JPH06192087A - Improving and therapeutic agent for emotional disturbance - Google Patents

Abstract

PURPOSE:To obtain a new improving and therapeutic agent for emotional disturbance capable of remarkably improving and treating the emotional disturbance without any side effect in a short time. CONSTITUTION:This improving and therapeutic agent for emotional disturbance comprises lithium ascorbate or lithium salt of ascorbic acid 2-phosphate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a remedy for emotional disorders, which comprises a lithium salt of ascorbic acid or a lithium salt of ascorbic acid-2-phosphate.

[0002]

2. Description of the Related Art Conventionally, lithium salts such as lithium carbonate have been known to prevent and treat emotional disorders.
Such a lithium salt is not yet sufficiently satisfactory in terms of side effects. The lithium salt of ascorbic acid can be obtained by, for example, Journal of Inorganic Biochemistry (J. Inorg. Biochem.) 45 , 73 (199).
In 2), the lithium salt of ascorbic acid-2-phosphate is
For example, the compounds described in JP-B-48-15605 can be used.

[0003]

Means for Solving the Problems As a result of intensive studies in view of such a situation, the present inventors have found that a lithium salt of ascorbic acid or a lithium salt of ascorbic acid-2-phosphate can be used as an agent for improving / treating emotional disorders. The inventors have found that they are useful and can be used safely, and have completed the present invention.

That is, the present invention provides (1) an agent for improving / treating emotional disorders, which comprises a lithium salt of ascorbic acid or a lithium salt of ascorbic acid-2-phosphate, (2)
The above (1) comprising a lithium salt of ascorbic acid
The present invention also provides a remedy for emotional disorder described above and (3) a remedy for emotional disorder described in (1) above, which comprises a lithium salt of ascorbic acid-2-phosphate.

The lithium salt of ascorbic acid or the lithium salt of ascorbic acid-2-phosphate used in the present invention may be a monolithium salt, a dilithium salt or a trilithium salt. Of these, monolithium salts are preferred. The binding site for lithium may be at any position where lithium can bind to ascorbic acid or ascorbic acid-2-phosphate to form these lithium salts.

The lithium salt of ascorbic acid used in the present invention can be prepared by a known method, for example, Journal of Inorganic Biochemistry (J. Inorg. Biochem.).
45 , 73 (1992) and the like, a lithium salt of ascorbic acid-2-phosphate can be prepared by a known method,
For example, each is produced by the method described in JP-B-48-15605. For example, it is produced by reacting ascorbic acid or ascorbic acid-2-phosphoric acid with a lithium compound such as lithium carbonate or lithium hydroxide. This reaction is carried out in a solvent that does not inhibit the reaction. As a preferable solvent, water and alcohols (eg, methanol, ethanol, etc.) are used in any lithium salt. The amount of lithium compounds such as lithium carbonate used is ascorbic acid lithium salt,
It is about 0.5 to 10 times the molar amount of ascorbic acid.
In the case of a lithium salt of ascorbic acid-2-phosphoric acid, it is used in an amount of about 0.3 to 5 times, preferably about 0.4 to 3 times the mol of ascorbic acid-2-phosphate. The reaction temperature is about 10 ° C. to 80 ° C. for any lithium salt. The reaction time is about 10 minutes to 6 hours for the lithium salt of ascorbic acid. Ascorbic acid-2
In the case of a lithium salt of phosphoric acid, it takes about 1 minute to 6 hours. The lithium salt of ascorbic acid or the lithium salt of ascorbic acid-2-phosphate thus produced can be isolated / purified by a means known per se (eg, silica gel, polystyrene resin, activated carbon, reversed-phase column chromatography, etc.). , Solvent extraction, concentration under reduced pressure, crystallization, recrystallization, etc.) for isolation and purification.

The ascorbic acid or ascorbic acid-2-phosphoric acid used as a raw material in the above production method is commercially available or is produced by a known method.

The lithium salts used in the present invention are low in toxicity and have an effect of improving / treating emotional disorders, and therefore can be used as a human emotional disorder improving / treating agent. Further, it can be used as a preventive agent for human emotional disorders. The lithium salt of ascorbic acid also has an analgesic action, a platelet aggregation inhibitory action, and an antiallergic action. Any of the lithium salts used in the present invention is mixed with a known pharmacologically acceptable carrier, excipient, diluent, etc.,
Safely orally or parenterally administering as a pharmaceutical composition [eg, tablets, capsules (including soft capsules, microcapsules), solutions, suppositories, injections, nasal preparations] according to a method known per se You can The dose is appropriately selected depending on the administration route and the degree of emotional disorder. When administered orally, any lithium salt generally doses within the range of about 500 mg to about 20 g / adult patient / day. The range of about 1 g to about 10 g / adult patient / day is particularly preferable. In the case of any lithium salt, the dose is about 200 mg to 5 g / adult patient, and the dose is 1 to 3 times a day. It may also be administered parenterally. in this case,
The dose may, of course, be within the above-mentioned range. For example, in the case of intravenous or intramuscular injection, an injectable solvent such as physiological saline is used. In the case of an intravenous drip infusion, any diluent such as an aqueous glucose solution can be used.

When manufacturing the above oral preparations such as tablets, binders (eg, hydroxypropylcellulose, hydroxymethylpropylmethylcellulose, macrogol, etc.), disintegrants (eg, starch, carboxymethylcellulose calcium, etc.), shaping agents An agent (eg, lactose, starch, etc.), a lubricant (eg, magnesium stearate, talc, etc.) and the like can be appropriately mixed. In the case of producing parenteral preparations such as injections, isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, paraoxy). Methyl benzoate, propyl paraoxybenzoate, etc.), buffering agents (eg, phosphate buffer, sodium acetate buffer, etc.) and the like can be appropriately added. By using the improving / therapeutic agent of the present invention, emotional disorders can be remarkably remedied and treated in a short time without any side effect. Therefore, the present invention greatly contributes to the fields of psychiatry and neurology. .

[0010]

EXAMPLES The present invention will be described in more detail below by showing Examples, Reference Examples and Test Examples, but the present invention is not limited to these. Reference Example 1 8.8 g (50 mM) of L-ascorbic acid was suspended in 20 ml of water, and 1.8 g (24.36 mM) of lithium carbonate as a powder was added thereto little by little while stirring. (CO ₂ is generated,
After natural filtration of the reaction solution (which became a homogeneous solution), 80 ml of ethanol was added to the reaction solution, which was stored overnight in a cool place. The precipitated needle crystals were collected by filtration, washed with ethanol, and dried in a desiccator to obtain ascorbic acid monohydrate. Lithium salt crystals were obtained (8.2
g, 90% yield). mp117-119 ° C

Reference Example 2 30 g of ascorbic acid-2-phosphoric acid magnesium salt (corresponding to 68 mM of ascorbic acid-2-phosphoric acid) was dissolved in 200 ml of distilled water and passed through a column of 200 ml of strongly acidic resin. To the obtained aqueous solution of ascorbic acid-2-phosphoric acid, 2.3 g (31 mM) of lithium carbonate as a powder was added little by little while stirring. 2 g of powdered activated carbon was added to the reaction solution, and after 10 minutes, the activated carbon was filtered off, and the filtrate was concentrated under reduced pressure at 40 ° C. or lower.
Ethanol was added to the concentrate little by little under reduced pressure by an evaporator under reduced pressure to dryness, washed with ethanol, collected by filtration, and vacuum dried to obtain 18.2 g of ascorbic acid-2-phosphate monolithium salt (yield 80.3%). was gotten. Elemental analysis value Calculated value as C ₆ H ₈ O ₉ PLi · ⅓H ₂ O (%) C: 26.95, H: 3.24, P: 11.58,
Li: 2.59 Measured value (%) C: 26.51, H: 3.19, P: 11.89,
Li: 2.80 The solubility of the above compound in water is 100 mg / 100 μl.
It was (water).

Reference Example 3 An aqueous solution of ascorbic acid-2-phosphoric acid was obtained in the same manner as in Reference Example 2, and 5.0 g (67 mM) of lithium carbonate was added to this aqueous solution.
Was added as a powder little by little with stirring. 2 g of powdered activated carbon was added to the reaction solution, and after 10 minutes, the activated carbon was filtered off, and the filtrate was added to 4
It concentrated under reduced pressure at 0 degreeC or less. Add 200 ml of acetone to the concentrated solution, stir for 30 minutes, and discard the supernatant liquid twice.
After washing with acetone, the solid was collected by filtration and dried under vacuum to obtain dilithium ascorbic acid-2-phosphate (18.2 g). Table 1 shows the elemental analysis results of the obtained dilithium ascorbic acid-2-phosphate salt.

[0013]

[Table 1] Solubility of the above compounds in water is 100 mg / 100 μl
It was (water).

Reference Example 4 An ascorbic acid-2-phosphoric acid aqueous solution was obtained in the same manner as in Reference Example 2, and 7.5 g (101 m) of lithium carbonate was added to this aqueous solution.
M) was added as a powder little by little with stirring. 2 g of powdered activated carbon was added to the reaction solution, and after 10 minutes, the activated carbon was filtered off, and the filtrate was concentrated under reduced pressure at 40 ° C. or lower. Acetone to concentrate 200
After adding ml, the mixture was stirred for 30 minutes and the supernatant was discarded. After washing with acetone, filtration and vacuum drying gave ascorbic acid-2.
-Trilithium phosphate salt (19.4 g) was obtained. Table 2 shows the results of elemental analysis of the obtained trilithium ascorbic acid-2-phosphate salt.

[0015]

[Table 2] Solubility of the above compounds in water is 100 mg / 200 μl
It was (water).

Example 1 A tablet containing 3 mg of the lithium salt of ascorbic acid obtained in Reference Example 1 and having the following composition was produced by a method known per se. Lithium ascorbate 3 mg Lactose 65 mg Corn starch 40 mg Hydroxypropyl cellulose 2 mg Magnesium stearate 0.2 mg 110.2 mg (per tablet)

Example 2 Ascorbic acid monolithium salt 50 obtained in Reference Example 1
A tablet containing 0 mg and having the following composition was produced by a method known per se. Ascorbic acid monolithium salt 500 mg Pregelatinized starch 15 mg Corn starch 22 mg Magnesium stearate 3 mg 540 mg (per tablet)

Example 3 A tablet containing 3 mg of ascorbic acid-2-phosphate monolithium salt obtained in Reference Example 2 and having the following composition was produced by a method known per se. Ascorbic acid-2-phosphate monolithium salt 3 mg Lactose 65 mg Corn starch 40 mg Hydroxypropyl cellulose 2 mg Magnesium stearate 0.2 mg 110.2 mg (per tablet)

Example 4 A tablet containing 500 mg of ascorbic acid-2-phosphate monolithium salt obtained in Reference Example 2 and having the following composition was produced by a method known per se. Ascorbic acid-2-phosphate monolithium salt 500 mg Pregelatinized starch 15 mg Corn starch 22 mg Magnesium stearate 3 mg 540 mg (per tablet)

Test Example 1 The toxicity and sedative action of the monolithium ascorbic acid salt obtained in Reference Example 1 were measured. [Method] The monolithium ascorbic acid salt obtained in Reference Example 1 was dissolved in physiological saline to a concentration of 5% (w / v) to prepare a test solution. Jc1: ICR female mouse (6 weeks old, weight 26.2 to 31.
5 g) and two Jc1: ICR male mice (6 weeks old, body weight 23.4 to 28.1 g), 30 ml / kg
1 ml / min was intravenously administered so that the amount of lithium ascorbate would be 1500 mg / kg. [Results] A sedative effect was observed 10 to 15 minutes after the administration, and the effect lasted 1 to 2 hours. No death of the mice was observed even one day after the administration, and the intravenous LD ₅₀
The value was 1500 mg / kg or more.

Test Example 2 Toxicity and sedative effect of oral administration of the monolithium ascorbic acid salt obtained in Reference Example 1 [Method] The monolithium ascorbic acid salt obtained in Reference Example 1 dissolved in distilled water for injection was used as Crj. : 667 mg / kg and 2,000 mg / k for each group of CD-1 (ICR) mouse male and female
G was orally administered once and observed for 2 weeks, and on the day of administration, the symptoms were examined by the multidimensional observation method of 1rwin. [Results] There was no case of death, and no abnormalities were observed in the change in body weight and autopsy findings. On the other hand, in the 1rwin multidimensional observation method, a dose-dependent sedative effect was observed from 30 minutes to 6 hours after administration.

Test Example 3 Toxicity and sedative effect of intravenous administration of the monolithium ascorbic acid salt obtained in Reference Example 1 [Method] The monolithium ascorbic acid salt obtained in Reference Example 1 dissolved in physiological saline was used as Jcl. : 500 mg / kg and 1,500 mg / kg were administered once to the tail vein of each of two male and female 1: 1 CR mice and observed for 7 days. [Results] There were no deaths, and autopsy findings showed no abnormalities in any dose group. On the other hand, a dose-dependent sedative effect was observed from 10 to 15 minutes to about 4 hours after administration.

Test Example 4 Human erythrocyte hemolytic test of ascorbic acid monolithium salt obtained in Reference Example 1 [Test materials and test method] Test Material 1) Test substance and reference substance Test substance (monolithium ascorbic acid salt obtained in Reference Example 1) and lithium carbonate (Wako Pure Chemical Industries (special grade)) reference substance 2 which is Reference substance 1 Sodium L-ascorbate
(Wako Pure Chemical Industries (special grade)) was used. Test substance and reference substance 1
When used, and 2 were dissolved in a physiological saline solution for injection and diluted to a predetermined concentration. 2) Red blood cell suspension (1) Blood used Blood collected from three healthy adult males and treated with heparin was used. (2) Preparation of erythrocyte suspension 400 ml of physiological saline was added to 20 ml of heparinized human blood and mixed to obtain 2000 r.p. p. m. The supernatant was removed by centrifugation for 2 minutes. This operation was repeated twice to wash the red blood cells, and then 10 ml of red blood cells were suspended in 200 ml of physiological saline to prepare a 5% red blood cell suspension. 2. Test method An equal amount of red blood cell suspension was added to 2.5 ml of each pre-warmed solution at 37 ° C, and the presence or absence of hemolysis immediately after mixing was visually observed. After further heating at 37 ° C, 24 hours later, 2000 r.
After centrifugation at pm for 2 minutes, 0.5 ml of the supernatant was added to 2.5 ml of distilled water, and the absorbance at 550 nm was measured using distilled water as a control. Red blood cells were added to distilled water to hemolyze it to 2.5%, and the mixture was heated at 37 ° C. and the same operation was performed. The ratio of the absorbance of each preparation to the absorbance at this time was defined as the hemolysis degree. The effectiveness of the test was confirmed by performing the same operation for the physiological saline solution. [Results] Hemolysis was not observed with the test substance and the control substance 1, sodium L-ascorbate, even at a concentration of 2.5 mg / ml. On the other hand, with reference substance 2, lithium carbonate, the amount is 0.0
Clear hemolysis was observed at a concentration of 31 mg / ml or more. That is, the test substance was much safer than lithium carbonate.

Test Example 5 Human Cell Growth Inhibitory Action of Ascorbic Acid Monolithium Salt Obtained in Reference Example 1 [Method] Lung cancer A549 was used as a human cell suitable for evaluation of growth inhibitory action in a short period, and the day after cell seeding. The ascorbic acid monolithium salt, the ascorbic acid sodium salt and the lithium carbonate obtained in Reference Example 1 were serially diluted and added, and the mixture was kept warm for 4 days. On day 5 of culture, the dye MTT was added, and the ratio of viable cells was calculated from the change in absorbance. [Results] At a concentration of 0.1 mM / liter to 1 mM / liter, ascorbic acid monolithium salt and sodium ascorbate salt had no effect, but lithium carbonate showed an inhibition tendency.

Test Example 6 Effect of monolithium ascorbic acid salt obtained in Reference Example 1 on microbial growth [Method] Minimum inhibitory concentration (MIC) by agar medium dilution method
Measurement (The Japanese Society of Chemotherapy Standard Method, Chemotherapy (Chemot
herapy), 29: 76-77, 1981) Culture conditions Mueller Hinton agar for bacteria (Mueller
-Hinton Agar) (Difco) (pH 7) 37 ° C,
20 hours Nutrient agar medium containing 1% glucose for mold and yeast (Nutri
ent Agar) (Difco (Difco)) (pH6) to the spot (5 [mu] l) inoculated with an inoculating bacterial liquid enrichment solution obtained by appropriately grown in bacteria medium was adjusted to 10 ⁶ cfu / ml and inoculated inoculator

Test Bacteria Gram-Positive Bacteria Bacillus subtilis I
FO 3134 Bacillus cereus (Bacillus cereus) I
FO 3514 Micrococcus luteus A
TCC 9341 Staphylococcus aure
us ) IFO 12732 Staphylococcus epidermidis ( Staphylococcu
s epidermidis ) IFO 12993 Gram-negative bacterium Escherichia coli I
FO 12734 Klebsiella pneumoniae (Klebsiella pneumonia
e ) IFO 3318 Enterobacter cloaca
e ) IFO 12937 Proteus vulgaris I
FO 3988 Pseudomonas aeruginosa (Pseudomonas aerugi
nosa ) IFO 13275 Mold Aspergillus niger I
FO 9455 Trichophyton Mentaglophytes
mentagrophytes ) IFO 5809 Yeast Candida albicans I
FO 1594 Test Concentration 100 mg / ml (10%) in agar medium was used as the highest concentration, and the pH was measured after adding 2-fold dilution to 10-stage medium (pH test paper on agar medium).

[Results] Ascorbic acid monolithium salt at 5%, Bacillus cereus, Pseudomonas aeruginosa, Trichophyton mentaglophytes, Micrococcus luteus, Stachylococcus epidermidis and Candida albicans at 10%. In addition, Aspergillus niger was prevented from developing. No growth inhibition was observed for other microorganisms even at 10%. On the other hand, for lithium carbonate, 0.125% was Aspergillus niger, and 0.25% was Bacillus subtilis, Bacillus cereus, Micrococcus luteus,
Stahirococcus epidermidis, Escherichia
Kori and Klebsiella Pneumonier were even better.
Staphylococcus aureus, Enterobacter cloake, Proteus vulgaris, Pseudomonas erginosa, Trichophyton mentaglofites and Candida albicans were stunted in 5%.
That is, ascorbic acid monolithium salt had far less effect on microbial growth than lithium carbonate.

Test Example 7 Analgesic effect of ascorbic acid monolithium salt obtained in Reference Example 1 [Method] 100 mg / kg of ascorbic acid monolithium salt obtained in Reference Example 1 was orally administered to 3 mice per group. Then 1
Phenylquinone 2 mg / kg was intraperitoneally administered after the lapse of time. Then, the grunting symptoms of the mice were observed for 5 to 10 minutes. [Results] A 40% inhibitory effect was observed as compared with the control group.

Test Example 8 Platelet Aggregation Inhibitory Action of Ascorbic Acid Monolithium Salt Obtained in Reference Example 1 [Method] Rabbit platelet-rich plasma was treated with 100 μg / ml of the ascorbic acid monolithium salt obtained in Reference Example 1. The adenosine diphosphate was added at a concentration of 0.4 μg / ml, and the platelet aggregation action was observed. [Results] A 32% inhibitory effect was observed.

Test Example 9 Leukotriene D ₄ antagonism (antiallergic action) of the ascorbic acid monolithium salt obtained in Reference Example 1 [Method] Atropine, diphenhydramine, indomethacin each at a concentration of 1 μg / ml physiological saline (37 ° C.) Inside, the isolated guinea pig ileum was suspended. Leukotriene D in the liquid
₄ 10 ng / μl and 3 μg / ml of the ascorbic acid monolithium salt obtained in Reference Example 1 were added, and the submaximal contraction reaction was observed. [Results] A 26% inhibitory effect was observed. From this, it is found that ascorbic acid monolithium salt has an antiallergic action.

Test Example 10 Sedative action of ascorbic acid-2-phosphate monolithium salt obtained in Reference Example 2 [Method] The ascorbic acid-2-phosphate monolithium salt obtained in Reference Example 2 was added per 1 kg of mouse. A test solution was prepared by dissolving it in physiological saline so as to have a concentration of 2.5 mmol / 5 ml. 5 Crj: C ₃ H / He female mice (11 weeks old) were intraperitoneally administered with 5 ml / kg (corresponding to 655 mg / kg of ascorbic acid-2-phosphate monolithium salt) of the above test solution. Was administered. As in the above, physiological saline alone was administered at 5 ml / kg to serve as a control. [Results] A sedative effect was not observed in the control group, but a sedative effect was observed in the administration of the test solution immediately after administration to 20 minutes after the administration.

Test Example 11 Toxicity of ascorbic acid-2-phosphate monolithium salt obtained in Reference Example 2 [Method] Ascorbic acid-2-phosphate monolithium salt obtained in Reference Example 2 in 3 mice per group Lithium salt 100 mg / kg was orally administered or 50 mg / kg was intraperitoneally administered and observed for 72 hours. [Results] No abnormal findings were observed in any of the administration groups.

[0033]

Industrial Applicability According to the present invention, there is provided an agent for improving / treating emotional disorders, which comprises a lithium salt of ascorbic acid or a lithium salt of ascorbic acid-2-phosphate. The affective disorder improving / therapeutic agent can be safely administered, and the affective disorder can be remarkably remarkably improved and treated in a short time without side effects.

Claims (3)

[Claims] 1. An agent for improving or treating an emotional disorder, which comprises a lithium salt of ascorbic acid or a lithium salt of ascorbic acid-2-phosphate. 2. The agent for improving / treating emotional disorders according to claim 1, which contains a lithium salt of ascorbic acid. 3. The agent for improving / treating emotional disorders according to claim 1, which comprises a lithium salt of ascorbic acid-2-phosphate.