JPS61103826A - Anti-inflammatory agent - Google Patents

Abstract

PURPOSE:To provide an anti-inflammatory agent having anti-inflammatory, antipyretic and analgesic activity, and extremely high safety, and suitable especially as an agent for external application, by using a specific unsaturated fatty acid, unsaturated alcohol or its esterified product as an active component. CONSTITUTION:The objective anti-inflammatory agent is produced by using a 8-24C unsaturated fatty acid having 1-3 C=C double bonds (preferably linoleic acid or linolenic acid), an unsaturated alcohol (preferably linoleyl alco hol, linolenyl alcohol, etc.) or its ester (preferably methyl ester, ethyl ester, etc.) as an active component. An antioxidant (e.g. dl-alpha-tocopherol) may be added to the above agent to improve the anti-inflammatory effect of the above compound. An anti-inflammatory, antipyretic and analgesic effect can be attained by applying the agent as an oral drug, injection, ointment, suppository, etc. It has high safety and low irritation.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to anti-inflammatory agents.

[Conventional technology]

Anti-inflammatory drugs can be broadly divided into steroids, non-steroids,
It is classified into three types: anti-inflammatory enzymes, and the main non-steroidal drugs are 1, such as aspirin.

phenylbutacin, indometacin/, flufenamic acid,
Examples include mefenamic acid, ibufenac, aminopyrine, and the like. Hitherto, these have been commonly used as antipyretic, analgesic, and anti-inflammatory agents for oral administration. In addition, recently, isidomethacin has been used externally as an ointment, but the effect of external application is significantly lower than that of oral administration.

[Problem that the invention seeks to solve]

In general, non-steroidal drugs have significantly weak effects when used as active ingredients in topical anti-inflammatory drugs.

In addition, in terms of side effects, when administered orally, it has a strong irritating effect on the stomach and is prone to causing gastric ulcers. The development of a drug has been eagerly awaited.

[Means for solving problems]

As a result of extensive research into non-steroidal anti-inflammatory agents under such circumstances, the present inventor found that certain unsaturated fatty acids, unsaturated alcohols, or esters thereof have anti-inflammatory, moisturizing, and antibacterial effects.

They discovered that it has anti-ulcer effects and completed the present invention.

That is, the present invention provides an anti-inflammatory agent containing as an active ingredient an unsaturated fatty acid having 8 to 24 carbon atoms or an unsaturated alcohol having 1 to 3 carbon-carbon double bonds, or an ester thereof, and an antioxidant. The present invention provides an anti-inflammatory agent containing.

Examples of unsaturated fatty acids used in the present invention include oleic acid, linoleic acid, lylunic acid, eicosenoic acid,
Examples include eicosadienoic acid, eicosatrienoic acid, and acid anhydrides thereof, among which linoleic acid and lilunic acid are particularly preferred. In addition, as an esterified product of unsaturated fatty acids, 1
Examples include monoglycerides, diglycerides, triglycerides, and lower alcohol esters having 1 to 5 carbon atoms, such as linoleic acid methyl ester, linoleic acid ethyl ester, linoleic acid floyl ester, linoleic acid methyl ester, and safflower oil.
Among these, methyl ester and ethyl ester are particularly preferred.

□ Used as a suitable unsaturated fatty acid in the present invention
Linoleic acid and linolenic acid can be obtained by known methods such as hydrolysis and fractionation of natural triglycerides. Moreover, linoleic acid monoglyceride and linoleic acid monoglyceride may be α-monoglyceride or β-monoglyceride, and natural monoglyceride can be fractionated and esterified.

It can be obtained by known methods such as transesterification or partial hydrolysis of triglycerides and diglycerides.

Furthermore, suitable examples of the unsaturated alcohol include oleyl alcohol, lylyl alcohol, lylunyl alcohol, and the like, with lylyl alcohol being particularly preferable.

Historically, the anti-inflammatory agent of the present invention may contain an antioxidant in order to improve its effectiveness. Antioxidants are generally found in cosmetics and quasi-drugs.

Commonly used in pharmaceuticals, etc. - alpha-tocopherol, nordihydroguaceretic acid, butylated hydroxyanisole, dibutylated hydroxytoluene, propyl gallate, erythorbic acid, sodium erythorbate, with antioxidant ability. Examples include crude drug extracts.

Examples of herbal medicines from which extracts of herbal medicines with antioxidant properties can be obtained include allspice and anise.

Hasil, caraway, cardamom, cinnamon
, clove (Cho), coriander (late W).

Fennel, garlic, ginger (main)
, Sansho, Pei Leaps, Mustard.

Nutmeg, onion, parsley.

Pepper, saffron, rosemary, salvia, thyme,
Turmeric, vanilla, paprika.

Examples include cloves, sesame, yokuinin, saiko, huangren, schisandra, gobaiko, koboku, dog huang, yamakaei, and peonypi.
Among these, rosemary, salvia, allspice, paprika, sesame, and thyme are preferred.

The antioxidant substance is 0.01 to 10 I to the anti-inflammatory agent of the present invention.
It is preferable to mix t% (hereinafter referred to as H).

The anti-inflammatory agent of the present invention can be administered orally, by injection (intravenously, subcutaneously, yV
J Meat), external administration, suppositories, and other methods, and can be used in various forms depending on the method of administration. Among these, administration as an external preparation is most preferred.

In the case of oral administration, the anti-inflammatory agent of the present invention can be used in either a solid preparation or a liquid preparation. Examples of solid preparations include tablets, granules, powders, capsules, and sugar-coated agents. These solid preparations contain saccharides commonly used in formulations.

Excipients such as cellulose; binders such as starch paste and methyl cellulose; additives such as fillers and disintegrants can be blended. Oral liquid preparations can be in the form of internal solutions, suspensions, emulsions, syrups, and the like. The dose for oral administration may be adjusted depending on symptoms, age, dosage form, etc., but for example, for adults, the dose should be 0.1 to 1.
000~/kg is preferred.

In the case of injection 1. The anti-inflammatory agent of the present invention is used in the form of an aqueous solution, suspension, oil-based or water-soluble emulsion, among others,
It is preferable to use it by dissolving it in an aqueous liquid medium such as sterile water or physiological saline. Furthermore.

If necessary, solubilizers, stabilizers, preservatives, tonicity agents, etc. commonly used in injection solutions can be added.

Injectable solutions are administered by intravenous injection, intramuscular injection, subcutaneous injection, or the like. Dosage depends on symptoms.

The dosage may be adjusted as appropriate depending on age, dosage form, administration method, etc.

For example, when injecting adults, it is 0.01 to 10,100 per day.
A range of O/kg is preferred.

For external use, the anti-inflammatory agent of the present invention can be used in various forms, such as lotions and emulsions.

Preferably, the composition is in the form of a cream, ointment, stick, solution dissolved in an organic solvent, pack, gel, or the like. These external preparations include oily substances, humectants, thickeners, preservatives, and emulsifiers when formulated.

Medicinal ingredients, fragrances, emulsion stabilizers, etc. can be used in combination. As the emulsifier, it is preferable to use a nonionic surfactant or a fatty acid salt alone or in combination. Suitable nonionic surfactants include, for example, sorbitan monostearate, glycerin monopalmitate, instearyl glyceryl ether, etc., and preferable fatty acid salts include, for example, sodium, potassium, and triethanolamine salts of stearic acid. Among them, instearyl glyceryl ether is particularly preferred since it enhances the effect of the anti-inflammatory agent of the present invention. The external preparation can further contain other anti-inflammatory agents, various plant extracts, etc. to promote the anti-inflammatory effect.

When the anti-inflammatory agent of the present invention is used externally.

In addition to its anti-moxibustion effect, it also has an inhibitory effect on insensitivity.

This effect is thought to be caused not by mere occlusion of the epidermis, but by its incorporation into the phospholipids constituting the epidermis.

For example, in the case of adults, the external preparation may contain unsaturated fatty acids or unsaturated alcohols and/or esterified products thereof.
What is necessary is just to apply an appropriate amount of i to 10% locally at the appropriate time to the relevant area.

When used as a suppository 1 In addition to the suppository base, the anti-inflammatory agent of the present invention may optionally contain an oily substance, an emulsifier, a medicinal ingredient,
You can use emulsion stabilizers, etc. Furthermore,
By adding other anti-inflammatory agents, various natural product extracts, etc., the anti-inflammatory effect can be improved and it can be used as a therapeutic agent for hemorrhoids.

In an acute toxicity test using ICR mice, the unsaturated fatty acids, unsaturated alcohols, and esters thereof used in the present invention were found to cause no deaths even when administered orally at 2t/'kl (maximum administrable dose). It is not recognized and is highly safe.

[Effect]

Next, the results of testing the pharmacological effects of the anti-inflammatory agent of the present invention will be shown.

(11 Effect on rat paw edema (test method) Male SD rats (5 weeks old) weighing 120-150? were used in groups of 10. Before applying the drug (Table 1), The volume taken was measured.Next.

A weight of 10 (1-) was dropped onto the footwork from a height of 1 m to give an inflammatory stimulus, and the drug was immediately applied.
After a period of time, the foot size of the tomb was measured, and the edema rate was calculated using the formula below. The results are shown in Table 1.

Table 1 Note) The value in parentheses indicates the ethanol solution concentration.

(2) Moisturizing effect (Test method) A group of 10 male and female SD rats, 5 weeks old, were used.

After hair removal on the back, 0.25M sodium dodecyl sulfate (S
DS) for 30 minutes, and before and after that, insensitive vaporization (TEW)
L) i was measured. Next, the following cream containing linoleic acid or a control cream containing no linoleic acid was applied to the hair removal site, and TEWL was measured 60 minutes later. The results are shown in Table 2.

Cream formula; Linoleic acid 0 or 10% Vaseline 6N rubitan sesquiolate 2 liquid lanolin
4isopropyl palmitate
8 Squalane 10 Solid paraffin 4 Glycerin 3 Purified water Balance Table 2 [Effects of the invention] As mentioned above, 1. The anti-inflammatory agent of the present invention can be administered orally, by injection, applied to the skin, as a suppository, etc. anti-inflammatory 1w4 fever,
It has desirable physical properties as an anti-inflammatory agent, such as exhibiting an analgesic effect, extremely high safety, and little irritation.

〔Example〕

Next, the present invention will be explained with reference to Examples. I Example 1 10 ml of linoleic acid was dissolved in 1 ml of physiological saline.

Make a solution using aseptic techniques, filter, and seal in ampoules.

After sterilization, an injection was produced.

Example 2 50 Da of linuric acid was thoroughly mixed with crystalline cellulose 630 In 9° carboxymethylcellulose sodium salt and sacrificed to produce tablets.

Example 3 ■Linoleic acid monoglyceride 1.
0 parts by weight ■ Prednisolone 0.0
5■ Ethyl aminobenzoate 1.0■
Tori Mido
0
．． 1 ■ Egg yolk lecithin 5.0 total 1
00 ■～■ were heated at 60°C and mixed well.

1. Formulate into a 5y-sized suppository manufacturing mold.

Example 4 ■ Rilunic acid monoglyceride 1.0
0 parts by weight ■Hydrocortisone 0.0
5■ Acetate shun-tocopherol i,
o.

■ Allantoin 1.00 ■ Ethyl aminobenzoate 1.5゜ ■ Isocacao (same as Example 3) Balance meter 100 Heat ■～■ at 60℃, mix well, and mold for producing ly-suppositories. Formulated at.

Example 5 ■ Vaseline 10.0 parts by weight ■ Lanolin 4.5 ■ Inglobil myristate 5.0 ■ Stearyl alcohol 5.0 ■ Liquid paraffin 4.5 ■ Benzoic acid propyl ester 0.1 ■ Sorbitan monostearate 2. 0 ■ Glycerol monostearate z.

■Polyoxyethylene sorbitan monostearate 1.5■
Benzoic acid methyl ester 0.10 Methyl linoleate 1.00 Semen water
Balance meter 100 ■Heat at Q170'C and stir gently.
Gradually add and emulsify ① to ①0, which were also heated to 70°C. Next, this is cooled to make a hemorrhoid ointment.

Example 6 Bath agent: Anhydrous sodium sulfate 29 Parts by weight Sodium hydrogen carbonate 55 Succinic acid 15 Linoleic acid 1 Color Pigment Appropriate amount Fragrance
A suitable amount of tablets having the above composition were manufactured. The pH of the 0.01% aqueous solution was 6.1.

Example 7 Glycerin 4.0 Parts by weight Ethyl linoleate 1.0 Polyoxyethylene hydrogenated castor oil 1.5 Ethanol
10.0 Sodium pyrrolidone carboxylate 2.0 Fragrance Trace amount ioo.

Example 8 W10 cream type anti-inflammatory agent: Ethyl linoleate 1.0 Tisetanol 0.5 Vaseline
6.0n rubitan sesquiolate
2.0 cholesterol
0.6 Liquid lanolin 4.0 Isopropyl palmitate 8.0 Squalane 10゜0 Solid paraffin
4.0 Butylparaben
0.1 Methylparaben 0.1 Glycerin 3.0 Fragrance
0.2 Purified water Balance Example 9 0/W cream type anti-inflammatory agent nistearic acid 2. Oes Propyl Linoleate 1.0 Cetanol 4.0 Vaseline
5.0 Squala/8.0 Hardened palm oil 4.0 Polyoxyethylene sorbitan monostearate (20E, 01 1.4
Lipophilic glyceryl monostearate 2. ．． 4
Butylparaben 0.1 Methylparaben 0.1 Glycerin
3.0 diglopyrene glycol
3. OL-Arginine 10.0 Potassium hydroxide 0.2 Purified water
Balance Example 10 Ointment-type anti-inflammatory agent: Propyl lylunate 1.0-white petrolatum 99.0 Example 11 Liquid-type anti-inflammatory agent; Butyl linoleate 1.0-thiethanol 99.0 Example 12 Toothpaste: Linoleic acid 1.0% dicalcium phosphate dihydrate 50.0 sorbitol
10.0 Glycerin 1
0.0 Sodium lauryl sulfate 2.0 Carboxymethyl cellulose 1.0 Fragrance
1.0 Ginger oleoresin 0.2 Sodium monofluorophosphate 0.3 Ethanol 2.0 Saccharin
0.1 Mutanase 0.
1 water balance meter 100 or more

Claims (1)

[Claims] 1, 8 to 8 carbon atoms having 1 to 3 carbon-carbon double bonds
An anti-inflammatory agent containing 24 unsaturated fatty acids, unsaturated alcohols, or esters thereof as active ingredients. 2.8 to 8 carbon atoms with 1 to 3 carbon-carbon double bonds
An anti-inflammatory agent containing 24 unsaturated fatty acids or unsaturated alcohols or their esters and antioxidants.