JPS62209016A - Antiallergic agent - Google Patents

Abstract

PURPOSE:A remedy for sneeze, pituita, cough, hay fever, etc., accompanied with respiratory inflammation such as bronchial asthma, allergic rhinitis, vasomotor rhinitis, acute rhinitis, cold, etc., containing oleic acid, salt or ester thereof as an active ingredient. CONSTITUTION:The aimed antiallergic agent containing oleic acid, salt or ester thereof as an active ingredient, which is orally or parenterally administered to humans or mammals. The dose is preferably about 90-120mg free oleic acid per day for a human adult in case of oral administration. An effective amount of oleic acid, etc., is used with a carrier or diluent.

Description

[Detailed description of the invention] field of invention The present invention relates to a novel antiallergic agent.

BACKGROUND OF THE INVENTION Various anti-allergic agents have been developed for the treatment of allergic diseases, but as the mechanisms of allergic reactions that cause allergic diseases have been elucidated, it has become easier to treat allergies directly, rather than symptomatically. There is a growing desire for the development of antiallergic agents that suppress reactions.

While investigating the pharmacological effects of certain crude drug ingredients, the present inventors unexpectedly discovered that oleic acid suppresses allergic reactions.
In particular, it has been found that it is extremely effective in suppressing histamine release reactions from mast cells due to antigen-antibody reactions, and is useful as an anti-allergic agent that directly suppresses allergic reactions.

Disclosure of the Invention The present invention provides an anti-allergic agent containing oleic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient.

Although oleic acid is a well-known fatty acid, no literature has been found that suggests that it exerts an excellent effect on suppressing allergic reactions.

In the present invention, this oleic acid is used as an active ingredient of an antiallergic agent, that is, as an antiallergic active ingredient. Oleic acid is available in the free acid form and in various pharmaceutically acceptable salts obtained by known methods, e.g.
It may be used in the form of salts such as alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as calcium and magnesium salts, or esters such as methyl, ethyl, propyl, benzyl, etc. .

As is known, oleic acid is also a food component, and its toxicity is very low (for example, L D s by intravenous injection in mice, value 230 u/&9), and it can be suitably used as a medicine.

Thus, the antiallergic agent of the present invention can be prepared by combining effective insect oleic acid or a pharmaceutically acceptable salt or ester thereof with a pharmaceutically acceptable carrier or diluent, such as an excipient, a binder, Disintegrants, lubricants, solvents,
Dosage forms for oral or parenteral administration, such as tablets, powders, granules, capsules, aerosols, syrups, injections, nasal sprays, in combination with tonicity agents, emulsifiers, suspending agents, and stabilizers. , ointments, creams, emulsions, lotions, etc. Preferably 1 to 1203 as free oleic acid
It is in dosage unit form containing IIF.

The antiallergic agent of the present invention can be used to treat allergic diseases, such as bronchial asthma, allergic rhinitis, vasomotor rhinitis, acute rhinitis, and sneezing, nasal discharge, and cough associated with upper respiratory infections such as the common cold.
It is administered orally or parenterally to humans or mammals for the treatment of hay fever, etc. The appropriate dosage for oral administration is about 90 to 120 xy of free oleic acid per molar of an adult human.

Example Next, the present invention will be explained in more detail with reference to Examples.

Example I Ingredients Parts by weight Oleic acid 30 Calcium phosphate 490 Crystalline cellulose
350 carboxymethyl cellulose
120 Magnesium Stearate
IO These ingredients are thoroughly mixed and an antiallergic tablet for oral administration is obtained by direct compression.

Example 2 Ingredients Parts by weight Oleic acid 380 Lactose
480 polyvinylpyrrolidone
45 hydroxypropyl cellulose
95 Using these ingredients, antiallergic granules for oral administration are obtained by wet granulation according to a conventional method.

Example 3 Ingredients Parts by weight Oleic acid 20 Beeswax
100 paraffin wax
60 lanolin
30 isopropyl myristate
60 Squalane 80 Liquid paraffin 250 Polyoxyethylene sorbitan monostearate 18 Propylene glycol 50 Borax
7 water
325 Using these ingredients, an antiallergic ointment is obtained according to a conventional method.

Example 4 Ingredients Parts by weight Oleic acid 50 Stearic acid
20 cetanol
5 lanolin
20 isopropyl myristate
20 squalane 30 liquid paraffin 80 polyoxyethylene cetyl ether t7 triethanolamine 10 glycerin
40 Fragrances and Preservatives
Adjust the appropriate amount of water to 1000 parts. Using these ingredients, obtain an anti-allergic emulsion according to a conventional method.

Example 5 Ingredients Parts by weight Oleic acid I Polyoxyethylene sorbitan monooleate (20EO) 1 Distilled water for injection Adjusted to 100 parts Using these ingredients, an antiallergic injection solution is obtained according to a conventional method.

Effects of the Invention In order to examine the antiallergic activity of oleic acid, the following tests were conducted.

(1) Test for suppressing histamine release from mast cells After killing male Wistar rats with body type 2509 by bleeding, intraperitoneally injected with physiological buffer solution (NaCI2
154mM, KCC2, 7mM5CaC12*0°9m
M, glucose 5.6mM 1HEPES 5mM.

pH 7.4, hereinafter referred to as PS) lOi (2) was injected and the abdomen was gently massaged for about 90 seconds, followed by laparotomy and the intraperitoneal cell fluid was collected. After centrifugation for 5 minutes, the resulting cell pellet was washed twice with PS. After washing, it was resuspended in fresh PS5xQ and mast cells were purified with >95% purity by Percall density gradient centrifugation. The purified mast cells were purified with P at a concentration of 4 x to' cells/1!Q.
Suspended in S, 50 μe was added to a test tube containing PSl and 6xQ.
Dispensed in portions.

1mM of oleic acid in a 0.25% sodium carboxymethyl cellulose (hereinafter referred to as CMC-Na) aqueous solution.
A suspension was prepared, subjected to ultrasonic treatment for 10 minutes under water cooling, and then diluted to a predetermined oleic acid concentration with a 0.25% CMC-Na aqueous solution to prepare a specimen suspension.

After adding 0.2 ml of the sample suspension to the test tube containing the above mast cell suspension and holding it at 37°C for 15 minutes, Compound 4 B/, which is known as a compound that has the effect of releasing histamine from mast cells, Solution 0 of 80 (manufactured by Wellcome), 2112 (final concentration 0.35)
μ9/xQ′) was added and further incubated at 37° C. for 10 minutes. Then, the reaction is stopped by cooling with water,
The mixture was centrifuged at 200×g for 10 minutes at 4° C., and the supernatant and cell pellet were separated.

0.8N perchloric acid 1xQ was added to the supernatant LxQ to prepare a sample for the optimum amount of free histamine. On the other hand, Ser Beret has 0
．． Add 4N perchloric acid 4112, heat in a boiling water bath for 10 minutes to completely release histamine remaining in the cells, centrifuge at 200x9 for 10 minutes, and remove the supernatant 2x.
Q was used as a sample for quantifying the amount of residual histamine. The amount of histamine in each sample was measured by a fluorescence method, and the histamine release rate was calculated from the following formula.

Similarly, the release rate of histamine was calculated using only oleic acid without adding Compound 48/80.

Compound 48/80 at various oleic acid concentrations
The histamine release rates with and without addition are shown in the attached Figure 1. Figure 1 shows the histamine release rate (%) on the vertical axis.
and a graph in which the oleic acid concentration (μM) is plotted on the horizontal axis, ◯ indicates the case where Compound 48/80 was added, and ◯ indicates the case where Compound 48/80 was not added.

As is clear from FIG. 1, oleic acid exhibits almost complete suppression of the histamine-releasing effect by the addition of compound 48/80 at concentrations of 108 M or higher.

(2) Histamine release inhibition test from the lungs of sensitized guinea pigs
0 cells/ic) and subcutaneously injected into male Hartley guinea pigs weighing 350-4009 to sensitize them. Two weeks after sensitization, the guinea pigs were bled to death and the lungs were removed. Tyrod (Tyr)
ode) After washing well with buffer, cut into pieces using a delicate cutter for about 1 m.
It was cut into n+3 pieces. The small piece 20019 was suspended in a test tube containing 1,9 x Q of Tyrode's buffer,
After incubation at 37°C for 5 minutes, the antigen ovalbumin solution (final concentration 50 μ9/xQ) 0 ,
lxQ was added and incubated for an additional 20 minutes.

The reaction was stopped by cooling the test tube with water, and the tube was centrifuged at 400×9 at 4° C. for 10 minutes to separate the supernatant and tissue pieces. 0.5 ml of 0.8 N perchloric acid was added to the supernatants of 0 and 5 MQ and mixed to prepare a sample for quantifying the amount of free histamine. On the other hand, add 0.4N perchloric acid 411Q to the tissue piece from which the supernatant has been completely removed.
was added, homogenized with Polytron, centrifuged at +000Xil for 10 minutes,
The obtained supernatant 2xQ was used as a sample for quantifying the amount of histamine remaining in the tissue. Histamine in each sample was determined by a fluorescence method, and the histamine release rate was calculated in the same manner as in Test (1) above.

Oleic acid is suspended in physiological saline and subjected to ultrasonication for 10 minutes under water cooling. Sensitized guinea pigs fasted for 8 hours were dosed orally at a concentration of 50+g/9 1 hour before hemorrhagic lethality. Similarly, physiological saline alone was orally administered to the control group.

The histamine release rates of the oleic acid administration group and the control group are shown in the attached Figure 2.

As is clear from FIG. 2, the histamine release rate in the oleic acid-administered group was much lower than that in the control group, indicating that oleic acid suppresses histamine release.

[Brief explanation of drawings]

FIG. 1 and FIG. 2 are graphs each showing the effect of oleic acid on inhibiting histamine release. Figure 1 Oleic acid concentrated N (, IJM)

Claims (1)

[Claims] (1) An anti-allergic agent characterized by containing oleic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient.