JPH11199482A - External preparation composition - Google Patents

Abstract

(57) [Problem] To provide an external preparation composition excellent in storage stability of indomethacin even in the presence of an oily drug such as vitamin E. SOLUTION: By mixing monohydric or dihydric alcohol having 3 or more carbon atoms and water, indomethacin in the external preparation is maintained in α-form crystal even in the presence of an oily drug,
An α-indomethacin-containing external preparation composition having improved storage stability is prepared.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an indomethacin-containing external preparation composition containing an oily drug represented by vitamin E and the like, which has excellent storage stability of indomethacin.

[0002]

2. Description of the Related Art Various anti-inflammatory analgesics have been used as remedies for extrinsic disorders such as bruises and sprains, and for body pain associated with muscle fatigue and stiff shoulders. Among them, compared with salicylic acid and methyl salicylate, which are conventionally widely used,
The use of antiphlogistic analgesics such as anthranilic acids, phenylacetic acids, indole, propionic acids, pyrazolones, benzothiazines and sulfonamides having higher anti-inflammatory analgesic effects is increasing.

Among them, many external preparations containing indomethacin, which is an indole compound, have been developed. Indomethacin is a compound having several crystal forms. The crystal forms include α-type, β-type and γ-type. Among them, γ-type is the most stable crystal type, and α-type crystal is known to be metastable.

[0004] In general, when a drug is transdermally administered, it is difficult to be absorbed transdermally unless the drug is in a dissolved state. For this reason, even in external preparations containing indomethacin, indomethacin is added in a dissolved state from the viewpoint of promoting percutaneous absorption.

[0005]

The external preparation containing indomethacin often contains other drugs at the same time.
In particular, it is highly necessary to blend vitamin Es as blood circulation promoters, benzyl nicotinate, and oily drugs such as menthol as anti-inflammatory agents. However, the present inventors have found that the storage stability of indomethacin decreases when these oily drugs are present in an external preparation together with indomethacin. Therefore, the present invention makes it possible to provide an external preparation composition excellent in storage stability of indomethacin while simultaneously mixing an oily drug represented by vitamin E and the like.

[0006]

Means for Solving the Problems The inventors of the present invention have found that by blending a monohydric or dihydric alcohol having 3 or more carbon atoms and water, an external application containing an oily drug and having excellent storage stability of indomethacin is provided. It has been found that an agent composition is prepared, and the present invention has been completed.

[0007] That is, the present invention provides an oily drug having 3 carbon atoms.
An external preparation containing α-type crystal indomethacin, comprising the above monohydric or dihydric alcohol and water.

The present inventors have studied the external use of indomethacin, and found that the metastable α-type crystal is more stable than the most stable type γ-type crystal when incorporated into an external preparation. And found to be advantageous in terms of efficacy.

[0009] Based on the above findings, a study was made on a formulation technique for maintaining indomethacin in an α-type crystal in the presence of an oily drug. In addition, it was revealed that indomethacin in an external preparation can be maintained in an α-form crystal even in the presence of an oily drug, and that an external preparation composition having improved storage stability can be prepared.

The oily drugs used in the present invention include tocopherol and tocopherol acetate which are blood circulation promoters,
Benzyl nicotinate; menthol, an anti-inflammatory agent; and the like.

The monohydric or dihydric alcohol having 3 or more carbon atoms used in the present invention includes propylene glycol, butylene glycol, polyethylene glycols, oleyl alcohol and the like.
The use of 3-butylene glycol is preferred.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The amount of indomethacin in the present invention may be the amount contained in a usual external preparation composition, for example, 0.1 to 5% by weight, particularly 0.1% by weight in the composition (in a plaster). 3 to 3% by weight is preferred.

The blending amount of the oily drug can be arbitrarily set according to the purpose of the blending. However, in order to exert the effect of the present invention significantly, a monohydric or dihydric alcohol having 3 or more carbon atoms is required. It is effective to adjust the weight ratio of the oily drug. For example, an oily drug and a monovalent or bivalent compound having 3 or more carbon atoms
It is preferable that the weight ratio of the alcohol to the alcohol is 1: 2 to 1:30, particularly 1:10 to 1:20. Here, if the amount of the oleaginous drug exceeds the above ratio, the storage stability of indomethacin cannot be sufficiently maintained.
In addition, the pH of the composition for external use of the present invention is adjusted to pH 3.5 to 6.0 in view of the stability of the compounded drug and skin irritation.
Is more preferable, and the range of pH 4.0 to 5.0 is more preferable.

The composition for external use containing α-type indomethacin of the present invention is prepared by mixing water, indomethacin, an oily drug and a monohydric or dihydric alcohol having 3 or more carbon atoms under an appropriate method under the above-mentioned conditions. Can be prepared. For example, an alcohol solution in which vitamin E and a monohydric or dihydric alcohol having 3 or more carbon atoms are added in the above-mentioned weight ratio, and indomethacin is further added, and an aqueous solution in which purified water or another drug is dissolved are added. It can be prepared by mixing. At this time, the mixing (weight) ratio of the alcohol solution to the purified water or the aqueous solution in which another drug is dissolved is preferably from 1: 9 to 2: 3.

The final dosage form of the composition for external use of the present invention includes creams, gels, patches and the like.
These can be produced by a usual method as described in Japanese Pharmacopoeia and the like.

[0016]

EFFECTS OF THE INVENTION The external preparation composition of the present invention maintains indomethacin in an external preparation in an α-form crystal and suppresses conversion to another crystal form over time, so that indomethacin can be stably produced over a long period of time. An external preparation that can be stored can be provided.

[0017]

The present invention will be described in more detail with reference to the following examples.

<Example 1> Gel (component) blending amount (g) indomethacin 0.5 vitamin E acetate 1.0 polyethylene glycol monostearate 5.0 diisopropyl adipate 3.0 1,3-butylene glycol 8. 0 Polyvinylpyrrolidone 0.5 Carboxyvinyl polymer 4.0 Diisopropanolamine Appropriate amount Purified water Total 100.0 g For the above components, a gel for external use was produced by a conventional method for producing a gel. It was confirmed by a polarizing microscope and an infrared spectrophotometer that the gel preparation contained α-type crystal indomethacin.

Example 2 Patch (Component) Compounding Amount (g) Indomethacin 0.5 Vitamin E Acetate 0.5 Polyoxyethylene Sorbitan Monooleate 1.0 Propylene Glycol 5.0 Polyacrylic Acid 7.0 Polyacrylic Acid Sodium 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 L-Menthol 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Appropriate amount Purified water Total 100.0 g For the above components, a patch for external use is manufactured by a conventional method for manufacturing a patch. did. It was confirmed by a polarizing microscope and an infrared spectrophotometer that the patch contained α-type crystal indomethacin.

Example 3 Patch (Component) Compounding Amount (g) Indomethacin 1.0 Vitamin E Acetate 1.0 Polyoxyethylene Sorbitan Monooleate 1.0 1,3-butylene glycol 4.0 Polyacrylic acid 7. 0 Sodium polyacrylate 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Appropriate amount Purified water Total 100.0 g For the above components, an external patch was produced by a conventional method of patch production. It was confirmed by a polarizing microscope and an infrared spectrophotometer that the patch contained α-type crystal indomethacin.

Example 4 Patch (Component) Compounding Amount (g) Indomethacin 0.5 Vitamin E 0.5 Polyoxyethylene Sorbitan Monooleate 1.0 1,3-butylene glycol 5.0 Polyethylene glycol 400 5.0 Polyacrylic acid 7.0 Sodium polyacrylate 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Appropriate amount Purified water Total 100.0 g For the above components, external application is carried out by a conventional method for the production of a patch. An agent was manufactured. It was confirmed by a polarizing microscope and an infrared spectrophotometer that the patch contained α-type crystal indomethacin.

Comparative Example 1 In Example 3, 1,3-
A patch was prepared by replacing butylene glycol with an equal amount of glycerol (a trihydric alcohol having 3 carbon atoms).

Comparative Example 2 A patch was prepared in the same manner as in Example 3 except that butylene glycol 1,3- was replaced with an equal amount of crotamiton (a non-alcoholic solvent).

<Test Example 1> Example 3 and Comparative Examples 1 and 2
Of 5 preparations in one bag, 8 under the condition of 40 ° C. and 75% RH.
After storing for a month, the stability (remaining amount) of indomethacin in the plaster was evaluated using a high performance liquid chromatograph. Table 1 shows the results.

[0025]

[Table 1]

It can be seen that the patch of Example 3 containing indomethacin as α-form crystals maintains the stability of indomethacin even under the above conditions.

Claims (2)

[Claims] 1. An external preparation containing α-type crystal indomethacin, comprising an oily drug, a monohydric or dihydric alcohol having 3 or more carbon atoms, and water. 2. An external preparation composition containing α-crystal indomethacin, characterized by mixing water and a suspension obtained by adding indomethacin and an oily drug to a monohydric or dihydric alcohol having 3 or more carbon atoms. Method of manufacturing a product.