JPH0987180A - Antiallergic agent containing phosphoric acid diester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antiallergic agent having low toxicity and excellent safety by using a specific phosphoric acid diester compound (salt) as a component. SOLUTION: A phosphoric acid diester compound (salt) of the formula (R1 and R2 are each H or methyl) is used as a component of the objective agent. The compound is properly compounded with additives such as excipient, binder, disintegrant, dispersing agent, resorption promoter, buffering agent, surfactant, dissolution assistant, preservative, isotonizing agent, stabilizer and pH modifier and administered at a daily rate of 1-100 mg for adult in one dose in the case of injection or 10-1,000 mg per dose in several doses a day for adult in the case of oral administration. In the case of using the agent as an eye lotion, it is applied to the eye at a concentration of 0.01-0.5 (W/V)% at a rate of several drops at a time and several times a day.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a useful antiallergic agent. More specifically, the present invention relates to a useful antiallergic agent containing a phosphodiester compound of ascorbic acid and tocopherol or a pharmacologically acceptable salt thereof.

[0002]

The phosphoric acid diester compound used in the anti-allergic agent of the present invention is an anti-cataract agent, a prophylactic / therapeutic agent for menopausal disorders, and a cosmetic product having a beautiful skin effect (Japanese Patent Publication No. 2-444).
78), antioxidants (JP-A-63-139972),
Anti-ulcer agent (JP-A-63-270626), anti-inflammatory agent (JP-B1-27044, JP-B-5-23274)
No.), a preventive / therapeutic agent for ischemic organ damage (Japanese Patent Laid-Open No. 2-111)
No. 722) and a Maillard reaction inhibitor (JP-A-3-1).
Various applications such as No. 61444) are already known.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have further searched for the drug efficacy of this phosphodiester and found that it is also useful as an antiallergic agent. The present invention
It has been completed based on this new knowledge.

The present invention provides an excellent antiallergic agent containing a phosphodiester compound or a pharmacologically acceptable salt thereof.

[0005]

That is, the present invention provides the following formula:

[0006]

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[In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a methyl group. ] The phosphoric acid diester compound represented by these or its pharmacologically acceptable salt (henceforth "this compound") is contained, and it relates to the antiallergic agent.

This compound is known to have various medicinal effects as described above, but it is not yet known to have an antiallergic effect.

The present compound used in the antiallergic agent of the present invention is, for example, Japanese Patent Publication No. 2-44478 or Japanese Patent Publication No.
It can be appropriately synthesized according to the method described in Japanese Patent No. 23274 or in accordance with these.

The present compound used in the antiallergic agent of the present invention, whether it is a free compound or a pharmacologically acceptable salt thereof, can be appropriately used for the purpose of the present invention. . As the pharmacologically acceptable salt,
Examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and any salt other than these may be used as long as it is a pharmacologically acceptable salt. Even if it is a thing, it can be used suitably.

The antiallergic agent of the present invention may contain one kind or two or more kinds of the present compounds in an appropriate combination depending on the purpose and need.

The present compound used as an active ingredient in the antiallergic agent of the present invention has extremely low toxicity and excellent safety, and therefore can be advantageously used for the purpose of the present invention [for example, L-ascorbic acid. , DL-α-tocopherol phosphate diester potassium (hereinafter EPC-
It is abbreviated as K. ₅₀ ): Oral administration: 5 g / kg (rat), intravenous injection: 100 mg / kg (rat) or more].

Examples of the allergic disease treated by the antiallergic agent of the present invention include bronchial asthma, hay fever, allergic rhinitis, dietary allergic gastritis, allergic diarrhea, ulcerative colitis, stomatitis, nodular arteries. Peritonitis, obstructive arterial endocarditis, endocarditis, atopic dermatitis, urticaria, eczema, contact dermatitis, fricten, sympathetic ophthalmitis, allergic conjunctivitis and allergic keratitis.

The antiallergic agent of the present invention is appropriately used orally or parenterally for the treatment of the above-mentioned various allergic diseases. As the form of the preparation,
For example, any of solid preparations such as tablets, granules, powders and capsules or liquid preparations such as injections, syrups, eye drops and nasal drops can be appropriately prepared by a known method. For these preparations, commonly used excipients, binders, disintegrants, dispersants, reabsorption promoters, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilizers and pH
Various additives such as a regulator may be appropriately used.

When the compound is used as an anti-allergic agent, the dose varies depending on the kind of the compound used, the kind of target disease, the age and weight of the patient, the indication, and the dosage form thereof. In the case of an agent, it is preferable to administer about 1 to 100 mg once a day for an adult, and in the case of an oral agent, it is preferable to administer a dose of about 10 to 1000 mg once a day for an adult. When used as an eye drop, the concentration is about 0.01
It is advisable to instill about (w / v)% to 0.5 (w / v)% once a few times and several times a day. Further, in the case of an ointment, it is preferable that the ointment contains about 1 to 10 (w / w)%.

The antiallergic agent of the present invention includes other antiallergic agents and / or other antiallergic agents unless they do not defeat the purpose of the present invention.
Alternatively, it may contain a component which exerts another kind of medicinal effect.

[0017]

The present invention will be described in more detail below with reference to Examples and Formulation Examples.

[Example 1] The present compound for palpebral conjunctival edema
Effect of substances Compound which is a free substance of histamine
The effect of the present compound on the eyelid conjunctival edema induced by 48/80 (condensation product of formaldehyde and N-methyl-p-methoxyphenethylamine) (manufactured by Sigma) was tested.

Test substance : 0.1% L-ascorbic acid, DL-α-tocopherol sodium phosphate diester (abbreviation: EPC-N)
a) (pH adjusted to 7.0 after dissolution in physiological saline) 0.1% diphenhydramine hydrochloride (antihistamine)
(Dissolved in physiological saline)

Test method : SD male rats weighing about 180 g were used.

Rats were divided into three groups, a control group, an EPC-Na administration group, and a diphenhydramine hydrochloride administration group, each of which was 0.0
20% of 08% compound 48/80 (dissolved in physiological saline) was injected under the conjunctiva of both eyelids to induce palpebral conjunctival edema. A physiological saline solution was used for the control group, 5 μl of each test substance for the EPC-Na administration group and the diphenhydramine hydrochloride administration group, 2 hours, 1 hour, 0.5 hours before the eyelid injection and 0.5 hours before the eyelid injection. , 1.5 hours and 2.5 hours later, eye drops were applied. 4 hours after compound 48/80 injection (1.5 hours after the final instillation), the rat was sacrificed, the edema generated in the eyelid was excised, the wet weight (mg) was measured, and it was suppressed to the control group. The rate (%) was calculated.

Test results : The results are shown in Table 1.

[Table 1] Effect group of this compound on eyelid conjunctival edema Group edema weight (mg) Suppression rate (%) Control group 114.4 ± 11.6-EPC-Na administration group 76.1 ± 11.6 ^* 33.5 Diphenhydramine hydrochloride administration group 63.2 ± 8.2 ^* 44.8 Each value Indicates the mean ± standard deviation (n = 8). Significantly different from control group ^* ; p <0.001.

As is clear from Table 1, in the EPC-Na administration group, the inhibition rate against eyelid conjunctival edema was 33.5% as compared with the control group. From the above results, it was found that the present compound is useful as an antiallergic agent.

Example 2 For Type III Allergic Conjunctivitis
Effect of the present compound on the effect of the present compound on type III allergic conjunctivitis was tested.

Test substance : 0.1% EPC-Na (dissolved in physiological saline) 0.15% dexamethasone sodium metasulfobenzoate (visualin ophthalmic solution: registered trademark, manufactured by Senju Pharmaceutical Co., Ltd.) (0.1% as dexamethasone, Hereinafter abbreviated as dexamethasone.)

Test method : Rats as control group, EPC-Na
The rats were divided into three groups, an administration group and a dexamethasone administration group, and 30 μl of rat anti-rabbit serum was injected under both eyelid conjunctiva. 5 μl of physiological saline for the control group, 5 μl of each substance for the test substance administration group, 2 hours and 1.5 hours for eyelid injection,
0.5 hours before and 0.5 hours, 1.5 hours after injection,
Eye drops were applied after 2.5 hours. The rats were sacrificed 0.5 hours after the final instillation, the wet weight (mg) of conjunctival edema was measured, and the inhibition rate (%) with respect to the control group was obtained.

Test results : The results are shown in Table 2.

[Table 2] Effect group of this compound on type III allergic conjunctivitis Group Edema weight (mg) Suppression rate (%) Control group 84.8 ± 6.9-EPC-Na administration group 57.4 ± 8.1 ^* 32.3 Dexamethasone administration group 58.2 ± 3.8 ^* 31.3 Each value Indicates the mean ± standard deviation (n = 4). Significantly different from control group ^* ; p <0.001.

As is clear from Table 2, the EPC-Na administration group and the dexamethasone administration group each significantly suppressed edema formation by about 30% as compared with the control group. From the above results, it was found that the present compound is useful as an antiallergic agent.

[Formulation Example 1] Oral tablet EPC-K 100 mg Lactose 75 mg Starch 20 mg Polyethylene glycol 6000 5 mg The above components are admixed by a conventional method to give one tablet.
A sugar coating may be added if necessary.

[Formulation Example 2] Injection EPC-K 200 mg Mannitol 5.0 g 1N-sodium hydroxide Appropriate amount distilled water Total amount 100 ml pH 6.5 The above components are mixed by a conventional method and sterile filtered. The filtrate is aseptically filled into glass ampoules in an amount of 5 ml each, and the mixture is sealed to obtain an injection.

[Formulation Example 3] Eye drops EPC-Na 0.1 g Boric acid 1.5 g Borax 0.3 g Methyl p-hydroxybenzoate 0.026 g Propyl p-oxybenzoate 0.014 g Sterilized purified water Total 100 ml The above ingredients are mixed by a conventional method to prepare an eye drop.

[Formulation Example 4] Ointment EPC-Na 5.0 g Glycerin 12.0 g Stearyl alcohol 25.0 g White petrolatum 25.0 g Methyl p-oxybenzoate 0.025 g Propyl p-oxybenzoate 0.015 g Sterilized Purified water Total amount 100 g The ingredients above are mixed by a conventional method to give an ointment.

[0033] The above components are mixed by a conventional method to obtain a gelling agent.

[0034] The above ingredients are mixed by a conventional method to give a syrup.

[0035]

The preparation of the present invention is useful as an antiallergic agent.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 31/665 ACJ A61K 31/665 ACJ ADA ADA

Claims (1)

[Claims] 1. The following formula: [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a methyl group. ] An anti-allergic agent comprising a phosphodiester compound represented by or a pharmaceutically acceptable salt thereof.