JPH08113537A - Indomethacin application agent - Google Patents

Abstract

PURPOSE: To obtain an indomethacin application agent excellent in both percutaneous absorbability and stability with time of the medicine. CONSTITUTION: This indomethacin application agent contains indomethacin as a pharmacodynamically effective ingredient in an amount of 0.1-1.5wt.% based on the total amount of a cross-linked type hydrous gel base, crotamiton as a dissolvent for indomethacin at 0.5-2 weight ratio based thereon, an alkylpyrrolidone in an amount of 1-10 times based on the indomethacin and glycerol as a humectant in an amount of 10-20wt.% based on the total amount of the base in the base consisting essentially of a hydrous gel prepared by cross-linking a partially neutralized sodium polyacrylate, carboxyvinyl polymer and gelatin in the presence of water with aluminum.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an indomethacin patch,
More specifically, it relates to a patch containing indomethacin as a medicinal component in an aqueous base.

[0002]

BACKGROUND OF THE INVENTION Indomethacin is a non-steroidal anti-inflammatory drug with excellent anti-inflammatory and analgesic effects, and is widely used in the field of orthopedics for the treatment of osteoarthritis, periarthritis of the shoulder, myalgia, etc. , Oral administration has side effects such as gastrointestinal disorders and loss of appetite. Therefore, in recent years, in order to prevent these side effects, liquid preparations, ointments, patches and the like containing indomethacin have been developed as transdermal absorption preparations.

However, in the case of a percutaneous absorption preparation, indomethacin is difficult to be dissolved in water or an oily solvent, so that it is difficult to dissolve it in a base material, and there is a problem that it is significantly decomposed with time. In order to solve these problems, conventionally, as a means for dissolving indomethacin, a method of dissolving indomethacin in menthol and glycerin (Japanese Patent Publication No. 1-24129).
No.), phenyl-substituted alkanol and polysorbate 8
0 (Japanese Patent Publication No. 3-31686), a method of dissolving in crotamiton (JP-A-4-82828), polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether and polyoxyethylene alkyl ether. -A method of dissolving in one or more of the telluric acid esters (Japanese Patent Publication No. 5-30807) and the like have been proposed.

As a method of further stabilizing indomethacin, a method of stabilizing indomethacin by containing indomethacin in a suspension in a base (Japanese Patent Laid-Open No. 255083/1993)
No.), an ester of an aliphatic monocarboxylic acid or dicarboxylic acid having 6 to 20 carbon atoms and a monovalent or polyvalent alcohol having 2 to 20 carbon atoms, and a divalent alcohol having 2 to 20 carbon atoms.
Method, a method of blending one or more selected from the group consisting of hydrocarbons having 15 to 32 carbon atoms, fatty acids having 6 to 20 carbon atoms, higher alcohols having 10 to 20 carbon atoms, and vegetable oils (Japanese Patent Laid-Open No. Hei 5)
No. 286856) has been proposed. However, the ones that satisfy both the stability over time and the transdermal absorbability are
It has not appeared yet.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and while taking full advantage of the general advantages of a patch as a percutaneous absorption preparation, percutaneous absorption and stability over time. It is an object of the present invention to provide an excellent indomethacin patch.

[0006]

Means for Solving the Problems As a result of intensive studies for achieving the above-mentioned object, the present inventor has found that in an aqueous patch containing crotamiton as a dissolving agent for indomethacin and glycerin as a moisturizing agent, these two components are used. It was found that the stability of indomethacin deteriorates as the blending amount of is increased. However, a patch containing a combination of a fixed weight ratio of crotamiton and alkylpyrrolidone as a dissolving agent for indomethacin to a crosslinkable hydrous base and a fixed amount of glycerin as a moisturizer is a transdermal indomethacin. It was found that the absorbability and the stability over time were extremely excellent, and the present invention was completed.

That is, the present invention relates to a crosslinked hydrous gel such as a base mainly composed of a hydrous gel obtained by cross-linking a partially neutralized sodium polyacrylate, carboxyvinyl polymer and gelatin with aluminum in the presence of water. 0.1 to 1.5% by weight of the total amount of indomethacin as a medicinal component, and 0.5 to 2 times the weight ratio of indomethacin to crotamiton and 1 to 10 times the weight of alkylpyrrolidone of indomethacin as a medicinal ingredient. The indomethacin patch contains 10 to 20% by weight of glycerin as the humectant based on the total amount of the base.

In the present invention, indomethacin is contained in the patch in a state of being dissolved in the dissolving agent. The content of this indomethacin may be any amount as long as it exerts a medicinal effect by percutaneous absorption, and is 0.1 to 1.5% by weight of the total amount of the base.

In the present invention, oily crotamiton and water-soluble alkylpyrrolidone are used in combination as the indomethacin solubilizer. Although crotamiton is excellent as a dissolution agent for indomethacin, the stability of indomethacin deteriorates when the amount of indomethacin is large, and it has the property of discoloring over a long period of time, and it maintains a stable emulsified state in an aqueous base. Difficult. For this reason, it is desirable to limit the amount of crotamiton to the minimum possible amount. However, when the amount of crotamiton is about twice the amount of indomethacin or less, indomethacin is precipitated in the base and it is difficult to be transdermally absorbed.

On the other hand, alkylpyrrolidone is an excellent solubilizer that is soluble in both water and oil and can be stably retained in an aqueous base and easily dissolves indomethacin, but when water is added to the solution, it is compared. Indomethacin is easily deposited. Therefore, it is difficult to stably hold indomethacin in an aqueous patch by blending only alkylpyrrolidone.

However, when crotamiton and alkylpyrrolidone are used in combination, even if the amount of crotamiton is 0.5 times the amount of indomethacin, indomethacin in the base does not precipitate, resulting in excellent transdermal absorbability. Indicates
Moreover, indomethacin is extremely stable even when the amount of crotamiton is double that of indomethacin.

Therefore, in the present invention, crotamiton is blended in a weight ratio of 0.5 to 2 times that of indomethacin. Stabilization of indomethacin becomes worse when it is blended in excess of twice the weight of indomethacin, and indomethacin precipitates over time in the base even if it is blended with 10 times the amount of alkylpyrrolidone if it is less than 0.5 times. , It becomes difficult to percutaneously absorb.

As the alkylpyrrolidone, N-methyl-
One or two or more of 2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, and N-octylpyrrolidone are mixed in a weight ratio of 1 to 10 times that of indomethacin.
If the amount is more than 10 times, the effect is not affected, and if the amount is less than 1 time, indomethacin precipitates and the transdermal absorbability deteriorates.

The crosslinkable hydrogel base is a base obtained by crosslinking gelatin with dialdehyde starch, a base obtained by crosslinking an aliphatic carboxylic acid salt with a metal salt, and a base obtained by crosslinking a polyacrylic acid salt with a compound having an epoxy group. Agents and the like are known, and any of them can be used in the present invention. Particularly, a partially neutralized sodium polyacrylate, carboxyvinyl polymer and gelatin are crosslinked with aluminum in the presence of water to give a pH of 4. It is preferable to use a cross-linked hydrogel base mainly composed of 5 to 6 hydrogel.

The sodium polyacrylate partially neutralized product is
Acrylic acid is partially neutralized and polymerized to a degree of neutralization of 40
˜70%, the lower the degree of neutralization, the lower the pH of the aqueous solution, and the stronger the adhesive strength of the patch. When the degree of neutralization is 40%, the adhesive strength when used as a patch is very strong, but it is slightly insoluble in water. On the other hand, when the degree of neutralization is 70%, the adhesive strength is good, but the adhesive strength is slightly weak. Those having a degree of neutralization of 50% are particularly preferable in terms of solubility in water, reactivity with aluminum, and adhesive strength when applied to the skin. The compounding amount thereof is 2 to 8% by weight, preferably 4 to 6% by weight based on the total amount of the base. If it is less than 2% by weight, the shape retention is poor, and if it exceeds 8% by weight, the viscosity during the patch preparation process becomes too high and uniform kneading becomes difficult, and the desired patch base cannot be obtained. .

Since carboxyvinyl polymer is an acidic water-soluble polymer, it functions as a pH adjusting agent and, at the same time, dissolves in humectants such as glycerin and propylene glycol. It suppresses the separation from the product and improves the tackiness. Further, since carboxyvinyl polymer has a property of improving the fluidity of the patch immediately after preparation, when the patch is applied to the support during the production process, its plasterability is improved. The carboxyvinyl polymer is 0.5 to 3% by weight, preferably 1 to 2% by weight.
Is compounded.

Gelatin improves the lasting tackiness of the adhesive patch during application and, at the same time, has the property of gelling when cooled, so that it is effective for preventing the adhesive patch from squeezing out from the support during the preparation process. To work. Therefore, 1 to 5% by weight, preferably 2 to 3% by weight of gelatin is added. By virtue of its formulation, the patch can maintain the adhesive force that lasts for a long time from the time of application to the time of peeling. If the blending amount is less than 1% by weight, the above effect is not exhibited, and if it exceeds 5% by weight, the gelatin gel becomes too strong and the adhesive force on the surface of the patch is weakened. It may become sol and peel off before it exhibits the original adhesive strength of gelatin.

As the crosslinking agent, a sparingly water-soluble aluminum compound, preferably a sparingly water-soluble aluminum hydroxide gel is used. In the presence of water, partially neutralized sodium polyacrylate, carboxyvinyl polymer, and gelatin are added with a poorly water-soluble aluminum compound, and an acid acts,
Aluminum gradually elutes, and the eluted aluminum reacts with partially neutralized sodium polyacrylate, carboxyvinyl polymer and gelatin to form a homogeneous hydrogel. At that time, the plasterability in the case of applying the patch to the support during the production process by adjusting the crosslinking rate and the degree of crosslinking, water retention as the patch, adhesiveness, shape retention,
It is possible to form a base having excellent drug release properties.

The stability of indomethacin depends on the pH of the base material, and the stability becomes extremely poor in the strong acid or alkaline region. The carboxyvinyl polymer has a pH adjusting action, but if necessary, a pH adjusting agent such as lactic acid or tartaric acid is added to adjust the base pH to 4.5 to 6.

As the moisturizing agent to be added to the aqueous patch,
It is generally 10% by weight based on the total amount of the base because it has excellent moisturizing properties, adhesiveness after moisture release, stability over time, etc., and is also excellent as a dispersion medium for water-soluble polymer raw materials in the patch preparation process.
Although the above glycerin is used, glycerin is also blended as a moisturizer in the present invention. The composition of this glycerin is
Although the stability of indomethacin is usually deteriorated, indomethacin is stabilized by blending 0.5 to 2 times the weight of crotamiton and 1 to 10 times the weight of alkylpyrrolidone of indomethacin in the present invention. 10 to 20% by weight of glycerin can be added. If it exceeds 20% by weight, the stability of indomethacin is deteriorated, which is not preferable. Further, when the amount of glycerin blended is less than 10% by weight, it is necessary to blend a large amount of other humectant to secure the use quality such as adhesiveness and water retention, which is disadvantageous in manufacturing cost and workability. Become. As long as the glycerin in the above range is blended, there is no risk of causing problems in use quality such as moisturizing property and adhesiveness of the patch, but if necessary, propylene glycol, sorbite-
You may mix and mix moisturizing agents, such as ale, water candy, and reduced maltose water candy.

In the present invention, if necessary, sodium polyacrylate, polyacrylic acid, sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, sodium alginate, polyvinyl alcohol, polyvinyl pyrrolidone. , Methyl vinyl ether / maleic anhydride copolymer, thickeners such as polyethylene oxide, kaolin, titanium oxide, light anhydrous silicic acid, extenders such as hydrous silicon dioxide, light liquid paraffin, polypten, oil components such as squalane, Surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester and sorbitan fatty acid ester, and cooling agents such as menthol, camphor and peppermint oil can be added.

The patch of the present invention is usually provided in such a form that it is coated or spread on an appropriate support in advance, and then a release paper or the like that can be peeled off at the time of use is attached to the application surface side. In such a case, as the support, cloth, non-woven fabric,
Any material such as a plastic sheet, a film, or paper can be used.

[0023]

EXAMPLES The present invention will be described below based on specific examples, but the present invention is not limited to the examples.

Mixing ratio of components shown in Table 1 (unit:% by weight)
The indomethacin patch of was prepared by the following method.

[0025]

[Table 1]

Production method of Examples 1 and 4: After adding a solution of carboxymethylcellulose sodium dispersed in glycerin to purified water, gelatin is added and dissolved. Then, a partially neutralized product of sodium polyacrylate, a dried aluminum hydroxide gel, and a liquid prepared by dispersing polyoxyethylene hydrogenated castor oil in glycerin and propylene glycol were added and sufficiently kneaded, and then carboxyvinyl polymer and sorbitan fatty acid ester. Is added to light liquid paraffin. Further, after adding a solution of indomethacin dissolved in crotamiton and N-methyl-2-pyrrolidone in advance, lactic acid was added and kneaded sufficiently to obtain an indomethacin patch. The obtained patch is spread on a non-woven fabric, covered with a polypropylene film and cut into 10 cm × 14 cm.

Preparation method of Example 2: Purified water, sorbitol, and a solution prepared by dispersing carboxymethylcellulose sodium in glycerin are added, and then gelatin is added and dissolved. Then, a partially neutralized product of sodium polyacrylate, dried aluminum hydroxide gel, and a liquid in which polyoxyethylene hydrogenated castor oil is dispersed in glycerin are added, and after sufficiently kneading, carboxyvinyl polymer and sorbitan fatty acid ester are converted into light liquid paraffin. Add the dispersed liquid. Furthermore, indomethacin was previously crotamiton, N-methyl-2-
After adding a solution of pyrrolidone and N-octylpyrrolidone dissolved therein, lactic acid was added and kneaded sufficiently to obtain an indomethacin patch. The obtained patch is spread on a non-woven fabric, covered with a polypropylene film and cut into 10 cm × 14 cm.

Production method of Example 3: Same as Example 1 except that N- (2-hydroxyethyl) pyrrolidone was added instead of N-methyl-2-pyrrolidone.

Process of Example 5: Purified water, sorbitol, and a solution of carboxymethylcellulose sodium dispersed in glycerin are added, and then gelatin is added and dissolved. Then, a partially neutralized product of sodium polyacrylate, a dry aluminum hydroxide gel, a liquid prepared by dispersing polyoxyethylene hydrogenated castor oil in propylene glycol and glycerin is added,
After sufficiently kneading, a liquid prepared by dispersing carboxyvinyl polymer and sorbitan fatty acid ester in light liquid paraffin is added. Further, after adding a solution of indomethacin dissolved in crotamiton and N-methyl-2-pyrrolidone in advance, lactic acid was added and kneaded sufficiently to obtain an indomethacin patch. The obtained patch is spread on a non-woven fabric, covered with a polypropylene film and cut into 10 cm × 14 cm.

As a comparative example, an indomethacin patch having the component composition (unit: weight%) shown in Table 2 was produced by the following method.

Production Method of Comparative Examples 1 to 6: A method according to Example 1. Production method of Comparative Example 7: Kaolin was dispersed in purified water and sorbitol, and a liquid prepared by dispersing sodium carboxymethylcellulose in glycerin was added, and further gelatin was added and dissolved. Then, add a solution of sodium polyacrylate, dried aluminum hydroxide gel, polyoxyethylene hydrogenated castor oil dispersed in glycerin, thoroughly knead, and then a solution of carboxyvinyl polymer and sorbitan fatty acid ester dispersed in light liquid paraffin. Add. Furthermore, after adding a solution in which indomethacin is dissolved in crotamiton in advance, lactic acid is added and thoroughly kneaded to obtain an indomethacin patch. The obtained patch is spread on a non-woven fabric, covered with a polypropylene film and cut into 10 cm × 14 cm.

[0032]

[Table 2]

Comparative Example 1 in which the glycerin content was varied,
Each of the indomethacin patches 2, 3, and 6 was sealed in an aluminum bag and stored in a constant temperature chamber at 50 ° C., and the indomethacin content (% of manufacturing time) at the time of production and after 2 weeks and 4 weeks after production was quantified. Compared. Table 3 shows the results. As the amount of glycerin added increases, the stability of indomethacin over time deteriorates.

[0034]

[Table 3]

Example 1 in which the amount of crotamiton mixed was varied
Each of the indomethacin patches of Comparative Examples 4, 5 and 6 was sealed in an aluminum bag and stored in a constant temperature chamber at 50 ° C., and the indomethacin content at the time of production and 2 weeks, 4 weeks and 7 weeks after production (vs. production). %) Was quantified and compared. Table 4 shows the comparison results
Shown in As the amount of crotamiton added increases, the stability of indomethacin over time deteriorates.

[0036]

[Table 4]

Each of the indomethacin patches of Examples 1 and 4 was sealed in an aluminum bag and stored in a thermostatic chamber at 50 ° C.
The results of quantifying the indomethacin content from the time of production to 7 weeks after production (vs.% at the time of production) are shown in Table 5 and stored in a constant temperature chamber at 40 ° C., and the indomethacin content from production to 6 months after production (vs. Table 6 shows the results of quantifying (% at manufacturing). It can be seen that all were stable.

[0038]

[Table 5]

[0039]

[Table 6]

[Transdermal Absorption Test] 0.7 g of the patch obtained in Examples 1 and 4 applied to a 7 cm ² non-woven fabric was applied to the abdomen of a male SD rat (body weight: about 300 g), and a bandage was prepared. Fixed in. 1 ml of blood was collected from the jugular vein at 4, 8 and 24 hours after application, plasma was separated, and the plasma concentration of the drug indomethacin was measured by GC / MS. For comparison, the indomethacin patch obtained in Comparative Example 7 was also measured in the same manner.

The area under the blood concentration-time curve (AUC: Area Un) was then determined from the plasma concentration obtained above.
der the blood concentrati
on-time curve), the bioavailability of the drug indomethacin was measured, and Example 1 was compared with Example 4 and Comparative Example 7 with the AUC in Example 1 being 100. The results of these measurements and comparisons are shown in Table 7. Note that FIG. 1 is a graph showing the measurement results of the drug concentration in plasma shown in Table 7.

[0042]

[Table 7]

[0043]

EFFECTS OF THE INVENTION As is clear from the above results, the indomethacin patch of the present invention has good stability over time of indomethacin and excellent transdermal absorbability. Can be expressed.

[Brief description of drawings]

FIG. 1 is a graph showing the drug concentration in plasma of Examples 1 and 4 and Comparative Example 1.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location A61K 47/34 N

Claims (3)

[Claims] 1. A crosslinkable hydrogel base, which comprises 0.1 to 1.5% by weight of indomethacin as a medicinal component, based on the total amount of the base.
0.5 to 2 of indomethacin as a dissolving agent in a weight ratio
An indomethacin patch comprising double crotamiton and 1 to 10 times alkylpyrrolidone, and 10 to 20% by weight of the total amount of the base as a moisturizing agent. 2. A cross-linkable hydrogel base is 2 to 2 parts of the total amount of the base.
8% by weight partially neutralized sodium polyacrylate and 0.
It is a base mainly composed of a hydrogel having a pH of 4.5 to 6 in which 5 to 3% by weight of carboxyvinyl polymer and 1 to 5% by weight of gelatin are crosslinked with aluminum in the presence of water. The indomethacin patch according to claim 1. 3. The alkylpyrrolidone is N-methyl-2.
-Pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, N-octylpyrrolidone, or one or more of them, The indomethacin patch according to claim 1.