JP5376785B2 - Pharmaceutical composition - Google Patents

Description

  The present invention relates to a composition for suppressing nerve elongation inhibition by 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 urinating, bowel movement abnormalities, numbness of limbs, pain, dizziness, ulceration, etc., markedly QOL Is a serious symptom. Since nerves have weak regenerative power, once such symptoms occur, they are difficult to heal and daily adverse effects should be avoided. Efforts such as improvement of lifestyle are taken as a countermeasure.

Also, regenerative medicine such as transplantation is mainly used for these symptoms. In recent years, there is a need for more convenient therapeutic and preventive drugs such as oral preparations.
Japanese Clinical Vol. 64, 8, 1553-1559 (2006.8.1)

  Compound 1 is known to cause symptoms such as anemia and immunodeficiency due to its deficiency. Since it is vulnerable to heat and susceptible to destruction by oxidation reactions, it is desirable to take it appropriately. However, on the other hand, the present inventors confirmed the inhibitory action of Compound 1 on nerve cells, and there was concern about adverse effects on nerves.

  The main object of the present invention is to provide a composition capable of suppressing the inhibition of nerve elongation of Compound 1. Furthermore, an object of the present invention is to provide a composition for promoting nerve elongation that can promote the elongation of nerve cells.

  As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention are represented by the general formula (1) in the compound represented by the formula (2) (hereinafter sometimes referred to as the compound 2). Compound (hereinafter, sometimes referred to as compound 1) has an effect of suppressing the nerve elongation inhibitory action, and further contains a compound represented by general formula (3) (hereinafter sometimes referred to as compound 3). As a result, it was found that not only the nerve elongation inhibitory action of Compound 1 was suppressed, but also the effect of promoting nerve elongation was obtained. The present invention has been completed as a result of further studies based on these findings.

That is, the present invention provides the following pharmaceutical compositions.
Item 1. A pharmaceutical composition comprising as an active ingredient at least one compound represented by the following general formula (1) and at least one compound represented by the following formula (2):

[In general formula (1), two

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

Item 2. Item 2. The pharmaceutical composition according to Item 1, further comprising at least one compound represented by the following general formula (3).

[In the formula (2), R represents —CN, —OH (H ₂ O), —CH ₃ or a group:

Show]
Item 3. Item 3. The pharmaceutical composition according to Item 1 or 2, which is a composition for suppressing nerve elongation inhibition by the compound represented by the formula (1) and a composition for promoting nerve elongation.
Item 4. Item 4. The amount according to any one of Items 1 to 3, wherein the compounding amount of the compound represented by Formula (2) is 10 to 4167 parts by weight with respect to 1 part by weight of the total amount of the compound represented by Formula (1). Composition.
Item 5. Item 2-4, wherein the total amount of the compound represented by Formula (3) is 1 to 83 parts by weight with respect to 1 part by weight of the compound represented by Formula (1). A composition according to 1.
Item 6. A method for suppressing nerve elongation inhibition by Compound 1, which comprises adding a compound represented by Formula (2) below in combination to at least one compound represented by Formula (1) below:

[In general formula (1), two

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

Item 7. (i) from at least one compound represented by the following formula (1), (ii) a compound represented by the following general formula (2); and (iii) a compound represented by the following general formula (3) A method of extending a nerve, comprising adding in combination with at least one selected from the group consisting of:

[In general formula (1), two

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

  According to the pharmaceutical composition of the present invention, Compound 2 can suppress the adverse effect of Compound 1 on nerve cells (inhibition of nerve elongation), and can obtain a suitable action of Compound 1. In addition, by adding at least one compound 3 to the composition, nerve elongation is significantly promoted.

  Such a composition of the present invention can obtain a suitable therapeutic effect by Compound 1, and is also effective for the prevention or treatment of neurological diseases that conventionally had to rely on regenerative medicine.

  The pharmaceutical composition of the present invention contains at least one compound 1 as well as compound 2 as active ingredients. 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.

In general formula (1), two

Are the same or different and each represents a single bond or a double bond, preferably a double bond. One of the compounds 1 may be used alone, or two or more may be used in combination. The total amount of Compound 1 in the composition of the present invention is about 0.25 to 40 mg, preferably about 0.5 to 20 mg, more preferably about 1 to 20 mg per day for adults (over 15 years old, body weight about 60 kg). About 10 mg.

(2) Compound 2
Compound 2 is a compound represented by the following general formula (2), which is known to act as an antipyretic analgesic, and is commercially available from Daito Corporation.

  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 as to achieve the effects of the present invention. The amount is about 4167 parts by weight, preferably about 208 to 521 parts by weight, more preferably about 208 to 416 parts by weight. By containing Compound 1 and Compound 2 at such a ratio, the nerve elongation inhibitory action of Compound 1 is more effectively suppressed. In particular, the compounding amount of compound 2 is within the range of the blending ratio, and is usually about 50 to 2400 mg, preferably about 100 to 1600 mg, more preferably 150 to about 100 to 1600 mg per day for an adult (over 15 years old, body weight about 60 kg). It is desirable to be about 800 mg.

(3) Compound 3
In addition to the above-mentioned compound 2, it is preferable to use at least one of compound 3 in combination with the above-mentioned two components because a nerve stretching effect is observed by compounding at least one of compound 3.

  Compound 3 is a compound represented by the following general formula (3), and is commercially available from DSM Nutrition Japan Co., Ltd.

[In the formula (2), R represents —CN, —OH (H ₂ O), —CH ₃ or a group:

Show]
In the general formula (3), R is preferably -CN. Although the said compound 3 may be used individually by 1 type, you may combine 2 or more types.

  The compounding quantity of the compound 3 in the composition of this invention can be suitably set based on the compounding quantity of the compound 1 so that there may exist the effect of this invention. If the total amount of Compound 1 is 1 part by weight, the compounding ratio of Compound 3 is generally about 1 to 83 parts by weight, preferably about 1.5 to 10 parts by weight, more preferably 2 to 10 parts by weight. About a part. With such a blending ratio, the nerve stretching action of the composition of the present invention is remarkably exhibited. In particular, the compounding amount of Compound 3 is within the range of the compounding ratio, and is about 0.25 to 2400 mg, about 0.5 to 1200 mg, and about 1 to 600 mg per day for adults (15 years old and over, weight about 60 kg) It is desirable.

  As one of the preferred embodiments in which the effect of suppressing the inhibition of nerve elongation by the compound 1 of the present invention is remarkably exhibited, the total amount of the compound 1 is 1 to 10 mg per day for adults (15 years old and over, body weight of about 60 kg). About 1 to 150 parts by weight per day of an adult (15 years old and over, body weight of about 60 kg) in a range of about 208 to 416 parts by weight of Compound 2 with respect to 1 part by weight of the total amount of Compound 1 The composition to contain is illustrated.

  Moreover, as one of the preferable embodiments in which the nerve elongation promoting effect of the present invention is remarkably exhibited, the total amount of Compound 1 is about 1 to 10 mg per day; the total amount of Compound 1 is 1 part by weight. Compound 2 is in the range of about 208 to 416 parts by weight and contains about 150 to 800 mg per day for adults (over 15 years old, body weight about 60 kg); Compound 3 is about 2 to 10 parts by weight in total Examples are compositions that are within the range and contain about 1 to 600 mg per day for adults (age 15 and over, body weight about 60 kg).

(4) 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 (including suspensions), tablets, pills, powders, granules, capsules (including soft capsules); liquid preparations such as liquids, drops, injections, and eye drops And parenteral preparations in the form of solid preparations such as tablets, pills and capsules (including soft capsules). The composition of the present invention is preferably in the form of a film-coated tablet, sugar-coated tablet, sweetener-coated tablet, capsule, sublingual tablet, intravenous injection, edible film and the like.

  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. Adult (15 years old and over) based on the dosage (calculated as a body weight of about 60 kg) per day, about 0.004 to 0.67 mg / kg, preferably about 0.0083 to 0.33 mg / kg, more preferably It is about 0.017 to 0.17 mg / kg.

(5) Method for suppressing nerve elongation inhibition and method for extending nerve The present invention comprises adding compound 2 in combination with at least one compound 1 to suppress nerve elongation inhibition by compound 1 And a method of extending a nerve, characterized by comprising adding at least one compound 1 in combination with at least one compound selected from the group consisting of compound 2 and compound 3. . Specific types, compounding amounts, and the like of Compound 1, Compound 2, and Compound 3 in the method of the present invention are as described in the above (1) to (3).

  Such a composition containing Compound 1 and Compound 2 of the present invention can remarkably suppress nerve elongation inhibition by Compound 1. Moreover, the composition containing Compound 3 in addition to Compound 1 and Compound 2 significantly promotes nerve elongation. Therefore, the composition of the present invention is a composition useful for the treatment of symptoms such as anemia and immunodeficiency, and also includes memory impairment such as dementia and Alzheimer's disease, facial nerve palsy, gastroasthenia, impotence, and external eye. Useful for the prevention or treatment of diseases that cause damage to the nerve pathways (or symptoms caused by disturbances in the nervous system pathways) such as muscle paralysis, dysuria, bowel movement abnormalities, numbness in the limbs, pain, dizziness, ulcers, etc. 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. under 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 the test substance at the concentration shown in Table 1 or 2 below (concentration in the liquid medium).
(4) 72 hours after (3), cells are stained with trypan blue and have a flat shape, and radial protrusions extending outward from the cells (cells extending dendrites) The number of was measured. Measurements were made in five visual fields, and the average value was used to calculate the nerve extension promotion rate from the following formula (I). 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)

  As is clear from Table 2 Comparative Example 1 and Comparative Example 2, Compound 1 was shown to have an elongation inhibitory effect on nerve cells. On the other hand, as shown in Example 1, the adverse effect of Compound 1 on nerve cells was suppressed by the combined use of Compound 2. Compound 2 is a component known to have antipyretic analgesic action and strong cytotoxicity, but it did not cause toxicity to nerve cells and also inhibited damage to nerve cells caused by compound 1. On the other hand, acetaminophen used as an antipyretic analgesic agent is similarly known to be cytotoxic (Comparative Example 4), and even when combined with Compound 1, the side effects of Compound 1 were not suppressed. (Comparative Examples 5 to 8).

  Furthermore, it has been shown that combining Compound 1, Compound 2, and Compound 3 not only suppresses damage to nerve cells of Compound 1, but also significantly promotes nerve elongation.

  The formulation example of this invention is shown below.

  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)

Nerve elongation promoting composition comprising as an active ingredient a compound 1 represented by the following general formula (1), a compound 2 represented by the following general formula (2), and a compound 3 represented by the following general formula (3) And the ratio (molar ratio) of compound 1 to compound 2 is compound 1: compound 2 = 4.8: 1000 to 2.4: 1000, and the ratio (molar ratio) of compound 1 to compound 3 is compound 1: compound. 3 = 2.4: 2.4 to 4.8: 10.8 The composition for promoting nerve elongation , characterized in that:

[In general formula (1), two

Represents a double bond];

[In General Formula (3), R represents -CN. ]. (i) Compound 1 represented by the following formula (1),
(ii) Compound 2 represented by the following general formula (2), and
(iii) Compound 3 represented by the following general formula (3)
In a ratio (molar ratio) of Compound 1: Compound 2 = 4.8: 1000 to 2.4: 1000 and Compound 1: Compound 3 = 2.4: 2.4 to 4.8: 10.8 A method of promoting nerve growth characterized by adding (except for medical practice for humans):

[In general formula (1), two

Represents a double bond];

[In General Formula (3), R represents -CN].