JPS62270524A - Anti-inflammatory analgesic for external use - Google Patents

Abstract

PURPOSE:To obtain the titled drug for external use, containing active components in stably dissolved state and having excellent transcutaneous absorbability and low skin irritation, by using indomethacin having excellent anti- inflammatory, analgesic and antipyretic effect as an active component and combining the component with a small amount of a specific solvent. CONSTITUTION:Indomethacin [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3- acetic acid] is dissolved in a mixture of polyethylene glycol lauryl ether, crotamiton and benzyl alcohol and the obtained solution is used as a component of the objective agent. The amount of indomethacin is about 0.1-10wt%, preferably about 0.5-2wt%. The content of the solvent is preferably 0.5-5wt% polyethylene glycol lauryl ether, 0.5-5wt% crotamiton and 0.5-5wt% benzyl alcohol in view of the solubility of indomethacin, feeling and skin irritation of the agent, etc.

Description

Detailed Description of the Invention 3. Detailed Description of the Invention [Field of Industrial Application] The present invention uses indomethacin [1-(p-chlorobenzoyl 15-methoxy-2-methylindole-3-acetic acid)] as an active ingredient. The present invention relates to an anti-inflammatory and analgesic external preparation containing the following.

[Conventional technology]

Indomethacin is widely used in clinical settings as a non-steroidal anti-inflammatory analgesic with excellent anti-inflammatory analgesic and antipyretic effects.

Indomethacin is currently used in the form of capsules or waste tablets, but when administered in these forms, there is a problem in that it exhibits various side effects including gastrointestinal disorders.

Therefore, in order to reduce such side effects, external preparations such as gel ointments, solutions, creams, and ointments have recently been developed, and some of them are already in use for treatment. These external preparations are gel ointments containing indomethacin, glycols such as propylene glycol, butylene glycol, and polyethylene glycol, lower alcohols, water, and gelling agents (Japanese Patent Publication No. 10886/1986).

Indomethacin is blended with polyalkylene glycol and polyethylene glycol C1o-Cl4 alkyl ether (Japanese Patent Publication No. 6 (>24764)). Indomethacin is blended with fatty acid polyethylene glycol ester, glycols, lower alcohols, and carboxyvinyl polymer, and p[ 1 adjusted to 4.5 to 6.2 (Japanese Patent Publication No. 56-51.410). Crotamiton, fatty acid polyethylene glycol ester, glycols, lower alcohol and/or acetone, water and carboxyvinyl polymer are added to indomethacin. Mix 9 parts and adjust the pH to 4.5 to 6.2 using a sub-tube.
6414). Indomethacin mixed with water-soluble cellulose ether, polyacrylic acid whose carboxyl group has been neutralized with a water-soluble amine, water, ethanol, or Impropatol (Japanese Patent Application Laid-Open No. 60-48921). Indomethacin was dissolved in a compound represented by the general formula RO-(C2[1,0)(c31+6o), where R represents an alkyl group or a hydrogen atom, and m and n represent O to 300]. Things (JP-A-61-2201.
Publication No. 1) etc. are publicly known.

Further, as a liquid preparation, indomethacin is blended with a lower alcohol and/or acetone, glycols and/or their esters (Japanese Patent Application Laid-Open No. 56-36411).

Indomethacin mixed with alcohols and fatty acid esters (Japanese Unexamined Patent Publication No. 57-1.28623).

Indomethacin with lower alcohol and/or acetone,
Those containing crotamiton, glycols and/or their esters (Japanese Unexamined Patent Publication No. 124.716/1983) are known.

Indomethacin may also be used as an ointment or cream.
An ointment containing a release improving agent selected from alcohols, polyhydric alcohols, fatty acid esters, surfactants, essential oils, and crotamiton (Japanese Patent Application Laid-Open No. 5'1-98209)
. A gel cream containing indomethacin, a higher fatty acid ester, an emulsifier, crotamiton, a gelling agent, a water-soluble basic substance, and water (Japanese Patent Application Laid-Open No. 185511/1983).

A cream containing indomethacin, crotamiton, a nonionic surfactant, a water-soluble polymer compound, and water (Japanese Patent Application Laid-open No. 11621.2/1983) is also known.

[Problem that the invention seeks to solve]

Indomethacin is difficult to dissolve in various solvents used in external preparations such as ointments and creams, and therefore it is extremely difficult to dissolve and preserve it uniformly in preparations. Crystallization may occur.

Furthermore, the stability of the solvent depends on the selection of the solvent, so the solvents that can be used are quite limited.

The various inventions mentioned above have been made to solve this problem.

However, many of the above-mentioned known techniques incorporate a large amount of glycols, typified by propylene glycol, as a solvent. However, for some time now, propylene glycol has not been considered preferable for use on the skin, and furthermore, since glycols are water-soluble, the use of oil-soluble base components has been limited. Furthermore, indomethacin that uses solvents other than glycols has insufficient solubility and crystals tend to precipitate, and a large amount of solvent must be added to achieve sufficient dissolution, resulting in high skin irritation. There was a tendency to Further, when using only volatile solvents such as alcohol, there are problems in that even when applied to the skin, the solvent is lost before it penetrates and crystals precipitate, making it impossible to fully exert the effect.

The present invention solves these problems of topical indomethacin, and stabilizes indomethacin in the base ingredient by using as little solvent as possible in combination without using glycols that have an adverse effect on the skin. The object of the present invention is to provide an anti-inflammatory and analgesic external preparation that is soluble in the skin, has excellent transdermal absorption, is less irritating to the skin, and can use a wide range of base components.

[Failure to solve the problem]

As a result of intensive research to achieve the above object, the present inventor found that by combining polyethylene glycol lauryl ethyl with crotamiton and benzyl alcohol, the solubility of indomethacin was improved. It has been found that an anti-inflammatory and analgesic topical preparation can be obtained in which indomethacin is stably dissolved in the base component, has excellent transdermal absorption, and has little skin irritation.

The present invention is an anti-inflammatory and analgesic external preparation prepared by dissolving indomethacin in a mixture of polyethylene glycol lauryl ether, crotamiton and benzyl alcohol.

Indomethacin [1-(p-chlorobenzoyl 15-methoxy-2-methylindole-3-
Acetic acid] is a nonsteroidal compound that has excellent anti-inflammatory, analgesic, and antipyretic effects.

The content of indomethacin in the external preparation of the present invention is not particularly limited as long as it exhibits its pharmacological effect, but is about 0.1
-10% by weight, preferably about 0.5-2% by weight.

The contents of polyethylene glycol lauryl ether, crotamiton (N-crotonyl-N-ethyl-〇-toluidine), and benzyl alcohol used in the present invention are not particularly limited, but the solubility of indomethacin and the feeling of use of the external preparation of the present invention are not particularly limited. , 0.5 to 5% by weight of polyethylene glycol lauryl ether due to skin irritation, etc., and 0.5% by weight of crotamiton.
It is preferable to set it as 5-5 weight% and benzyl alcohol 0.5-5 weight%.

Moreover, it is preferable that the average molecular weight of the polyethylene glycol lauryl ether used in the present invention is 340 to 610. In addition, when the average molecular weight is 340 or less, skin irritation becomes high, and when it is 610 or more, it is solid,
This is not preferred because it is difficult to dissolve and mix.

To obtain the external preparation of the present invention, indomethacin, which is an active ingredient, is dissolved in a mixture of polyethylene glycol lauryl ether, crotamiton, and hbenzyl alcohol, and prepared into an external preparation such as a gel ointment, liquid, or spray by a conventional method. be able to.

If necessary, stabilizers such as thiosulfate, IJium, etc., p++ regulators, absorption promoters, etc. can be added.

When preparing a gel ointment, indomethacin is dissolved in a mixture of polyethylene glycol lauryl ether, crotamiton and benzyl alcohol, and if necessary, a higher fatty acid ester such as diisopropyl adipate is added as an absorption enhancer and mixed. Prepare the active ingredient phase. Separately, a polymer compound such as carboxyvinyl polymer as a thickener is added to the above mixture and stirred to swell. Further, if necessary, an antioxidant such as thiosulfate, IJum, etc. is added as a stabilizer and dissolved.

The previously prepared active ingredient phase is mixed with this while stirring,
Furthermore, a water-soluble base such as diisopropanolamine dissolved in purified water as a neutralizing agent is mixed with stirring to obtain a uniform gel-like ointment.

When preparing a liquid formulation, prepare the active ingredient phase in the same manner as above,
If necessary, purified water in which an antioxidant such as sodium thiosulfate is dissolved as a stabilizer and a lower alcohol such as ethanol are added and mixed to obtain a uniform solution.

Furthermore, a spray agent can be obtained by filling a non-gas spray container with this liquid agent.

In addition to the above explanation, external bases, stabilizers, and other additives known in the art can be appropriately selected and used. Moreover, the preparation conditions for the external preparation can also be appropriately selected and prepared.

The results of a stability test, a transdermal absorption test, and a skin irritation test of the anti-inflammatory and analgesic external preparation of the present invention are shown.

[A) Stability Test After production, the presence or absence of crystal precipitation of indomethacin under each storage condition was observed. Storage conditions include room temperature (11-25℃)
) and in a cold place (5°C) were used. The results are shown in Table 1, where - indicates no crystal precipitation, 10 indicates crystal precipitation, and the number of days in parentheses indicates the number of days after production until crystal precipitation was observed.

Table 1 In Examples 1 and 2 of the present invention and Comparative Example 12, no indomethacin crystals were formed after 3 months of storage under both room temperature and cold storage conditions.

CB] Percutaneous absorption test A group of 5 male Wistar rats weighing approximately 240 g were used, and the ventral region with pricked hair was 3 x 4.5 cm.
Apply 40 mg of each test drug to the area of i with a glass spatula, and measure the blood concentration of indomethacin 2.4.8 hours later (C, C-ECD: detection limit 1 ng/mI?') I
,Ta. The results are shown in Table 2.

Table 2 As is clear from the above table, the external preparation of the present invention showed a blood concentration of indomethacin that was approximately 2 to 3 times higher than that of the comparative example, and was found to have excellent transdermal absorption.

[CI Skin Irritation Test A patch test (open) was conducted on 25 adult male volunteers. 0.2 g of each test drug was rubbed on the back of the volunteer for 30 seconds, allowed to air dry, and
4. Skin irritation was determined at 48 hours according to Japanese standards. The results are shown in Table 3.

Table 3 As is clear from the above table, the external preparation of the present invention was found to have lower skin irritation than the comparative example.

The comparative examples shown below were used for comparison of the external preparation of the present invention in each of the above-mentioned tests.

Comparative Example 1 A gel ointment containing 1% indomethacin was prepared by removing polyethylene glycol lauryl ether from the formulation of Example 1.

Comparative Example 2 A gel ointment containing 1% indomethacin was prepared by removing crotamiton from the formulation of Example 1.

Comparative Example 3 A gel ointment containing 72271% India was prepared by removing benzyl alcohol from the formulation of Example 1.

Comparative Example 4 A gel ointment containing 1% indomethacin was prepared using 10.0 g of propylene glycol in place of polyethylene glycol lauryl ether, crotamiton and hbenzyl alcohol in the formulation of Example 1.

Comparison Example 5 Propylene glycol 10. A gel ointment containing 1% indomethacin prepared using Og.

Comparative Example 6 Polyethylene glycol 400.10,0 instead of crotamiton and benzyl alcohol in the formulation of Example 1
A gel ointment containing 1% indomethacin prepared using g.

Comparative Example 7 A liquid preparation containing 1% indomethacin was prepared by removing polyethylene glycol lauryl ether from the formulation of Example 2.

Comparative Example 8 A liquid preparation containing 1% indomethacin was prepared by removing crotamiton from the formulation of Example 2.

Comparative Example 9 A liquid preparation containing 1% indomethacin prepared by removing benzyl alcohol from the formulation of Example 2.

a Comparative Example 10 Propylene glycol 15. instead of polyethylene glycol lauryl ether, crotamiton and hbenzyl alcohol in the formulation of Example 2. A liquid preparation containing 1% indomethacin prepared using Og.

Comparative Example 11 Propylene glycol 15. instead of polyethylene glycol lauryl ether and benzyl alcohol in the formulation of Example 2. Indomethacin 1 prepared using Og
% containing liquid.

Comparative Example 12 Butylene glycol 15. instead of polyethylene glycol lauryl ether and benzyl alcohol in the formulation of Example 2. Indomethacin 1% prepared using Og
Containing liquid.

〔Example〕

Examples of the present invention will be shown below and will be described in more detail, but the present invention is not limited to these examples and various modifications are possible.

■b Example 1 (gel ointment) Polyethylene glycol lauryl ether (N manufactured by Nippon Surfactant Industries Co., Ltd.) was added to 1.0 g of indomethacin.
IKKOL BL-9EX>2.0g, crotamiton 3.0g, benzyl alcohol 1.5'g and diisopropyl adipate 2.0g were added and dissolved, and the mixture (I
) was prepared.

Separately, add 1.0 g of diisopropanolamine to 10 g of purified water,
0 g to prepare a mixture (II).

Carboxyvinyl polymer (Hibis Wako-104N manufactured by Wako Pure Chemical Industries, Ltd., 5 g to 40.0 g of ethanol)
and 38.0 g of purified water, stirred to expand, added mixture (I) and stirred until homogeneous, then added mixture (II> and stirred to form a homogeneous gel-like mixture. It was made into an ointment.

Example 2 (Liquid) 1.0 g of indomethacin, 3.0 g of polyethylene glycol lauryl ether, and 3.0 g of crotamiton. A mixture (1) was prepared by adding and dissolving Og and 2.5 g of benzyl alcohol.

Add 50ml of ethanol to mixture (1) and mix, then add 30.0g of purified water and ethanol to make a total of 110ml.
The volume was adjusted to 0 ml to obtain a uniform solution.

Example 3 (Spray agent) The liquid agent obtained in Example 2 was filled into a non-gas spray container to prepare a spray agent.

〔Effect of the invention〕

The present invention is an anti-inflammatory and analgesic external preparation that stably dissolves indomethacin, which is difficult to dissolve, in a base component of an external preparation, has excellent percutaneous absorption, and has low skin irritation.

Claims (2)

[Claims] (1) An anti-inflammatory and analgesic external preparation containing a solution of indomethacin dissolved in a mixture of polyethylene glycol lauryl ether, crotamiton and benzyl alcohol. (2) The anti-inflammatory and analgesic external preparation according to claim (1), which is in the form of a gel ointment, liquid, or spray.