JPS646168B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a central nervous system antipyretic and analgesic agent containing aminobenzoic acid or its salts having the following general formula as an active ingredient. The present inventor has discovered that aminobenzoic acid or its salts represented by the following general formula (hereinafter referred to as the present substance) exhibits antipyretic and analgesic effects on the central nervous system, while the present substance has low toxicity, low antibacterial activity, and mutagenicity. The present inventors have found that the drug does not exhibit any of the following: therefore, it can be administered for a long period of time and has pharmaceutical suitability, leading to the present invention. (Including salts thereof) Therefore, an object of the present invention is to provide a drug having antipyretic and analgesic effects on the central nervous system, which can be administered over a long period of time, especially orally. The present invention will be explained in detail below. The active ingredient of the present invention is an aminobenzoic acid having the above general formula or a pharmaceutically acceptable inorganic salt of a metal, such as a salt of Al, Cu, alkali metal, alkaline earth metal (such as Na, K, Mg, Ca, etc.). It is. These salts are prepared by common methods known to those skilled in the art. The active ingredient of the present invention is p-aminobenzoic acid, o-
Includes aminobenzoic acid, m-aminobenzoic acid, or their respective salts. However, among these substances, Na salts of the above-mentioned aminobenzoic acids are particularly preferred from the viewpoint of medicinal efficacy and safety. Next, the toxicological and pharmacological properties of this substance will be explained in order. (1) Acute toxicity Acute toxicity was investigated using ICR-JCL mice by various routes of administration. For oral administration, the substance was dissolved in distilled water, and for other administrations, the substance was dissolved in physiological saline and adjusted to a predetermined amount using a stomach probe or syringe. After administration, the symptoms of toxicity were continued to be observed, the mortality rate over time was determined for up to 7 days, and the LD ₅₀ value was determined. Survival cases,
In both cases of death, autopsies were performed to obtain findings. LD ₅₀ values are Litchfield
Wilcoxon) calculation method. The results are shown in Table 1. From the above results, it can be seen that high LD ₅₀ was exhibited in all cases, and therefore, this substance can be safely applied as a medicine.

[Table] (2) Mutagenicity Mutagenicity was investigated using the following method. Using a recombinant repair-deficient strain (Bacillus subtilis M45) and a recombinant repair-carrying strain (Bacillus subtilis H17), use a small pipette to prepare a B-agar medium (10 g of meat extract, 10 g of polypeptone, 5 g of NaCl, 15 g of agar, 1000 ml of distilled water,
PH7.0) and streaked the starting points so that they did not touch. This substance was dissolved in sterile water, and 0.04 ml of the solution was used to stain a paper circle with a diameter of 8 cm, placed so as to cover the starting point of the streak, and after culturing overnight at 37°C, the length of the zone of growth inhibition was measured. Kanamycin was used as a negative control, and mitomycin was used as a positive control. The results are shown in Table 2. It can be seen from Table 2 below that this substance does not exhibit mutagenicity. This shows that this substance is not carcinogenic even when used continuously over a long period of time, and can be said to be extremely safe.

【table】

[Table] (3) Central nervous system depressant effect (a) Analgesic effect Mechanical stimulation method (pressure stimulation method) Takagi, Kameyama et al.'s pressure stimulation device (manufactured by Natsume Seisakusho) was used. The test animals used were ICR-JCL mice (♀).
Apply pressure to the ridge of the mouse until the pain threshold is 50-80mm
Those showing Hg were selected and each group consisted of 10 animals. After oral administration of the sample, measurements were performed over time, and the analgesic effect was determined based on the pressure and time (seconds) required until the test animal showed a pseudo-escape response. Chemical stimulation method ICR-JCL mice, 1 group of 5-6 week old (♀)
Thirty minutes after oral administration of the sample, 0.6% acetic acid solution was added to 10 mice according to the method of Koster et al (1959).
Injected intraperitoneally per ml/10g mouse body weight, and further 10
After 10 minutes, the number of writings that occurred in the mice was counted, and the inhibition rate (%) relative to the control group was determined using the following formula. (1-T/C)×100=IR (%) T: Average number of writings in the administration group C: Average number of writings in the control group The results are shown in Table 3.

[Table] (b) Antipyretic effect According to the method of Winter et al (1961), a suspension of 20% brewer's yeast was administered subcutaneously to 6 rats per group, and after fasting for 19 hours, each sample was administered orally. The rectal temperature was measured, and the fever suppression rate relative to the body temperature of the control fever rat at the peak of the effect of the sample was determined from the following formula. C ₁ - T / C ₁ - C ₂ × 100 = IR (%) T: Average body temperature of the administration group C ₁ : Average body temperature of rats with fever C ₂ : Average body temperature of control untreated rats The results are shown in Table 4.

[Table] As can be understood from the above test results, this substance can be usefully applied as a central nervous system antipyretic analgesic. Next, formulation for applying this substance as the above-mentioned therapeutic agent will be explained. This substance can be applied in various forms when used as a central nervous system antipyretic analgesic. In addition, this substance is
It can be used alone or in admixture with pharmaceutically acceptable diluents and other agents. The substances can also be applied orally or parenterally and may take any form suitable for their administration. Additionally, the substance can be presented in dosage unit form, including powders, granules, tablets, dragees, capsules, suppositories, suspensions, solutions, emulsions, ampoules, etc., provided they contain an effective dosage.
It can take various forms such as an injection solution. It should therefore be understood that the medicament of the present invention can be prepared by applying any conventionally known formulation means. The content of the substance (active ingredient) in the drug of the present invention can be adjusted within a wide range of 0.01 to 100%, preferably 0.1 to 70% (by weight). As mentioned above, the drug of the present invention is administered orally or parenterally to humans and animals, with oral administration being particularly preferred. In this case, oral administration also includes sublingual administration, and parenteral administration includes subcutaneous, intramuscular, intravenous, etc. injections and infusions. The dosage of the drug of the present invention depends on whether the subject is an animal or a human, and is influenced by age, individual differences, medical conditions, etc. In some cases, doses outside the range shown below may be administered, but in general, the drug is administered to humans. In this case, the oral dosage of this substance is 0.1 to 500 per kg body weight per day.
mg, preferably 1 to 250 mg, and the parenteral dosage is 0.01 to 30 mg per day, preferably 1 kg body weight.
Administer 0.1 to 10 mg in 1 to 4 divided doses. Specific examples of formulation of the drug of the present invention are shown below as examples. Parts in the examples indicate weight unless otherwise specified. Example 1 10 parts of sodium p-aminobenzoate, 15 parts of heavy magnesium oxide, and 75 parts of lactose are uniformly mixed to make a powder or fine granules. Also, this powder is put into a capsule container to form a capsule. Example 2 o-Aminobenzoic acid 45 parts Starch 15 parts Lactose 16 parts Crystalline cellulose 21 parts Polyvinyl alcohol 3 parts Water 30 parts were uniformly mixed and kneaded, then pulverized and granulated, dried,
It is sieved and made into granules. Example 3 4 parts of calcium stearate was added to 96 parts of the granules obtained in Example 2, and the mixture was compressed to form tablets with a diameter of 10 mm. Example 4 Granules were prepared in the same manner as in Example 2 using 94 parts of para-aminobenzoic acid, 6 parts of polyvinyl alcohol, and 30 parts of water. 10 parts of crystalline cellulose is added to 90 parts of the obtained granules and compressed to form tablets with a diameter of 8 mm. Syrup, gelatin, and precipitated calcium carbonate are added to the tablets to form sugar-coated tablets. Example 5 0.6 parts of sodium p-aminobenzoate, 2.4 parts of nonionic surfactant, and 97 parts of physiological saline are added, mixed, and sterilized to prepare an injection. Example 6 This example shows a method for preparing sodium p-aminobenzoate. 1 containing p-aminobenzoic acid and an equivalent amount of NaOH
% aqueous solution, the solution was filtered, and the resulting solution was concentrated under reduced pressure, rapidly washed with excess ether, and further dried under reduced pressure. The yield is
It was 95%. The ultraviolet absorption of the resulting aqueous solution of sodium p-aminobenzoate was measured.
The absorption maximum was obtained at 288 mμ. The infrared absorption spectrum is shown in FIG. 1 of the attached drawings.

[Brief explanation of drawings]

Figure 1 of the accompanying drawings shows the infrared absorption spectrum of sodium p-aminobenzoate.

Claims (1)

[Claims] 1. General formula An antipyretic analgesic for the central nervous system, characterized in that the active ingredient is aminobenzoic acid or a salt thereof. 2. The central nervous system antipyretic analgesic agent according to claim 1, wherein the salt is a sodium salt.