KR20060124732A - Medicinal composition for preventing or treating neural disorders accompanying topical lowering in brain blood flow - Google Patents

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

Pharmaceutical composition for preventing or treating neural disorders accompanying topical lowering in brain blood flow}

The present invention relates to a pharmaceutical composition for the prevention or treatment of neurological disorders caused by localized cerebral blood flow.

Recently, with the progress of an aging society, various cerebrovascular diseases have increased. In addition, nervous system disorders centering on conscious disorders caused by serious liver diseases such as severe hepatitis and cirrhosis are increasing.

Generally, the causative diseases are various, but the lowering of the local cerebral blood flow is classified into thrombosis, embolism, and thrombosis, and it is considered that the oxygen deficiency, the decrease of the substrate supply, and the accumulation of metabolites proceed simultaneously. . Although the type and extent of neurological disorders differ depending on the cause of the disease and the degree of lowering blood flow, the prevention and treatment of these disorders are important because they cause damage to the patient's QOL even if the disease is relatively mild as well as a serious disorder. In addition, it is important to prevent the occurrence of neurological disorders in advance, and it is also recognized as a feature that the disorder is required for the treatment effect.

Relatively mild neurological disorders include, for example, a decrease in age-related perception or memory, a decrease in cognitive ability and concentration, lack of mental clarity and clarity, and problems with mental vigor and short-term memory and learning. Patients who are present are also important as treatment targets.

One of the nervous system disorders is, for example, hepatic encephalopathy. Hepatic encephalopathy is a neuropsychiatric symptom centered on conscious disorder caused by severe liver disorders such as severe hepatitis and cirrhosis. The psychosomatic symptoms in hepatic encephalopathy have been considered to be insufficient or invisible before the onset of hepatic encephalopathy or the manifestation of overt encephalopathy. However, in recent years, the neuropsychiatric symptoms are not evident, such as overt hepatic encephalopathy, and a condition in which sensitive and quantitative psychological function tests are indicated in cirrhosis, which is not clinically recognized as hepatic encephalopathy. Has been revealed and is called latent hepatic encephalopathy. There are no unified diagnostic criteria or psychological neurological tests for the diagnosis of latent hepatic encephalopathy.However, a method for comprehensively diagnosing abnormalities by performing a mental neurological function test (other than a symbol follow-up test) and a neurological test (except for an EEG) has been tried. [Reference: Kato Akinobu, Vol. 47, No. 1, July 2003, July 2003, 63-73, July 28, 2003] (page 63 first, pages 67-71 3 Concept of latent hepatic encephalopathy) )]. The rate of transition from latent hepatic encephalopathy to overt encephalopathy is not yet clear, but has been reported at around 40% and is expected to be very high. Therefore, the usefulness of the medicine which has the effect of lowering the transition rate of latent hepatic encephalopathy to overt encephalopathy is considered high.

As a therapeutic agent for neurological disorders, vasodilators and the like have a certain effect, but are carefully administered to the above-mentioned patients in consideration of side effects. In that case, great care must be taken in the selection of the medicament corresponding to the underlying disease of the patient, the determination of the dosage, and the administration period. In addition, although prophylactic agents are sometimes administered prophylactically, there are many cases in which administration is stopped due to the occurrence of side effects.

Low molecular weight compounds and brain cells that prevent neuronal cell death, such as neuroprotective drugs, while improving the deterioration of local cerebral blood flow, reducing side effects, and expecting to provide a rapid therapeutic effect or a prophylactic effect. Although methods for treatment with many drugs, such as metabolic enhancers, have been proposed, it has not been possible to identify drugs that have a clinical effect quickly and without side effects of neuropathy caused by local blood flow in the brain.

As a side chain amino acid (BCAA) preparation which uses isoleucine, leucine, and valine as an active ingredient for the purpose of improving hypoalbuminemia in patients with cirrhosis, etc., Ribect (trademark) made by Ajinomoto Co., Ltd. is used. The usefulness of such side chain amino acid preparations for cirrhosis is mainly examined and reported, such as improvement of nitrogen balance, hypoalbuminemia, and increase of muscle protein mass. There are the following reports.

Japanese Unexamined Patent Application Publication No. Hei 1-80823 (lines 8 to 3 below the upper right column on page 148, and 2 lines below the upper right column on page 151) has a brain which is part of the brain due to ischemia or oxygen deficiency as the life expectancy is extended. Disability increases, and representative examples thereof are cerebral ischemic attacks and senile dementia, and L-isoleucine has been described as a drug for treating it.

Japanese Unexamined Patent Application Publication No. Hei 1-80823 (line 8 to 3 under the right upper egg on page 148 and line 2 under the upper right egg on page 151) after intraperitoneal administration of L-leucine until the respiratory arrest of arterial ligation mice. The experimental results indicate that the time to the prolonged respiratory arrest in mice is prolonged by the administration of L-leucine, indicating that intraperitoneal administration of L-leucine is effective for prolonging survival time under cerebral ischemia or oxygen deficiency. Doing. However, Japanese Unexamined Patent Application Publication No. Hei 1-80823 (line 8 to 3 under the right upper egg on page 148 and line 2 below the upper right egg on page 151) has the effect of L-leucine administration on neurological disorders due to local cerebral blood flow. It is not described at all.

Japanese Unexamined Patent Application Publication No. 2-172915 (Bottom left, page 96, lines 7 to 6 below) shows that side chain amino acids are ingested in patients with senile dementia for 3 months, and a simple intellectual function test is performed to intake side chain amino acids. As described above, there is a description that recovery of intellectual function can be seen, and that the metabolic improvement effect of brain cells is thought to be effective. However, it has been described that it was effective for the intellectual function test when the side chain amino acid was simply administered, and it suggests the usefulness when the dementia of the test subject is caused by abnormal brain cell metabolism. There is no description that it is useful for the accompanying patients, but it is useful for neurological disorders caused by a decrease in local cerebral blood flow, which is based on hepatic encephalopathy caused by hepatic disease other than dementia patients.

In Japanese Patent Application Publication No. 2814529 ((3), page 6, column 9 to 4 below), an ischemic brain disorder therapeutic drug is proposed by using an amino acid selected from isoleucine, leucine, and arginine in combination with glucose. Experimental data are described in which oral administration of arginine and glucose in combination and single administration respectively reduce the nucleus of the uterus. From these results, it has been described that representative nutrients such as arginine and glucose can suppress or lower abnormal abnormality of glutamic acid in the brain due to cerebral ischemia, thereby preventing and treating brain disorders represented by arch nucleus disorders. However, in Japanese Patent Application Publication No. 2814529 ((3), page 6, column 9 to 4 below), no experiments have been conducted on whether isoleucine and leucine have the same effect as arginine. For example, it is not described whether it is effective in the improvement of neurological symptoms by improving the nucleus of the uterus, and experimental data suggesting improvement of the cerebral ischemia itself, that is, the neurological disorder caused by local cerebral blood flow, is also described. Not.

Literature: References by Kato Akinobu, `` A Liver Pancreas '', Volume 1, No. 47, July 2003, pages 63-73, July 28, 2003 (Page 63 for the first time, pages 67-71 3 of latent hepatic encephalopathy) CONCLUSIONS)] describes that there is a symptom diagnosed as latent hepatic encephalopathy as a pre-stage of hepatic encephalopathy.

In addition, the present inventors administered intravenously to a cirrhosis patient with a fluid for treating hepatic encephalopathy containing a plurality of amino acids such as branched chain amino acid (BCAA) and arginine (trade name: Morihepamin®, manufactured by Ajinomoto Co., Ltd.), Brain blood flow SPECT (single photon emission computed tomography) images were analyzed before and after administration, and it has already been reported that cerebral blood flow is increased and local cerebral blood flow disorder is improved. See Moto Iwasa, Vol. 43, Suppl. (3), November 5, 14, Published by the Japanese Society of Soybean Society, 34th Japanese Society of Soybean Society, Main Summit, A page 271, liver S6-4].

However, since the effect of improving the blood flow to the cerebrovascular fluid by the fluid is not denied the effects of changes in the circulating dynamics caused by the fluid administration, vasodilation by arginine contained in the fluid, etc. It is not known at all whether there is an improvement effect on blood flow disorder, and whether the effect is short-lived by oral administration.

Problems to be Solved by the Invention

It is an object of the present invention to provide a novel pharmaceutical composition comprising side chain amino acids for treating or preventing neurological disorders by improving lowering of local cerebral blood flow.

Means to solve the problem

The present invention has isoleucine, leucine and valine as active ingredients, and their mass ratio is 1: 1.9 to 2.2: 1.1 to 1.3, orally and enterally administered, wherein the prevention of neuropathy caused by local cerebral blood flow is lowered. Or to pharmaceutical compositions for use in therapy.

It is preferable that the dosage of one active ingredient in the pharmaceutical composition of this invention is 1.0-50 g. The pharmaceutical composition of the present invention is effective for the prophylactic treatment of neurological disorders of the central nervous system. The pharmaceutical composition of the present invention is to improve cerebral blood flow lowering in any one or two or more of the thalamus, subject ash and parietal. The pharmaceutical composition of the present invention is effective for the prophylactic treatment of neurological disorders caused by latent hepatic encephalopathy. A particularly useful use in the pharmaceutical composition of the present invention is the prevention of the transition from latent hepatic encephalopathy to overt encephalopathy.

Effects of the Invention

According to the pharmaceutical composition of the present invention, it is possible to improve local cerebral blood flow lowering by simple administration of oral or enteral administration, and to prevent or treat neurological disorders caused by the local cerebral blood flow lowering. In particular, it is useful for preventing the transition from latent hepatic encephalopathy to overt encephalopathy.

1 is a diagram showing the results of investigating 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 investigating changes in cerebral blood flow before and after corn starch granule administration using SPM analysis of SPECT images.

Best Mode for Carrying Out the Invention

Hereinafter, the present invention will be described in detail.

MEANS TO SOLVE THE PROBLEM In the case of orally administering the composition containing a side chain amino acid as an active ingredient, this inventor examined the influence on the local cerebral blood flow by the analysis of a cerebral blood flow SPECT image. As a result, it has been found that the electrical composition has the effect of improving the local cerebral blood flow disorder observed by the interpretation of the cerebral blood flow SPECT image, specifically, the effect of increasing the cerebral blood flow in the thalamus, subject ganglia and parietal, whereby local cerebral blood flow It has been found that prevention or treatment of neurological disorders caused by degradation is possible.

The present inventors also found that the pharmaceutical composition of the present invention lowers the rate of transition from latent hepatic encephalopathy to overt hepatic encephalopathy.

Here, the structure of the brain will be described.

The hepatic brain can be distinguished into a sagittal top, a sagittal and a sagittal layer, superimposed on one another. The thalamus can also be distinguished as dorsal thalamus and ventral thalamus.

The dorsal thalamus is the end of the sensory and perceptual pathways (skin perception, taste, sight, hearing, and vestibule) and is in contact with the cerebral cortex. The ventral thalamus is a continuation of the midbrain overlying, which is considered to be the area of motility of the hepatic brain. Movement disorder and seizure of pain are treated by thalamic stereotactic surgery. In addition, by cutting the thalamus cortex, which is a specific part of the thalamus, it is possible to see a state of becoming excited from a state of excitement, and at the same time, general indifference and personality flattening. In addition, language disorders are caused by disorders of the thalamus. As such, impairment of the thalamus affects sensory organs, including movement and vision.

The subject society (the marginal circumference) surrounds the corpus callosum, is located in the margin of the corpus callum, and is divided from the dentate gyrus by the hippocampus on the tail side, and ends in the marginal section and the subcortical region. Subject cortex affects the hypothalamus and plant nervous system. The limbic system of the subject society plays an important role in the regulation of basic life processes such as food intake, digestion and reproduction.

The parietal lobe ends in the parietal lobe, which is called somatic perceptual cortex, and consists of a first zone, a second zone, and a third zone. The second section records the position and movement of the body. If the head is invaded, the symbolic accident may occur. In other words, the lack of understanding of letters and numbers makes reading, writing, and counting impossible, and the three-dimensional concept of space is violated.

Accordingly, the present invention can prevent and treat various neurological disorders by improving local cerebral blood flow lowering in thalamus, subject gyrus and parietal brain.

Moreover, the prophylactic or therapeutic agent of this invention can be used suitably in the patient whose neurological disorder is latent hepatic encephalopathy.

The prophylactic or therapeutic pharmaceutical composition of the present invention preferably contains isoleucine, leucine, and valine as active ingredients, and contains a pharmaceutical acceptable substance.

As for isomers of leucine, isoleucine and valine used as active ingredients in the present invention, any of L-form, D-form and DL-form can be used, but L-form is preferred from the viewpoint of being present in nature. Do.

In the compounding ratio (weight ratio) of isoleucine, leucine, and valine, it is more preferable to use it in the composition range which becomes isoleucine / leucine / valine = 1 / 1.9-2.2 / 1.1-1.3.

When calculating the dosage (intake) of the active ingredient used in the present invention described above, the active ingredient of the medicament of the present invention (the medicament used for the purpose of the treatment, prevention, etc. of a disease disorder aimed by the present invention) Since the range of calculations is determined, the side chain amino acids to be ingested or administered for purposes other than this, for example, from normal dietary needs or for the treatment of a separate disease, should be included in the above calculations. There is no need.

For example, it is not necessary to calculate the amount of isoleucine, leucine and valine per day ingested from a normal diet by subtracting from the daily dose of the active ingredient in the present invention.

The pharmaceutical composition of the present invention is administered orally. In this case, the dosage varies depending on the symptoms, age and administration method of the patient to be administered, but is usually about 0.1 to 30.0 g of isoleucine, 0.1 g to 30.0 g of leucine and 0.1 to 30.0 g of valine per day. For general adults, preferably about 0.5 to 10.0 g of isoleucine, about 0.5 to 10.0 g of leucine and about 0.5 to 10.0 g of valine, more preferably about 1.0 to 5.0 g of isoleucine, about 2.0 to 8.0 g of leucine and about 1.0 to 5.0 g of valine It is enough. Moreover, as a dosage per dose, you may administer the said daily dose once, or may divide and administer into several times, In the case of oral administration, it is preferable that it is 20 g or less per dose, More preferably, it is 10 g or less.

The pharmaceutical composition of this invention can be manufactured by a conventional method. It may include various pharmacologically acceptable substances for preparation (as an adjuvant, etc.). Formulation materials can be appropriately selected depending on the formulation of the preparation, but examples include excipients, diluents, additives, disintegrants, binders, coatings, lubricants, glidants, lubricants, flavors, sweeteners, solubilizers, and the like. Can be. Specific examples of preparation materials include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycols and solvents, for example For example, sterile water and monohydric or polyhydric alcohols such as glycerol.

As a substance for preparation, it is preferable to contain one or more types selected from flavoring agents, odorants, excipients or coating agents which do not impair the digestive tract absorption of the active ingredient.

In addition, the agent for preparation for the preparation of a reverse-absorbent preparation can be suitably selected so that the prophylactic or therapeutic agent of the present invention can absorb the effective amount of the active ingredient for improving local cerebral blood flow lowering within 1 hour. .

In the present invention, it can be used together with other pharmacological components (pharmaceutical active substances), for example, in combination or in combination, in which case the active ingredients aimed in the present invention, preferably L-isoleucine, L-leucine and It is included in the pharmaceutical composition of the present invention as long as it contains a mixture of L-valine in a preferred ratio of electricity and exhibits the desired electropharmacological activity. In addition, in this invention, each amino acid used for the active ingredient can also be used in the form of a salt with respect to one part or all part.

The pharmaceutical composition of the present invention, as described above, in the form of various pharmaceutical formulations known or developed in the future, as described above, for example, oral administration, intraperitoneal administration, percutaneous administration, jugular vein administration, inhalation administration, etc. It may be prepared in a dosage form. In order to prepare the medicament of the present invention in the form of such various pharmaceutical preparations, known or future methods may be appropriately employed.

In the form of these various pharmaceutical preparations, for example, in the form of suitable solid or liquid preparations, for example granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions , Drip agents, injectable solutions, preparations to prolong the release of the active substance, and the like.

It is a matter of course that the medicament of the present invention in the form of the formulation exemplified above should contain an electrical component in an amount effective to exhibit drug efficacy.

Although "Libact ^(R) granules" are commercially available as side chain amino acid preparations, the preparations contain L-isoleucine (952 mg), L-leucine (1904 mg), and L-valine (1144 mg), which are granules that can be orally administered. In view of the above, it is an agent useful as one form of the pharmaceutical composition of the present invention.

Although an Example demonstrates this invention more concretely, this invention is not limited by the following example.

Example 1

Clinical trial example 1 (local cerebrovascular improvement effect)

The effect of the side chain amino acid preparation of the present invention on local cerebral blood flow was tested.

(Dose subject and administration)

Ten out of 35 patients diagnosed as cirrhosis were orally administered two (9.48 g) side chain amino acid preparations (trade name: Ribect ^(R) granules, manufactured by Ajinomoto Co., Ltd.) containing the active ingredients shown in Table 1 ( BCAA granules administration group), and analysis of the cerebral blood flow SPECT image before and after administration.

BCAA granules: 10 patients (6 males, 4 females, 8 had no history of overt hepatic encephalopathy, 2 had repeated encephalopathy, but no case had encephalopathy at the time of examination)

As a control, corn starch was orally administered in the same amount as the side chain amino acid preparation (corn starch group), and the same analysis as the BCAA granule administration group was performed.

Corn starch group: 9 (6 males, 3 females, 8 had no history of overt hepatic encephalopathy, 1 had repeated encephalopathy, but no cases with encephalopathy at the time of examination)

Active ingredient contained in 1 packet (4.74 g) of Rebact ^(R) granule L-inoleucine 952 mg L-leucine 1904 mg L-valine 1144 mg

(Interpretation of Cerebral Blood Flow SPECT Images)

In each group, the patient was stabilized, lying on the stomach 26 minutes before the dose, and injected with 1.5 ml of 99mTc-ethyl cysteinate dimer (ECD) using a SPECT device GCA-9300A / DI manufactured by Toshiba. Baseline SPECT was taken prior to administration of both formulations. Subsequently, 60 minutes after administration of both formulations, 1.5 ml of ECD was administered again and SPECT was performed.

Statistical analysis of SPECT images was performed using Statistical Parametric Mapping (SPM) software (SPM97). In addition, the region of interest was set in the frontal lobe, parietal lobe, temporal lobe, occipital lobe, and cerebellum, and the changes in cerebral blood flow before and after administration of both agents were examined. The results are shown in FIGS. 1 and 2.

As a result of the test, the brain blood flow did not change before and after administration in the corn starch group (Fig. 2), but in the BCAA-administered group, an increase in cerebral blood flow was observed in three sites of the subject ash, parietal and thalamus within 1 hour after administration ( 1).

Since side chain amino acid administration increased cerebral blood flow in subjects, parietal and thalamus and alleviated local blood flow disorders, branched chain amino acids acted directly on the central nervous system and were found to be useful in patients with latent hepatic encephalopathy.

Example 2

Clinical Trial Example 2 (Preventive encephalopathy prevention effect in patients with potential hepatic encephalopathy)

The effect of the side chain amino acid preparations of the invention on the rate of transition to latent encephalopathy was investigated.

9.48 g of the same side chain amino acid preparation (trade name: Rebact ^(R) granules, manufactured by Ajinomoto Co., Ltd.) as used in Example 1 among 10 patients diagnosed with cirrhosis, which was determined to have latent encephalopathy by neurological function test. Was administered orally for 2 to 42 months.

Two out of 10 patients had manifestations of hepatic encephalopathy (20% progression rate).

The following reports have been made regarding the transition to encephalopathy in patients with latent hepatic encephalopathy. According to Manuel Romero-Gomez, MD et al., Subclinical Hepatic Encephalopathy Predicts the Development of Overt Hepatic Encephalopathy, THE AMERICAN JOURNAL OF GASTROENTER OLOGY, Vol. 96, No. 9, 2001, pp. 2718-2723. Of 34 latent encephalopathy, 16 (47%) are said to have shifted to encephalopathy. In addition, according to Ieneke JC Hartmann, MD et al., The Prognostic Significance of Subclinical Hepatic Encephalopathy, THE AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol. 95, No. 8, 2000, pp.2029-2034. Of the patients with sexual encephalopathy, 10 (40%) were reported to have developed encephalopathy.

It is considered that the rate of development of overt encephalopathy was reduced by administration of the side chain amino acid granules compared with 20% of the results of this example, with the transition rate in the case of no treatment being 40%.

The increase in the local intracranial blood flow by administration of the side chain amino acid shown in Example 1 is one improvement factor, and can be evaluated as preventing the onset of overt encephalopathy.

According to the pharmaceutical composition of the present invention, it is possible to improve local cerebral blood flow lowering by simple administration of oral or enteral administration, and to prevent or treat neurological disorders caused by the local cerebral blood flow lowering. In particular, it is useful for preventing the transition from latent hepatic encephalopathy to overt encephalopathy.

Claims (5)

Isoleucine, leucine and valine as active ingredients, and their mass ratio is 1: 1.9 to 2.2: 1.1 to 1.3, characterized in that oral or enteral administration, to prevent or treat neurological disorders due to local cerebral blood flow Pharmaceutical composition for use. The pharmaceutical composition according to claim 1, wherein the neurological disorder caused by local cerebral blood flow lowering is central nervous system disorder. The pharmaceutical composition according to claim 1 or 2, for improving cerebral blood flow lowering in any one or two or more of the thalamus, subject society, and parietal head. The pharmaceutical composition according to any one of claims 1 to 3, wherein the neurological disorder due to local cerebral blood flow lowering is due to latent hepatic encephalopathy. The pharmaceutical composition according to any one of claims 1 to 4, wherein the prevention of neurological disorder due to localized cerebral blood flow is prevented from shifting from latent hepatic encephalopathy to overt encephalopathy.

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