JP2002029970A - Cataplasm - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an indomethacin-formulated cataplasm in which the indomethacin has excellent stability. SOLUTION: This cataplasm obtained by dissolving the indomethacin in polyethylene glycol and then homogeneously dispersing the solution in a water- containing gel.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a patch excellent in storage stability of compounded indomethacin.

[0002]

2. Description of the Related Art At present, various anti-inflammatory analgesics are used as remedies for pain associated with stiff shoulders and muscle fatigue, bruises, sprains and the like. Among them, indomethacin, which is a nonsteroidal anti-inflammatory analgesic, is widely used not only as an oral preparation but also as a transdermal absorption type external preparation because of its excellent inhibitory action on prostaglandin synthesis. The topical formulation of indomethacin has a point that storage stability and the like must be improved, and is disclosed in JP-A-05-286856 and JP-A-05-2686.
55083, JP-A-05-271077, JP-A-05-27077
JP-A-5-286857, JP-A-08-113537, JP-A-10-158165 and the like have made various attempts to improve them. However, the storage stability of indomethacin cannot be said to be still sufficient because of its balance with transdermal absorption. Further, in order to improve the transdermal absorbability of indomethacin, indomethacin is dissolved in crotamiton and then added to the preparation.
However, indomethacin in a dissolved state lacks storage stability in a formulation. Therefore, development of a patch stably containing indomethacin and having good transdermal absorption has been awaited.

[0003]

The object of the present invention is to solve the above-mentioned problems, and an object of the present invention is to provide a preparation wherein indomethacin is stably retained in a patch without impairing transdermal absorbability. .

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, after dissolving indomethacin in polyethylene glycol, and dispersing the same in a hydrogel, the formulation was improved. Of indomethacin was stabilized, and a patch having good storage stability was obtained without impairing the transdermal absorbability of indomethacin. Thus, the present invention was completed. That is, the present invention provides, in a hydrogel, a patch prepared by dispersing indomethacin dissolved in polyethylene glycol, and a patch prepared by dissolving indomethacin in polyethylene glycol and dispersing it in a hydrogel. Regarding the manufacturing method.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The polyethylene glycol used for dissolving indomethacin according to the present invention includes polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1540, polyethylene glycol. 2000, polyethylene glycol 3400, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 80
00, polyethylene glycol 20000, etc., especially polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 40
0, polyethylene glycol 600 is preferred. The blending amount of polyethylene glycol in the hydrogel is 2 to 20% by weight, preferably 2.5 to 15% by weight. In other words, if the blending amount of polyethylene glycol in the hydrogel is less than 2% by weight, indomethacin is not sufficiently dissolved in the polyethylene glycol and it is difficult to uniformly disperse indomethacin in the hydrogel, so that indomethacin is stably applied. Cannot be retained in the drug. On the other hand, if the amount of polyethylene glycol in the hydrogel exceeds 20% by weight, a decrease in gel viscosity causes a deterioration in shape retention, making it difficult to mold as a patch.

The amount of water in the hydrogel is 30 to 60% by weight, preferably 35 to 55% by weight. That is, if the amount of water in the hydrogel is less than 30% by weight, the flexibility of the hydrogel is poor, and the spreadability on the support is poor. On the other hand, if the amount of water in the hydrogel is more than 60% by weight, the hydrogel becomes too soft and difficult to form as a patch. There are no particular restrictions on the components that make up the hydrogel, for example, water-soluble polymers, excipients,
A humectant, a stabilizer, a cross-linking agent, and the like can be added. Examples of the water-soluble polymer include gelatin, hydrolyzed gelatin, polyacrylic acid, polyacrylate, partially neutralized polyacrylic acid, starch polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, Methylcellulose, carmellose sodium, carboxyvinyl polymer, methoxyethylene maleic anhydride copolymer, N-vinylacetamide copolymer and the like can be used alone or in combination of two or more.
The compounding amount is 3 to 20% by weight, preferably 5 to 1%.
5% by weight.

As the excipient, for example, kaolin, titanium oxide, light anhydrous silicic acid, zinc oxide or the like can be used alone or in combination of two or more. The compounding amount is 0.5 to 10% by weight. As a moisturizer,
For example, concentrated glycerin, D-sorbitol, propylene glycol, dipropylene glycol, butylene glycol, pyrrolidone carboxylate and the like can be used alone or in combination of two or more. The amount is 15 to 45% by weight, preferably 20 to 35% by weight. If glycerin is blended, a further stabilizing effect can be obtained. As other stabilizers, those usually used as stabilizers of this type of preparation can be used, for example, edetate, paraoxybenzoate, tartaric acid, etc. can be used alone or in combination of two or more. .

As the cross-linking agent, for example, aluminum hydroxide, aluminum glycinate, dihydroxyaluminum aminoacetate, synthetic hydrotalcite, polyvalent metal compounds such as metal aluminate metasilicate, or the like may be used alone or in combination of two or more. Can be. Further, if necessary, an absorption promoter, a preservative, an antioxidant, a plasticizer, an emulsifier, a surfactant and the like can be added. Examples of the backing for the patch include porous materials such as polyethylene, polypropylene, polyvinyl chloride, polyester, nylon, and polyurethane, foams, woven fabrics, and nonwoven fabrics, as well as films or sheets and porous materials, foams, woven fabrics, and nonwoven fabrics. And the like can be used. As the plastic film for coating the plaster surface, polyethylene, polypropylene, polyester, or those obtained by releasing these with silicone can be used. The patch of the present invention can be produced by spreading the plaster for a patch composed of the above components on a support and covering the surface of the plaster with a plastic film.

[0009]

EXAMPLES The present invention will be described in detail with reference to the following Examples, but the scope of the present invention is not limited to the following Examples.

EXAMPLE 1 2.25 g of polyvinyl alcohol, 1.2 g of tartaric acid, 7
30 g of 0% D-sorbitol, 3 g of kaolin, 3 g of carmellose sodium, 5 g of partially neutralized polyacrylic acid,
Dihydroxyaluminum amino acetate 0.07
g, sodium edetate 0.1 g, polysorbate 80
An aqueous gel was prepared by uniformly mixing 0.3 g and an appropriate amount of purified water. Next, 10 g of polyethylene glycol 200
After dissolving 0.5 g of indomethacin in the mixture, the mixture was uniformly dispersed in the previously prepared hydrogel to obtain a plaster for a patch. The plaster was spread on a stretchable nonwoven fabric, and the plaster surface was covered with a polypropylene film to prepare a patch.

Example 2 2.25 g of polyvinyl alcohol, 1.2 g of tartaric acid, 7
0% D-sorbitol 20 g, kaolin 3 g, concentrated glycerin 20 g, carmellose sodium 3 g, partially neutralized polyacrylic acid 5 g, dihydroxyaluminum amino acetate 0.07 g, sodium edetate 0.1
g, 0.3 g of polysorbate 80 and an appropriate amount of purified water were uniformly mixed to prepare a hydrogel. Next, 0.5 g of indomethacin was added to 4.5 g of polyethylene glycol 200.
g and 0.15 g of p-hydroxybenzoate were dissolved and then dispersed uniformly in the previously prepared hydrogel to obtain a plaster for patch. The plaster was spread on a stretchable nonwoven fabric, and the plaster surface was covered with a polypropylene film to prepare a patch.

Example 3 Example 2 was repeated except that polyethylene glycol 200 in Example 2 was replaced with an equal amount of polyethylene glycol 400.
The same patch as the above component was prepared.

Example 4 Example 2 was repeated except that polyethylene glycol 200 of Example 2 was replaced with an equal amount of polyethylene glycol 600.
The same patch as the above component was prepared.

EXAMPLE 5 1.0 g of gelatin and 0.4 g of polyvinyl alcohol were added to 5
It was dissolved in 5.6 g of purified water heated to 0 ° C. This solution, 3 g of carmellose sodium, 5 g of partially neutralized polyacrylic acid, 23 g of concentrated glycerin, 0.3 g of hydroxypropylcellulose, 70% D-sorbitol 14
g, kaolin 3 g, titanium oxide 0.5 g, polyvinyl alcohol 2.74 g, metal metasilicate aluminate 0.1 g.
06 g, sodium edetate 0.1 g, and an appropriate amount of purified water were uniformly mixed to prepare a hydrogel. Next, 0.5 g of indomethacin was added to 4.5 g of polyethylene glycol 400.
After dissolving 0.25 g of g, l-menthol and 0.15 g of p-hydroxybenzoic acid ester, they were uniformly dispersed in the previously prepared hydrogel to obtain a plaster for a patch. The plaster was spread on a stretchable nonwoven fabric, and the plaster surface was covered with a polypropylene film to prepare a patch.

Comparative Example 1 A patch was prepared in the same manner as in Example 1 except that the polyethylene glycol 200 of Example 1 was replaced with an equal amount of crotamiton. The following tests were performed to clarify the effects of the present invention.

Test Example 1 The patches of Examples 1, 2, 3, 4, 5 and Comparative Example 1 were sealed in an aluminum bag as five bags, and then stored at 50 ° C. for one month. The indomethacin content in the patch was measured by high performance liquid chromatography (HPLC). Table 1 shows the results.

[0017]

[Table 1]

From the results shown in Table 1, the patches of Examples 1, 2, 3, 4, and 5 according to the present invention in which indomethacin was dissolved in polyethylene glycol and uniformly dispersed in a hydrogel were obtained under the above conditions. It was confirmed that the decrease in the content of indomethacin with time over time was suppressed and that it was stable in the patch.

Test Example 2 Using Example 4 and Comparative Example 1, an in vitro skin permeability test was performed. That is, the abdominal skin of a male Wistar rat was treated with the dermis side as the receptor layer side, and
It was mounted on a vertical diffusion cell (effective diffusion area 1.77 cm ² ) in which hot water of ° C. was circulated around the periphery. Phosphate buffer (pH 7.4) was used for the receptor layer. Each preparation was stuck on the stratum corneum side, sampling was performed with time, and the cumulative amount of indomethacin permeated through the skin was measured by HPLC. The result is shown in FIG. As shown in FIG. 1, the patch of Example 4 according to the present invention had the same amount of indomethacin accumulated permeation as Comparative Example 1, and good transdermal absorbability was observed. This allows
It can be seen that the patch of the present invention has percutaneous absorption equivalent to that of the indomethacin-dissolving patch.

[0020]

Industrial Applicability According to the present invention, indomethacin is dissolved in polyethylene glycol and uniformly dispersed in a hydrogel, whereby indomethacin can be stably compounded in the preparation. Thus, it has become possible to provide a patch having significantly improved stability over time of indomethacin.

[Brief description of the drawings]

FIG. 1 shows the results of indomethacin cumulative skin permeation amount of Example 4 and Comparative Example 1.

Claims (5)

[Claims] 1. A patch prepared by dispersing indomethacin dissolved in polyethylene glycol in a hydrogel. 2. The patch according to claim 1, wherein the amount of polyethylene glycol in the hydrogel is 2 to 20% by weight. 3. The water-containing gel has a water content of 30 to 60% by weight.
The patch according to claim 1, which is: 4. The patch according to claim 1, wherein the amount of polyethylene glycol in the hydrogel is 2 to 20% by weight and the amount of water is 30 to 60% by weight. 5. A method for producing a patch, comprising dissolving indomethacin in polyethylene glycol and then dispersing it in a hydrogel.