an example, L-isoleucine has been described as an agent for treating this.
[0010] 特許文献 1には、 L一口イシンを腹腔内投与した後、動脈結さっしたマウスの呼吸停 止までの時間が測定されており、 L一口イシン投与によりマウスの呼吸停止までの時間
が延長するとの実験結果を示し、この結果力 L一口イシンの腹腔内投与が脳虚血又 は酸素欠乏下の生存時間延長に有効であるとしている。しかし、特許文献 1には、局 所脳血流低下に伴う神経系障害に対する L一口イシン投与の効果についてはなんら 記載されていない。 [0010] Patent Document 1 measures the time from the intraperitoneal administration of L-mouthlet isine to the cessation of respiration of a mouse with an arterial connection. The results show that the intraperitoneal administration of L-bit isine is effective for prolonging the survival time under cerebral ischemia or oxygen deprivation. However, Patent Document 1 does not disclose the effect of L-mouth isine administration on a nervous system disorder associated with a decrease in local cerebral blood flow.
[0011] 特許文献 2には、分岐鎖アミノ酸を老人性痴呆患者に 3ヶ月間摂取させ、簡易知的 機能検査を実施し、分岐鎖アミノ酸の摂取を続けることにより、知的機能の回復がみ られ、脳細胞の代謝改善効果があつたと考えられるとの記載がある。しかし、単に分 岐鎖アミノ酸を投与した場合の知的機能検査に効果があったことが記載され、被験 患者の痴呆が脳細胞代謝異常による場合の有用性を示唆しているものの、局所脳 血流低下に伴う神経系障害を伴う患者に有用であることや、痴呆患者以外の例えば 肝臓疾患による肝性脳症を基礎疾患とする局所脳血流低下に伴う神経系障害に有 用であるとの記載はない。 [0011] Patent Document 2 discloses that recovery of intellectual function is observed by allowing a senile dementia patient to take a branched-chain amino acid for 3 months, conducting a simple intellectual function test, and continuing to take a branched-chain amino acid. It is described that the effect of improving the metabolism of brain cells was considered to have been achieved. However, it was described that the effect of intellectual function tests when simply using branched-chain amino acids was effective, suggesting the usefulness of dementia in test patients due to abnormalities in brain cell metabolism. It is useful for patients with nervous system impairment due to decreased blood flow, and is useful for patients other than dementia patients, for example, nervous system impairment due to regional cerebral blood flow decrease based on hepatic encephalopathy due to liver disease. There is no description.
[0012] 特許文献 3では、イソロイシン、ロイシン、アルギニンから選ばれるアミノ酸とダルコ一 スを併用することによる虚血性脳障害治療薬が提案されており、マウスにアルギニン とグノレコースを併用した経口投与およびそれぞれ単独投与により、弓状核障害が減 少する実験データが記載されている。この結果より、アルギニンやグルコースなどの 代表的栄養素が脳虚血による脳内グルタミン酸の異常上昇を抑制あるいは低下させ 、弓状核障害で代表される脳障害を予防し、これを治療することができると記載され ている。し力し、特許文献 3においては、イソロイシンとロイシンについて、アルギニン と同様な効果を奏するかはなんらの実験もなされておらず、脳内局所の例えば弓状 核障害改善による神経症状の改善に効果があるかは記載されていないし、脳虚血そ のもの、すなわち局所脳血流低下に伴う神経系障害を改善することを示唆する実験 データも説明も記載されてレ、なレ、。 [0012] Patent Document 3 proposes a therapeutic drug for ischemic encephalopathy by using a combination of an amino acid selected from isoleucine, leucine, and arginine with dalcos. Experimental data show that arcuate nucleus damage is reduced by single administration. From these results, typical nutrients such as arginine and glucose can suppress or reduce abnormal elevation of glutamic acid in the brain due to cerebral ischemia, and prevent and treat encephalopathy represented by arcuate nucleus disorder It is described. In Patent Document 3, no experiment has been conducted to determine whether isoleucine and leucine exert the same effect as arginine, and it is effective in improving neurological symptoms by improving dysfunction of arcuate nuclei in the brain. It is not described whether or not there is, and cerebral ischemia itself, that is, both experimental data and explanations suggesting that it improves nervous system disorders associated with regional cerebral blood flow reduction, is described.
[0013] 非特許文献 1には、肝性の顕性脳症の前段階として潜在性肝性脳症と診断される 症状があることが記載されてレ、る。 [0013] Non-Patent Document 1 describes that there is a condition diagnosed as occult hepatic encephalopathy as a pre-stage of hepatic overt encephalopathy.
[0014] さらに本発明者らは、肝硬変患者に対して分岐鎖アミノ酸 (BCAA)およびアルギニ ン等複数のアミノ酸を含有する肝性脳症治療用輸液剤（商品名 モリへパミン (登録 商標）、味の素社製)を経静脈的に投与し、投与前後で脳血流 SPECT (Single
photon emission computed tomography)画像の角军析を行レ、、月 血流は増カ卩し局所 脳血流障害が改善する事を既に報告している（非特許文献 2参照）。 Further, the present inventors have proposed an infusion for treating hepatic encephalopathy (trade name: Morihepamine (registered trademark), Ajinomoto) containing multiple amino acids such as branched-chain amino acids (BCAA) and arginine for patients with cirrhosis. Was administered intravenously and cerebral blood flow SPECT ( S ingle Photon emission computed tomography) has been performed, and it has already been reported that lunar blood flow is increased and local cerebral blood flow disorder is improved (see Non-Patent Document 2).
[0015] しかし、前記輸液剤による脳血流改善効果は、輸液投与に伴う循環動態の変化、 輸液に含まれるアルギニンによる血管拡張作用などの影響を受けている可能性を否 定できていないため、分岐鎖アミノ酸に局所脳血流障害の改善効果があるか否か、 また経口投与により短時間に効果を奏するか否かは全く明らかにされていなかった。 特許文献 1 :特開平 1一 180823号公報（148頁右上欄下から 8— 3行、 151頁右上欄 下 2行） [0015] However, since the cerebral blood flow improving effect of the infusion solution cannot be determined to be possibly affected by changes in circulatory dynamics due to infusion administration, vasodilation by arginine contained in the infusion solution, and the like. It has not been clarified at all whether or not branched-chain amino acids have an effect of improving local cerebral blood flow disorder and whether or not oral administration exerts an effect in a short time. Patent Document 1: JP-A-11-180823 (8-3 lines from the bottom right of page 148, 2 lines of bottom right from page 151)
特許文献 2 :特開平 2 - 172915号公報（96頁左下欄、下から 7 6行） Patent Document 2: JP-A-2-172915 (lower left column of page 96, line 76 from the bottom)
特許文献 3：特許登録 2814529号公報 ( (3)頁第 6欄下から 9一 4行） Patent Literature 3: Patent Registration No. 2814529 (page (3), column 6, line 9-14)
非特許文献 1 :加藤章信著、「肝胆膝」 47卷 1号、 2003年 7月、 63— 73頁、 2003年 Non-Patent Document 1: Akinobu Kato, "Kipobi-knee" Vol. 47, No. 1, July 2003, pp. 63-73, 2003
7月 28日発行（63頁 1はじめに、 67— 71頁 3潜在性肝性脳症の概念） Published on July 28 (page 63 1 introduction, 67-71 3 concept of occult hepatic encephalopathy)
非特許文献 2 :岩佐元雄著、「肝臓」第 43卷 Suppl. (3)、平成 14年 11月 5日、 日 本肝臓学会発行、第 34回 日本肝臓学会東部会講演要旨、 A271頁、肝 S6 - 4 発明の開示 Non-Patent Document 2: Motoo Iwasa, Liver, Vol. 43, Suppl. (3), November 5, 2002, Published by The Japanese Society of Hepatology, 34th Annual Meeting of the Japanese Society of Hepatology, A271, Liver S6-4 Disclosure of the Invention
発明が解決しょうとする課題 Problems to be solved by the invention
[0016] 本発明は、局所脳血流の低下を改善し神経系障害を治療または予防するための 分岐鎖アミノ酸を含む新規な医薬組成物を提供する事を目的とする。 [0016] An object of the present invention is to provide a novel pharmaceutical composition containing a branched-chain amino acid for improving a decrease in local cerebral blood flow and treating or preventing a nervous system disorder.
課題を解決するための手段 Means for solving the problem
[0017] 本発明は、イソロイシン、ロイシン及びパリンを有効成分とし、それらの質量比が 1： 1 . 9-2. 2 : 1. 1 - 1. 3であり、経口'経腸で投与することを特徴とする、局所脳血流 低下に伴う神経障害の予防または治療に使用するための医薬組成物に関する。 [0017] The present invention comprises isoleucine, leucine and palin as active ingredients, and the mass ratio thereof is 1: 1.9-2.2: 1.1-1.3. The present invention relates to a pharmaceutical composition for use in the prevention or treatment of neuropathy associated with a decrease in local cerebral blood flow.
[0018] 本発明の医薬組成物における 1回の有効成分の投与量は、 1.0— 50gであることが 好ましい。本発明の医薬組成物は、中枢神経系の神経系障害の予防治療に有効で ある。本発明の医薬組成物は、視床、帯状回、頭頂のいずれか 1箇所若しくは 2箇所 以上の脳血流低下を改善するものである。本発明の医薬組成物は、潜在性肝性脳 症に起因する神経系障害の予防治療に有効である。本発明の医薬組成物における 特に有用な用途は、潜在性肝性脳症から顕性脳症への移行予防である。
発明の効果 [0018] The dose of the active ingredient in the pharmaceutical composition of the present invention at one time is preferably 1.0 to 50 g. The pharmaceutical composition of the present invention is effective for the prophylactic treatment of nervous system disorders of the central nervous system. The pharmaceutical composition of the present invention improves cerebral blood flow reduction at one or more of the thalamus, cingulate, or parietal. The pharmaceutical composition of the present invention is effective for preventing and treating a nervous system disorder caused by occult hepatic encephalopathy. A particularly useful use of the pharmaceutical composition of the present invention is to prevent the transition from occult hepatic encephalopathy to overt encephalopathy. The invention's effect
[0019] 本発明の医薬組成物によれば、経口または経腸投与という簡便な投与によって局 所脳血流低下を改善することができ、該局所脳血流低下に伴う神経系障害の予防ま たは治療が可能となる。とくに、潜在肝性脳症から顕性脳症への移行予防に有用で ある。 [0019] According to the pharmaceutical composition of the present invention, local cerebral blood flow decrease can be improved by simple administration such as oral or enteral administration, and nervous system disorders associated with the local cerebral blood flow decrease can be prevented. Or treatment is possible. In particular, it is useful for preventing the transition from occult hepatic encephalopathy to overt encephalopathy.
図面の簡単な説明 Brief Description of Drawings
[0020] [図 1]図 1は BCAA顆粒投与前後の脳血流の変化を SPECT画像の SPM解析を用 いて調べた結果を示す図である。 FIG. 1 shows the results of examining changes in cerebral blood flow before and after BCAA granule administration using SPM analysis of SPECT images.
[図 2]図 2はコーンスターチ顆粒投与前後の脳血流の変化を SPECT画像の SPM解 析を用いて調べた結果を示す図である。 [Fig. 2] Fig. 2 is a diagram showing the results of examining changes in cerebral blood flow before and after administration of corn starch granules using SPM analysis of SPECT images.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
[0021] 以下、本発明を具体的に説明する。 Hereinafter, the present invention will be described specifically.
本発明者らは、分岐鎖アミノ酸を有効成分として含有する組成物を経口投与した場 合について、脳血流 SPECT画像の解析による局所脳血流に対する影響を検討した 。その結果、前記組成物が、脳血流 SPECT画像の解析により観察される局所脳血 流障害を改善する効果、具体的には視床、帯状回および頭頂の脳血流増加効果を 有することを見出し、それによつて局所脳血流低下に伴う神経系障害の予防または 治療が可能であることを見出した。 The present inventors examined the effects of oral administration of a composition containing a branched-chain amino acid as an active ingredient on regional cerebral blood flow by analyzing cerebral blood flow SPECT images. As a result, they found that the composition had an effect of improving regional cerebral blood flow disorders observed by analysis of cerebral blood flow SPECT images, specifically, an effect of increasing cerebral blood flow in the thalamus, cingulate gyrus and parietal. It has been found that this makes it possible to prevent or treat nervous system disorders associated with a decrease in local cerebral blood flow.
[0022] また、本発明者らは、本発明の医薬組成物が潜在性肝性脳症の顕性肝性脳症へ の移行率を下げることも見出した。 [0022] The present inventors have also found that the pharmaceutical composition of the present invention reduces the rate of subclinical hepatic encephalopathy transition to overt hepatic encephalopathy.
[0023] ここで、脳の構成について説明する。 Here, the configuration of the brain will be described.
間脳は互いに積み重なった、視床上部、視床、視床下部の層に区別することがで きる。視床はさらに背側視床と腹側視床に区別することができる。 The diencephalon can be distinguished between the layers of the upper thalamus, the thalamus, and the hypothalamus stacked on top of each other. The thalamus can be further distinguished into dorsal and ventral thalamus.
[0024] 背側視床は、感覚路および知覚路 (皮膚知覚、味覚、視覚、聴覚及び前庭覚路） の終わるところであり、大脳皮質と連絡している。腹側視床は中脳被蓋の続きであり、 この領域は間脳の運動性領域とみなされている。運動障害や痛みの発作は、視床の 定位手術によって治療される。また視床の特定部位である視床皮質路を切断するこ とにより興奮状態から沈静状態になること、同時に総体的な無関心と人格の平坦ィ匕
がみられる。さらに視床枕の障害によって言語障害がおこる。このように、視床の障害 は運動や視覚を初めとする感覚器官に影響する。 [0024] The dorsal thalamus terminates the sensory and sensory tracts (skin perception, taste, sight, hearing, and vestibular tract) and is in communication with the cerebral cortex. The ventral thalamus is a continuation of the midbrain tectum, and this area is considered the motor area of the diencephalon. Motor impairment and painful attacks are treated with stereotaxic thalamus surgery. In addition, by cutting the thalamocortical tract, which is a specific part of the thalamus, the state changes from an excitement state to a calm state, and at the same time, general indifference and flatness of personality. Is seen. In addition, language disorders are caused by thalamic pillow disorders. Thus, impairment of the thalamus affects sensory organs, including movement and vision.
[0025] 帯状回 (辺縁回）は脳梁を取り巻いており、脳梁辺縁に位置し尾側では海馬溝によ つて歯状回から分けられており、吻側では終板傍回と梁下野に終わっている。帯状 回の皮質は視床下部と植物神経系に影響を及ぼしている。帯状回等の辺縁系は食 物の摂取、消化および生殖といった基本的な生命過程の調節に大切な役割を演じ ている。 [0025] The cingulate gyrus (peripheral gyrus) surrounds the corpus callosum, is located at the margin of the corpus callosum, is separated from the dentate gyrus by the hippocampal sulcus on the caudal side, and is located on the rostral side with the paraventricular gyrus It ends in Hiroshino. The cingulate cortex affects the hypothalamus and the plant nervous system. The limbic system, such as the cingulate, plays an important role in regulating basic life processes such as food intake, digestion and reproduction.
[0026] 頭頂 (頭頂葉）には知覚路が終わっており、ここを体性知覚性皮質といい、第 1野、 第 2野及び第 3野からなっている。第 2野では体肢の位置と運動を記録している。頭 頂がおかされた場合には象徴思考の障害が起こってくる。すなわち文字や数字の理 解力がなくなるために、読み書きや数を数え計算することが不能となり、三次元的な 空間概念がおかされる。 [0026] The sensory tract ends at the parietal (parietal lobe), which is called the somatosensory cortex, and consists of the first, second, and third areas. In the second area, the positions and movements of the limbs are recorded. When the crown is broken, the disorder of symbolic thinking occurs. In other words, since the ability to understand letters and numbers is lost, it becomes impossible to read, write, count and calculate, and the three-dimensional concept of space is broken.
[0027] したがって、本願発明は視床、帯状回そして頭頂の局所脳血流低下を改善するこ とにより、各種の神経系障害を予防、治療することができる。 [0027] Therefore, the present invention can prevent and treat various nervous system disorders by ameliorating a decrease in local cerebral blood flow in the thalamus, cingulate and parietal.
[0028] また、神経系障害が潜在性肝性脳症である患者において好適に本発明の予防ま たは治療剤を用いることができる。 [0028] Further, the prophylactic or therapeutic agent of the present invention can be suitably used in patients whose nervous system disorder is occult hepatic encephalopathy.
[0029] 本発明の予防または治療のための医薬組成物は、イソロイシン、ロイシン、及びバリ ンを有効成分とし、医薬上で許容される製剤用物質を含有させることが好ましレ、。 [0029] The pharmaceutical composition for prevention or treatment of the present invention preferably contains isoleucine, leucine, and valine as active ingredients and contains a pharmaceutically acceptable substance for a pharmaceutical preparation.
[0030] 本発明において有効成分として使用するロイシン、イソロイシン及びパリンの異性体 に関しては、 L一体、 D—体、及び DL—体何れも使用可能であるが、天然に存在する とレ、う観点から L-体が好ましレ、。 [0030] Regarding the isomers of leucine, isoleucine and palin used as the active ingredient in the present invention, any of L-, D- and DL-isomers can be used, but if they exist in nature, the viewpoint is that From L-body preferred.
[0031] イソロイシン、ロイシン及びパリンの配合割合（重量比）におレ、て、イソロイシン Zロイ シン/バリン = 1/1.9一 2.2/1.1 1.3となるような組成範囲で使用することがより 好ましい。 [0031] It is more preferable to use isoleucine, leucine and palin in a composition range such that isoleucine Z-leucine / valine = 1 / 1.9-1 2.2 / 1.1 1.3 in the mixing ratio (weight ratio).
[0032] 上記本発明で使用する有効成分の投与量 (摂取量）について算定する際、本発明 の薬剤 (本発明で目的とする疾患異常の治療、予防等の目的で使用される薬剤）の 有効成分として前記の算定範囲が決められているので、これとは別目的で、例えば 通常の食生活の必要から、或いは別の疾患の治療目的で、摂取又は投与される分
岐鎖アミノ酸につレ、てはこれを前記算定に含める必要はなレ、。 [0032] When calculating the dose (uptake) of the active ingredient used in the present invention, the amount of the drug of the present invention (the drug used for the treatment, prevention, etc. of the disease abnormality intended in the present invention) is determined. Since the above calculation range is determined as an active ingredient, the amount to be ingested or administered for another purpose, for example, from the necessity of a normal diet or for the treatment of another disease, is determined. For branched-chain amino acids, it is not necessary to include this in the calculation.
[0033] 例えば、通常の食生活から摂取される 1日当たりのイソロイシン、ロイシン及びパリン の量を前記本発明における有効成分の 1日当たりの投与量力 控除して算定する必 要はない。 For example, it is not necessary to calculate the daily amount of isoleucine, leucine and palin ingested from a normal diet by subtracting the daily power of the active ingredient in the present invention.
[0034] 本発明の医薬組成物は、経口投与される。この場合、投与量は投与する患者の症 状、年齢、投与方法によって異なるが、通常、一日当たりとして、イソロイシン 0.1— 3 0.0g、ロイシン O. lg— 30.0g、及びパリン 0.1— 30.0g程度である。一般成人の場合 、好ましくは一日当たりとして、イソロイシン 0.5 10.0g、ロイシン 0.5 10.0g、及び バリン 0.5 10.0g程度、より好ましくはイソロイシン 1.0— 5.0g、ロイシン 2.0— 8.0g、 及びパリン 1.0 5.0g程度である。また 1投与当たりの投与量としては、上記 1日当た りの投与量を 1度に投与しても、数回に分けて投与しても良ぐ経口投与の場合は、 1 投与当たり 20g以下であることが好ましぐさらに好ましくは 10g以下である。 [0034] The pharmaceutical composition of the present invention is administered orally. In this case, the dose varies depending on the condition, age, and administration method of the patient to be administered, but is usually about 0.1-30.0 g of isoleucine, 30.0 g of leucine O.lg-30.0 g, and 0.1-30.0 g of parin per day. is there. In the case of a general adult, preferably about 0.5 10.0 g of isoleucine, 0.5 10.0 g of leucine, and 0.5 10.0 g of valine per day, more preferably about 1.0-5.0 g of isoleucine 1.0-5.0 g, leucine 2.0-8.0 g, and parin 1.0 per day is there. In the case of oral administration, in which the above daily dose can be administered once or in several divided doses, the dose per administration should be 20 g or less per administration. Is more preferably 10 g or less.
[0035] 本発明の医薬組成物は、常法により調製することができる。薬理学的に許容し得る 各種の製剤用物質 (補助剤等として)を含むこともできる。製剤用物質は製剤の剤形 により適宜選択することができるが、例えば、賦形剤、希釈剤、添加剤、崩壊剤、結合 剤、被覆剤、潤滑剤、滑走剤、滑沢剤、風味剤、甘味剤、可溶化剤等を挙げることが できる。更に、製剤用物質を具体的に例示すると、炭酸マグネシウム、二酸化チタン 、ラタトース、マンニトール及びその他の糖類、タルク、牛乳蛋白、ゼラチン、澱粉、セ ルロース及びその誘導体、動物及び植物油、ポリエチレングリコール、及び溶剤、例 えば滅菌水及び一価又は多価アルコール、例えばグリセロールを挙げることができる [0035] The pharmaceutical composition of the present invention can be prepared by a conventional method. It may also contain various pharmacologically acceptable substances for preparations (as auxiliaries and the like). Pharmaceutical substances can be appropriately selected according to the dosage form of the pharmaceutical preparation.Examples include excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, lubricants, lubricants, and flavoring agents. , Sweeteners, solubilizers and the like. Furthermore, specific examples of substances for preparation include magnesium carbonate, titanium dioxide, ratatose, mannitol and other saccharides, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents. For example, sterile water and monohydric or polyhydric alcohols, such as glycerol.
[0036] 製剤用物質としては有効成分の消化管吸収を損なうことのなレ、、矯味剤、矯臭剤、 賦形剤、又はコーティング剤から選ばれた少なくとも 1種類を含有させることが好まし レ、。 [0036] It is preferable that the drug substance contains at least one selected from flavoring agents, flavoring agents, excipients, and coating agents without impairing the gastrointestinal absorption of the active ingredient. ,.
[0037] さらに、本発明の予防または治療剤により 1時間以内に局所脳血流低下を改善さ せるための有効量の有効成分を消化管吸収させることができるよう、易吸収性の製剤 に調製するための製剤用物質が好適に選ばれ得る。 [0037] Furthermore, an easily absorbable preparation is prepared so that the prophylactic or therapeutic agent of the present invention can absorb an effective amount of an effective ingredient for improving local cerebral blood flow reduction within one hour by gastrointestinal tract absorption. For the preparation can be suitably selected.
[0038] 本発明においては、他の薬理成分（医薬活性物質）と共に、例えば混合又は組み
合わせて使用することができ、このような場合本発明で目的とする有効成分、好ましく は L イソロイシン、 L一口イシン及び L バリンの混合物を、特に前記好ましい比率で 含有し目的とする前記薬理活性を示すものであれば本発明の医薬組成物に含まれ る。尚、本発明においてその有効成分に使用する個々のアミノ酸は、その一部又は 全部についてそれぞれ塩の形態で使用することもできる。 [0038] In the present invention, for example, mixed or combined with other pharmacological components (pharmaceutically active substances) In such a case, the active ingredient intended in the present invention, preferably a mixture of L-isoleucine, L-one-isine and L-valine, is contained at the above-mentioned preferred ratio, and the desired pharmacological activity is obtained. If indicated, they are included in the pharmaceutical composition of the present invention. In the present invention, each or all of the individual amino acids used as the active ingredient can be used in the form of a salt.
[0039] 本発明の医薬組成物は、前述の如く公知の又は将来開発される様々な医薬製剤 の形態、前述の如く例えば、経口投与、腹腔内投与、経皮的投与、経静脈投与、吸 入投与等各種の投与形態に調製することができる。本発明の薬剤をこれ等様々な医 薬製剤の形態に調製するためには公知の又は将来開発される方法を適宜採用する こと力 Sできる。 [0039] The pharmaceutical composition of the present invention may be in the form of various pharmaceutical preparations known or to be developed as described above, for example, as described above, for example, oral administration, intraperitoneal administration, transdermal administration, intravenous administration, inhalation, It can be prepared into various administration forms such as a co-administration. In order to prepare the drug of the present invention in the form of these various pharmaceutical preparations, known or future-developed methods can be appropriately adopted.
[0040] これら様々な医薬製剤の形態として、例えば適当な固形又は液状の製剤形態、例 えば顆粒、粉剤、被覆錠剤、錠剤、（マイクロ）カプセル、坐剤、シロップ、ジュース、 懸濁液、乳濁液、滴下剤、注射用溶液、活性物質の放出を延長する製剤等を挙げる こと力 Sできる。 [0040] These various forms of pharmaceutical preparations include, for example, appropriate solid or liquid preparation forms, for example, granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, milks Suspensions, drops, solutions for injection, preparations that prolong the release of the active substance, and the like can be mentioned.
[0041] 以上に例示した製剤形態にある本発明の薬剤には、薬効を奏するに有効な量の前 記成分を含有すべきことは当然のことである。 [0041] It goes without saying that the drug of the present invention in the preparation form exemplified above should contain the above-mentioned components in an effective amount for exhibiting a medicinal effect.
[0042] 分岐鎖アミノ酸製剤として「リーバタト (R)顆粒」が市販されているが、該製剤には L[0042] As a branched-chain amino acid preparation, "Ribatato (R) granule" is commercially available.
—イソロイシン（952mg)、 L—ロイシン（1904mg)、 L—バリン（1144mg)が含有されて おり、経口投与可能な顆粒剤であることから、本発明の医薬組成物の一形態として有 用な製剤である。 A formulation useful as one form of the pharmaceutical composition of the present invention, which contains isoleucine (952 mg), L-leucine (1904 mg), and L-valine (1144 mg) and is an orally administrable granule. It is.
[0043] 実施例を挙げて本発明をより具体的に説明するが、本発明は以下の実施例によつ て限定されるものではない。 [0043] The present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples.
実施例 1 Example 1
[0044] 臨床試験例 1 (局所脳血流改善効果） [0044] Clinical test example 1 (Effect of improving local cerebral blood flow)
本発明の分岐鎖アミノ酸製剤の局所脳血流に対する効果について試験を行った。 (投与対象および投与） The effect of the branched-chain amino acid preparation of the present invention on local cerebral blood flow was tested. (Subjects and administration)
肝硬変と診断された患者 35名中 10名に対して、表 1に示した有効成分を含有する 分岐鎖アミノ酸製剤（商品名：リーバタト (R)顆粒、味の素社製） 2包（9.48g)を経口投
与し (BCAA顆粒投与群）、投与前後の脳血流 SPECT画像の解析を施行した。 Against 35 people out of 10 patients diagnosed with cirrhosis, branched chain amino acid preparation containing the active ingredients shown in Table 1 (trade name: Ribatato (R) granules, Ajinomoto Co., Ltd.) 2 wrapped a (9.48 g) Oral throw (BCAA granule administration group), and cerebral blood flow SPECT images before and after administration were analyzed.
BCAA顆粒投与群： 10例（男性 6例、女性 4例で、 8例は顕性肝性脳症の既往がな ぐ 2例は脳症を反復していた力 検査時、顕性脳症を有する症例はなかった。 対照として、コーンスターチを分岐鎖アミノ酸製剤と同量経口投与し (コーンスター チ群）、 BCAA顆粒投与群と同様の解析を施行した。 ) BCAA granule administration group: 10 patients (6 males, 4 females, 8 had no history of overt hepatic encephalopathy 2 cases had repeated encephalopathy As a control, cornstarch was orally administered in the same amount as the branched-chain amino acid preparation (cornstarch group), and the same analysis as in the BCAA granule administration group was performed.)
コーンスターチ群： 9例（男性 6例、女性 3例で、 8例は顕性肝性脳症の既往がなぐ Cornstarch group: 9 cases (6 men and 3 women, 8 cases have no history of overt hepatic encephalopathy)
1例は脳症を反復していたが、検查時、顕性脳症を有する症例はなかった。 ) One case had repeated encephalopathy, but at the time of examination, no case had overt encephalopathy. )
[表 1] リーバクト (R)顆粒 1包 （4.7 4 g) 中に含まれる有効成分
[Table 1] Active ingredients contained in one rebact (R) granule (4.7 4 g)
[0046] (脳血流 SPECT画像の解析） (Analysis of cerebral blood flow SPECT image)
各群共、服用 26分前に患者を安静、仰臥位とし、 1.5mlの 99mTc-ethyl cysteinate dimer (ECD)を注入、東芝製 SPECT装置 GCA—9300A/DIを用 レ、て両剤投与前のベースライン SPECTを撮影した。続いて、両剤投与後 60分後に 再度 ECD 1.5mlを投与、 SPECTを施行した。 In each group, the patient was rested and in a supine position 26 minutes before taking the drug, injected with 1.5 ml of 99mTc-ethyl cysteinate dimer (ECD), and used the Toshiba SPECT device GCA-9300A / DI to prepare the base before administration of both drugs. I took a line SPECT. Subsequently, 60 minutes after the administration of both drugs, 1.5 ml of ECD was again administered, and SPECT was performed.
Statistical Parametric Mapping (SPM)ソフトウェア（SPM97)を用い、 SPE SPE using Statistical Parametric Mapping (SPM) software (SPM97)
CT画像の統計解析を行った。さらに、前頭葉、頭頂葉、側頭葉、後頭葉、小脳に関 心領域を設定、両剤投与前後の脳血流変化を調べた。結果を図 1および図 2に示す Statistical analysis of CT images was performed. Furthermore, frontal lobes, parietal lobes, temporal lobes, occipital lobes, and cerebellum-related areas were set, and changes in cerebral blood flow before and after administration of both drugs were examined. The results are shown in Figures 1 and 2.
[0047] 試験の結果、コーンスターチ群では投与前後で脳血流量は変化しなかったが（図 2 )、 BCAA投与群では、投与後 1時間で、帯状回、頭頂、および視床の 3部位に脳血 流の増加が認められた（図 1 )。 [0047] As a result of the test, cerebral blood flow did not change before and after administration in the cornstarch group (Fig. 2), but in the BCAA administration group, one hour after administration, cerebral gyrus, parietal, and thalamus were found in three sites. Increased blood flow was observed (Figure 1).
分岐鎖アミノ酸投与により、帯状回、頭頂、および視床の脳血流は増加し、局所血 流障害が軽快したことから、分岐鎖アミノ酸は直接中枢神経系に作用し、潜在性肝 性脳症患者に有用であることが判った。
実施例 2 Administration of branched-chain amino acids increased cerebral blood flow in the cingulate, parietal, and thalamus, and alleviated local blood flow disorder.Branched-chain amino acids act directly on the central nervous system and are useful in patients with occult hepatic encephalopathy. It proved useful. Example 2
[0048] 臨床試験例 2 (潜在性肝性脳症患者の顕性脳症予防効果） [0048] Clinical Test Example 2 (Effect of overt encephalopathy in patients with occult hepatic encephalopathy)
本発明分岐鎖アミノ酸製剤の、潜在性脳症の顕性化への移行率に対する効果を 調べた。 The effect of the branched-chain amino acid preparation of the present invention on the rate of subclinical encephalopathy transition to manifestation was examined.
肝硬変と診断された患者 35名中、神経機能検査から潜在性脳症と判定された患 者 10名に対して、実施例 1で用いたものと同じ分岐鎖アミノ酸製剤（商品名：リーバク ト (R)顆粒、味の素社製） 9.48gを 2— 42ヶ月間経口投与した。 Of the 35 patients diagnosed with liver cirrhosis, the same branched-chain amino acid preparation as used in Example 1 (brand name: Rebact (R) ) Granules, manufactured by Ajinomoto Co.) 9.48 g was orally administered for 2 to 42 months.
患者 10名中 2名に肝性脳症の顕性化が見られた (移行率 20%)。 Hepatic encephalopathy was evident in 2 out of 10 patients (transition rate 20%).
[0049] 潜在性肝性脳症患者の顕性脳症への移行に関して次の報告がある。 Manuel [0049] The following reports have been made regarding the transition of patients with latent hepatic encephalopathy to overt encephalopathy. Manuel
Romero— Gomez, M. D. et al., Subclinical Hepatic Encephalopathy Predicts the Development of Overt Hepatic Encephalopathy, THE AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol.96, No.9, 2001 , pp.2718- 2723によれば、 34名 の潜在性脳症の患者のうち、 16名（47%)が顕性脳症に移行したとされている。また 、 Ieneke j . C. riartmann, M. D. et al., The Prognostic igmficance of Romero— According to Gomez, MD et al., Subclinical Hepatic Encephalopathy Predicts the Development of Overt Hepatic Encephalopathy, THE AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol.96, No.9, 2001, pp.2718-2723, a potential of 34 people Of the patients with encephalopathy, 16 (47%) reportedly had overt encephalopathy. Also, Ieneke j. C. riartmann, MD. Et al., The Prognostic igmficance of
Subclinical Hepatic Encephalopathy, THE AMERICAN JOURNAL OF Subclinical Hepatic Encephalopathy, THE AMERICAN JOURNAL OF
GASTROENTEROLOGY, Vol.95, No.8, 2000， pp.2029-2034)によれば 25名の潜在 性脳症の患者のうち、 10名（40%)が顕性脳症に移行したとされている。 According to GASTROENTEROLOGY, Vol.95, No.8, 2000, pp.2029-2034), out of 25 patients with occult encephalopathy, 10 (40%) have developed overt encephalopathy.
[0050] そこで無処理の場合の移行率を 40%として本実施例の結果 20%と比較すると、分 岐鎖アミノ酸顆粒の投与により顕性脳症への発症率が低下したと考えられる。 [0050] Therefore, when the transfer rate in the case of no treatment was set to 40%, and compared with the result of this example of 20%, it is considered that the incidence of overt encephalopathy was reduced by administration of the branched-chain amino acid granules.
実施例 1で示された分岐鎖アミノ酸投与による局所脳内血流量の増加がひとつの 改善要因となり、顕性脳症発症を予防していると評価できる。 The increase in local cerebral blood flow due to the administration of the branched-chain amino acid shown in Example 1 is one of the improvement factors, and it can be evaluated that the onset of overt encephalopathy is prevented.
産業上の利用可能性 Industrial applicability
[0051] 本発明の医薬組成物によれば、経口または経腸投与という簡便な投与によって局 所脳血流低下を改善することができ、該局所脳血流低下に伴う神経系障害の予防ま たは治療が可能となる。とくに、潜在肝性脳症から顕性脳症への移行予防に有用で ある。
According to the pharmaceutical composition of the present invention, local cerebral blood flow decrease can be improved by simple administration such as oral or enteral administration, and nervous system disorders associated with the local cerebral blood flow decrease can be prevented. Or treatment is possible. In particular, it is useful for preventing the transition from occult hepatic encephalopathy to overt encephalopathy.
Claims
[1] イソロイシン、ロイシン、バリンを有効成分とし、それらの質量比が 1 : 1. 9-2. 2 : 1. 1 一 1. 3であり、経口または経腸で投与することを特徴とする、局所脳血流低下に伴う 神経系障害の予防または治療に使用するための医薬組成物。 [1] Isoleucine, leucine, and valine as active ingredients, and their mass ratio is 1: 1.9-2.2: 1.1.1-3, and is characterized by being administered orally or enterally And a pharmaceutical composition for use in the prevention or treatment of a nervous system disorder associated with a decrease in local cerebral blood flow.
[2] 局所脳血流低下に伴う神経系障害が中枢神経系障害である請求項 1に記載の医薬 組成物。 [2] The pharmaceutical composition according to [1], wherein the nervous system disorder associated with regional cerebral blood flow decrease is a central nervous system disorder.
[3] 視床、帯状回、頭頂のいずれか 1箇所若しくは 2箇所以上の脳血流低下を改善する ための請求項 1または 2に記載の医薬組成物。 [3] The pharmaceutical composition according to claim 1 or 2, for ameliorating a decrease in cerebral blood flow at one or more of the thalamus, cingulate or parietal.
[4] 局所脳血流低下に伴う神経系障害が潜在性肝性脳症に起因するものである請求項[4] The nervous system disorder associated with a decrease in regional cerebral blood flow is caused by occult hepatic encephalopathy.
1一 3のいずれか 1項に記載の医薬組成物。 The pharmaceutical composition according to any one of items 1-3.
[5] 局所脳血流低下に伴う神経系障害の予防が、潜在性肝性脳症から顕性脳症への移 行予防であることを特徴とする請求項 1一 4のいずれ力 1項に記載の医薬組成物。
[5] The method according to any one of [1] to [14], wherein the prevention of a nervous system disorder caused by a decrease in local cerebral blood flow is prevention of a transition from occult hepatic encephalopathy to overt encephalopathy. Pharmaceutical composition.
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| JP2005517446A JPWO2005072721A1 (en) | 2004-01-28 | 2005-01-26 | Pharmaceutical composition for prevention or treatment of nervous system disorders associated with decreased local cerebral blood flow |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0276813A (en) * | 1988-05-06 | 1990-03-16 | Ajinomoto Co Inc | Remedy for neurodegenerative disorder |
| JPH02172915A (en) * | 1988-12-23 | 1990-07-04 | Ajinomoto Co Inc | Cerebral cell metabolism improving composition |
-
2005
- 2005-01-26 WO PCT/JP2005/000973 patent/WO2005072721A1/en active Application Filing
- 2005-01-26 JP JP2005517446A patent/JPWO2005072721A1/en active Pending
- 2005-01-26 KR KR1020067017347A patent/KR20060124732A/en not_active Application Discontinuation
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2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0276813A (en) * | 1988-05-06 | 1990-03-16 | Ajinomoto Co Inc | Remedy for neurodegenerative disorder |
| JPH02172915A (en) * | 1988-12-23 | 1990-07-04 | Ajinomoto Co Inc | Cerebral cell metabolism improving composition |
Non-Patent Citations (1)
| Title |
|---|
| MUTO Y. ET AL: "BCAA-G (Bunkisa Amino Acid Karyu) no Ippan Rinsho Shiken", JJPEN, vol. 11, no. 9, 1989, pages 1119 - 1134, XP002991265 * |
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| JPWO2005072721A1 (en) | 2007-09-06 |
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