JP5366386B2 - Nerve cell activation and nerve elongation promoting composition - Google Patents

Description

  The present invention relates to a composition for activating nerve cells and promoting nerve elongation containing a compound represented by the formula (1).

A nerve is composed of nerve cells, and is divided into a central nervous system that exists in the midline of the body for information integration, and a peripheral nervous system that exists as a separate fiber existing outside the center. This is a convenient distinction depending on the location, and there is no significant difference in their functional structure. When a failure occurs in these tissues, various symptoms occur due to impaired information transmission. For example, it begins with memory impairment such as dementia and Alzheimer's disease, facial paralysis, gastroasthenia, impotence, extraocular muscle paralysis, difficulty in urinating, bowel movement abnormalities, numbness in limbs, pain, dizziness, ulceration, etc. Is a serious symptom. Since nerves have weak regenerative power, regenerative medicine such as transplantation is mainly used for such symptoms. On the other hand, in recent years, methods using therapeutic agents such as internal preparations and preventive agents are being adopted as simpler therapeutic methods. As a treatment method using an internal preparation, it is known that methylcobalamin is administered at a high dose as a component that promotes the repair of a nerve when it is damaged. Against this background, a further therapeutic drug for promoting nerve regeneration has been demanded.
Japanese clinical VOL. 64, 8, 1553-1559 (2006.8.1)

  The main object of the present invention is to provide a composition having an excellent nerve cell activation action and nerve elongation action.

  As a result of intensive studies to solve the above problems, the present inventors have found that a compound represented by the following formula (1) (hereinafter, sometimes referred to as compound 1) has an excellent nerve cell activation action and nerve. It was found to have an elongation action. Compound 1 has a structure similar to that of methylcobalamin, which is one type of coenzyme type vitamin B12, but does not have a methyl group which is the active center of methylcobalamin and has a different action. Compound 1 is known to have a hematopoietic action and may be used for the purpose of improving various symptoms associated with anemia (such as dizziness, lightheadedness, numbness of limbs). The nerve cell activation action and nerve elongation promoting action of Compound 1 were found for the first time in the present invention.

  The inventors of the present invention further enhance the nerve cell activation effect and nerve elongation effect by compounding compound 1 with a compound represented by the following general formula (2) (hereinafter sometimes referred to as compound 2). I found it. The present invention has been completed as a result of further studies based on these findings.

That is, the present invention provides the following composition for activating nerve cells and promoting nerve elongation.
Item 1. A composition for promoting nerve cell activation and nerve elongation, comprising a compound represented by the following formula (1) as an active ingredient.

項２．さらに、下記一般式（２）で表される化合物の少なくとも１種を含有することを特徴とする項１に記載の組成物。

Item 2. Item 2. The composition according to Item 1, further comprising at least one compound represented by the following general formula (2).

［一般式（２）中、２つの

[In general formula (2), two

は同一又は異なって単結合又は二重結合を示す］
項３．前記式（１）で表される化合物１重量部に対して前記一般式（２）で表される化合物を総量で０．００００２〜７．５重量部含有する項１又は２に記載の組成物。
項４．下記式（１）で表される化合物を添加することを特徴とする、神経細胞賦活及び神経伸長促進方法。

Are the same or different and represent a single bond or a double bond]
Item 3. Item 3. The composition according to Item 1 or 2, wherein the total amount of the compound represented by the general formula (2) is 0.00002 to 7.5 parts by weight with respect to 1 part by weight of the compound represented by the formula (1). .
Item 4. A method for promoting nerve cell activation and nerve elongation, comprising adding a compound represented by the following formula (1).

The composition of the present invention exhibits an excellent nerve cell activation action and nerve elongation promoting action on nerve cells. Such compositions of the present invention, particularly, in the conventional effective in therapy of neurological diseases had to rely on regenerative medicine.

  The composition for activating nerve cells and promoting nerve elongation of the present invention contains Compound 1 represented by the following formula (1) as an active ingredient. In the present invention, the nerve cell activation action refers to enhancing the activity / function of nerve cells. Further, the nerve elongation promoting action refers to promoting nerve axon elongation. Hereinafter, each component will be described.

(1) Compound 1
Compound 1 is a compound represented by the following formula (1), and is commercially available from DSM Nutrition Japan Co., Ltd.

本発明の組成物における化合物１の配合量は、本発明の効果を奏するように適宜設定することができるが、成人（１５才以上、体重約６０ｋｇ）１日量あたり０．０１２５〜２４００ｍｇ程度、好ましくは０．０２５〜１２００ｍｇ程度、より好ましくは０．０５〜６００ｍｇ程度である。この様な配合量であれば、本発明の組成物の神経賦活作用及び神経伸長促進作用が顕著に発揮される。

The compounding amount of Compound 1 in the composition of the present invention can be appropriately set so as to exhibit the effects of the present invention, but it is about 0.0125 to 2400 mg per day for adults (15 years old and over, body weight of about 60 kg), Preferably it is about 0.025-1200 mg, More preferably, it is about 0.05-600 mg. With such a blending amount, the nerve activation action and nerve elongation promoting action of the composition of the present invention are remarkably exhibited.

(2) Compound 2
Compound 2 is a compound represented by the following general formula (2), which is known to act as a mammalian anti-anemic factor, and is commercially available from DSM Nutrition Japan Co., Ltd.

一般式（１）中、２つの

In general formula (1), two

は同一又は異なって単結合又は二重結合を示し、二重結合であることが好ましい。上記化合物２を１種単独で用いてもよいが、２種以上を組み合わせて用いてもよい。

Are the same or different and each represents a single bond or a double bond, preferably a double bond. Although the said compound 2 may be used individually by 1 type, you may use it in combination of 2 or more type.

  The compounding amount of Compound 2 in the composition of the present invention can be appropriately set based on the compounding amount of Compound 1 so that the effects of the present invention can be obtained, and the total amount is usually 0 with respect to 1 part by weight of Compound 1. About 0.0002 to 7.5 parts by weight, preferably about 0.01 to 2.9 parts by weight, and more preferably about 0.02 to 1 part by weight. By containing Compound 1 and Compound 2 in such a ratio, the nerve cell activation action and nerve elongation promoting action of Compound 1 are enhanced. Especially the compounding quantity of the compound 2 is in the range of the said compounding ratio, Comprising: Adults (15 years old and over, body weight about 60 kg) About 0.0125-40 mg per day, about 0.025-20 mg, 0.05- It is desirable to be about 10 mg.

  As one of the preferred embodiments in which the effects of the present invention are remarkably exhibited, Compound (1) contains about 0.05 to 600 mg of Compound 1 per day for adults (over 15 years old, body weight of about 60 kg); A composition containing about 0.05 to 10 mg of Compound 2 in an amount in the range of about 0.02 to 1 part by weight with respect to parts by weight is exemplified.

(3) Dosage form The composition of the present invention can be prepared into various pharmaceutical dosage forms, whether orally or parenterally, according to a conventionally known method. For example, liquid preparations (including syrups) Oral preparations in the form of solid preparations such as liquid preparations, tablets, pills, powders, granules, capsules (including soft capsules), films; liquid preparations such as liquids, drops, injections, eye drops, tablets, Examples include parenteral preparations in the form of solid preparations such as pills and capsules (including soft capsules).

  Since compound 1 is known to partially undergo metabolism in the liver and change its structure, the composition of the present invention includes livers such as sublingual tablets, intravenous injections, and edible films. A form with less influence of metabolism is preferred.

  When the composition of the present invention is a liquid preparation, it can be stored frozen, or it may be stored after removing moisture by lyophilization or the like. Freeze-dried preparations, dry syrups and the like are used by dissolving again by adding distilled water for injection, sterilized water or the like at the time of use.

  For example, when the composition of the present invention is prepared as an injection, drip, etc., as a diluent, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan Fatty acid esters and the like can be used. In this case, a sufficient amount of sodium chloride, glucose or glycerin for adjusting a solution that is isotonic with the body fluid may be contained in the composition of the present invention. Moreover, you may add the solubilizing agent, buffering agent, soothing agent, etc. which are generally used in this field | area.

  When the composition of the present invention is prepared as a solid agent, for example, in the case of a tablet, a carrier conventionally known in this field can be widely used as a carrier. Examples of such carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, silicic acid; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin Binders such as solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, crystalline cellulose, hydroxypropylcellulose, hypromellose, sodium alginate; dry starch, agar powder, laminaran powder, sodium bicarbonate, polyoxyethylene sorbitan fatty acid Disintegrants such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, crospovidone, povidone, low-substituted hydroxypropylcellulose; stearin, cocoa butter, water Disintegration inhibitors such as additive oils; Absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; Moisturizers such as glycerin; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Purified talc and stearin Lubricants such as acid salts, boric acid powder, and polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. Moreover, the composition containing the said active ingredient can be filled into the conventionally well-known capsule which uses gelatin, a pullulan, starch, gum arabic, hydroxypropyl methylcellulose (HPMC), etc. as a raw material, and can be set as a capsule.

  Moreover, when preparing in the form of a pill, a conventionally well-known thing can be widely used as a support | carrier in this field | area. Examples include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, and disintegrants such as laminaran and agar. Can be used.

  In addition to the above, for example, surfactants, absorption promoters, adsorbents, fillers, preservatives, stabilizers, emulsifiers, solubilizers, salts that regulate osmotic pressure, dosage units of the preparations obtained It can be appropriately selected and used according to the form.

  Moreover, you may contain other active ingredients, such as an amino acid, vitamins, and inorganic salts. Examples of other active ingredients include valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid , Amino acids such as hydroxylysine, arginine, ornithine, histidine; vitamins such as vitamin A1, vitamin A2, carotene, lycopene (provitamin A), vitamin B6, vitamin B1, vitamin B2, ascorbic acid, nicotinamide, biotin; Examples thereof include alkali metal salts such as sodium chloride and potassium chloride, and inorganic salts such as citrate, acetate and phosphate.

  The dose of the composition of the present invention is not particularly limited as long as the effect of the present invention is exhibited, and can be appropriately set depending on the dosage form, patient age, sex, degree of medical condition, etc. Based on the dose, adult (15 years old and over, body weight about 60 kg) daily dose is about 0.0002 to 40 mg / kg, preferably about 0.0004 to 20 mg / kg, more preferably 0.0008 to 10 mg / kg. It is about kg.

(4) Method for Promoting Nerve Cell Activation and Nerve Elongation The present invention provides a method for promoting nerve cell activation and nerve elongation characterized by administering Compound 1. Specific types and blending amounts of Compound 1 and Compound 2 in the method of the present invention are as described in (1) and (2) above.

The composition of the present invention thus obtained can exert excellent nerve cell activating action and nerve elongation promoting action, so dementia, memory impairment such as Alzheimer's disease, facial nerve paralysis, gastroasthenia, impotence, external ophthalmoplegia dysuria, bowel function, limb numbness, pain, lightheadedness, useful for therapy of diseases caused damage to transmission path of the nervous system, such as ulcers (or disease caused by disorders of the nervous system pathway) It is.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Formulation Examples, but the present invention is not limited thereto.
<Test example>
(1) Cryopreserved P19 EC cells cells (mouse embryonic tumor cell line provided by RIKEN) were cultured in a DMEM liquid medium containing 15% of inactivated fetal bovine serum (hereinafter referred to as FBS).
(2) The cells were cultured at 1 × 10 ⁵ cells / ml / well in a DMEM liquid medium (without FBS) containing retinoic acid (1 μM) at 37 ° C. and a CO ₂ concentration of 5% for 1 day.
(Use a 6-well plate and culture at 2 mL per well)
(3) The supernatant was removed and cultured in a liquid medium containing a test substance having a concentration shown in Tables 1 to 3 below (concentration in the liquid medium).
(4) After 12 hours, the number of floating cells was measured, and the nerve cell activation rate was calculated from the following formula. In this test example, the floating cell is a neuronal cell that cannot be obtained with sufficient function and activity and has died. The results are shown in Tables 1-3.
Nerve cell activation rate = (A / B) × 100 (%)
A: At the time of administration of each test substance: (initial cell number-floating cell number) / initial cell number B: When the test substance is not administered (corresponding to Comparative Example 1): (initial cell number-floating cell number) / initial cell number
(5) 60 hours after the above (4), the cells are stained with trypan blue and have a flat shape, and radial protrusions extending outward from the cells (cells extending dendrites) ) Number was measured. Measurement was performed in five fields of view, and the nerve elongation promotion rate was calculated from the following formula (I) using the average value. The results are shown in Tables 1 and 2.
Formula (I): nerve cell elongation promotion rate = (A / B) × 100 (%)
A: (Dendrite cell number / total cell number) of each visual field at the time of administration of each test substance
B: (number of dendritic cells / total number of cells) in each visual field when test substance is not administered (corresponding to Comparative Example 1)

実施例１から明らかなように、化合物１を培地に添加することによって、神経細胞の賦活作用及び神経細胞伸長促進作用が認められた。また、実施例２〜８に示されるように、化合物１及び化合物２を添加することによってより神経細胞の賦活作用及び神経細胞伸長促進作用が増強された。
以下に本発明の処方例を示す。

As is clear from Example 1, by adding Compound 1 to the medium, an activation effect on nerve cells and an action for promoting elongation of nerve cells were observed. Further, as shown in Examples 2 to 8, addition of Compound 1 and Compound 2 enhanced the nerve cell activation action and nerve cell elongation promoting action.
The formulation example of this invention is shown below.

処方例１〜５を、手足のしびれを訴える患者に服用させる有効性試験を実施したところ、各処方例の有効性及び有用性が確認された。

When the effectiveness test which makes the patient who complains of numbness of limbs take the prescription examples 1-5, the effectiveness and usefulness of each prescription example were confirmed.

Claims (2)

The compound represented by the following formula (1) and the compound represented by the formula (2) are the compounds represented by the formula (1): the compound represented by the formula (2) = 4.8: 0.0017- The composition for nerve cell activation and nerve elongation promotion characterized by containing in the ratio (molar ratio) of 1.2: 1.2 :

[In general formula (2), two

Are the same or different and each represents a single bond or a double bond]. The compound represented by the following formula (1) and the compound represented by the formula (2) are added to the nerve cell, the compound represented by the formula (1): the compound represented by the formula (2) = 4.8: Nerve cell activation and nerve elongation promoting method (excluding medical practice for humans ), characterized by adding 0.0017 to 1.2: 1.2 (molar ratio ) :

[In general formula (2), two

Are the same or different and each represents a single bond or a double bond].