KR950010146B1 - Patch for treatment of stomatitis - Google Patents

Abstract

The patch for treating a stomatitis is produced by (a) adding a steroidic antiphlogistic to a mixed solution obtd. by dissolving a citric acid into a glycerin, and suspending the mixture, (b) adding a hydrophilic polymer to the suspension to obtain a viscous polymer mixture, (c) casting the mixture on the release liner of a silicone paper to form an even film, (d) heating the film to to crosslink-coupling the polymer, and (e) coating a non-permeable supporting film on the matrix layer of the linear/ matrix composite layer. The steroidic antiphlogistic is pref. triamcinolone acetonide, and the hydrophilic polymer is pref. karaya gum, arabia gum, carboxymethyl cellulose, hydroxymethyl cellulose or polyacrylic acid.

Description

Patches for Stomatitis

1 is a cross-sectional view of a patch according to the invention.

2 is a graph showing the release rate of triamcinolone acetonide from triamcinolone acetonide-containing patch according to the present invention.

The present invention relates to a patch for treating stomatitis and a method of manufacturing the same. In particular, the present invention relates to patches that exhibit localized controlled release of drugs in the oral cavity.

The drugs used to treat stomatitis until now are mainly manufactured in the form of ointments, liquids, and the like. However, these ointments or liquids were easily dissolved and removed by saliva, and thus could not be expected to have a lasting effect, and thus there was an inconvenience of applying the drug several times a day. In addition, depending on the user, the application amount is not constant, so the proper amount of drug could not be continuously administered at a certain level.

Accordingly, the present inventors have extensively studied a method capable of continuously supplying an appropriate amount of drug to a desired site for a long time, and thus, the present invention has been completed.

The present invention relates to a patch for treating stomatitis, comprising a hydrophilic polymer matrix layer containing a steroid anti-inflammatory agent, in particular, a non-permeable support membrane and a release-liner removed immediately before use. (See Figure 1).

The patch agent of the present invention can be directly adhered to the oral mucosa without using a separate adhesive because the biocompatible and hydrophilic polymer is used as the drug-containing matrix layer, and the drug-containing polymer matrix layer is impermeable support Since it is covered by the membrane, the drug contained in the matrix layer is not released to the site other than the application site or saliva cannot penetrate into the matrix so that the drug contained in the matrix can be continuously supplied to the intended application site without loss. It is.

Any polymer that can be used to construct the patch of the present invention may be any biocompatible and hydrophilic polymer, for example karaya rubber, gum arabic, carboxymethylcellulose (CMC), hydroxypropylmethylcellulose ( HPMC), polyacrylic acid (Carbopol 934) and the like can be used. Preferred among them are karaya rubber, polyacrylic acid or a mixture thereof, and particularly preferred is karaya rubber having excellent biocompatibility as a natural product.

Karaya rubber which is particularly preferably used to construct the matrix layer of the patch of the present invention contains 8% of acetyl group and 37% of uronic acid residue, D-galactose, L-rhamnose and D-galactouronic acid and the like. It is composed of about 9.5 million natural polysaccharides.

The polymer constituting the matrix layer may be added in an amount of 40 to 50% by weight based on the total weight of the matrix.

The matrix layer of the patch of the present invention is also added citric acid as a crosslinking agent for improving the physical properties of the matrix and glycerin for adjusting the flexibility and crosslinkability of the patch. Glycerin is added in an amount of 40 to 50% by weight based on the total weight of the matrix and citric acid is added in an amount of 10 to 20% by weight relative to the polymer.

Anti-inflammatory agents for the treatment of stomatitis, which can be formulated with patches according to the invention, are preferably triamcinolone acetonide, beclomethasone dipropionate, betamethasone, dexamethasone, fluorcinolone acetonide, fluorinide, flumethasone, It is a steroidal anti-inflammatory agent such as hydrocortisone, prednisolone, prednisone and the like. Particularly preferred anti-inflammatory agents are triamcinolone acetonides. The amount of the steroidal anti-inflammatory agent may be determined differently depending on the effective dose range of each component, but is generally added in an amount of 0.01% by weight to 0.1% by weight based on the total weight of the matrix.

The matrix layer of the patch of the invention composed of the components as described above preferably has a thickness of 0.05mm to 2.0mm.

The non-permeable support membrane attached to one side of the matrix layer of the patch according to the invention is constructed on the basis of Eudragit RS100. That is, 26 wt% of Eudrasil RS100 is mixed with 3 to 5 wt% of a plasticizer triacetin, and the mixture is dissolved in 69 wt% of acetone, and then the film is molded according to a solution casting method and the resulting film is produced. Film prepared by drying at 50 ° C. for 24 hours is used as a non-permeable support membrane of the patch of the present invention.

Such a non-permeable support membrane is more desirable for the thin film as long as it provides the desired properties for the patch of the present invention, that is, does not permeate the drug component and saliva contained in the matrix layer. Generally, a film of 0.05 mm to 0.3 mm thickness is used as the non-permeable support membrane.

The patch according to the invention is also provided with a release liner attached to the other side of the matrix layer. This release liner is provided to prevent contamination of the matrix layer and to improve the packageability of the product and is removed immediately before use. As a release type liner, salicon paper is generally used. It is preferable that the release type liner composed of such silicone paper is generally 0.03 mm to 0.05 mm thick.

As described above, the patch of the present invention comprising a matrix layer composed of a polymer, glycerin, citric acid, and an anti-inflammatory agent, a non-permeable support membrane, and a peelable liner continuously releases the therapeutic drug to the application site, thereby concentrating local therapeutic effects for a long time. In addition to protecting the lesions of stomatitis from saliva and other stimuli, the therapeutic effect can be enhanced. In addition, the patch of the present invention is a hydrophilic matrix type patch having excellent adhesiveness, and does not give foreign users a feeling of foreign matter.

Patches according to the present invention can be prepared by the following method. That is, a steroidal anti-inflammatory agent for the treatment of stomatitis is added to the mixed solution obtained by dissolving citric acid in glycerin, and then suspended homogeneously, and a hydrophilic polymer is added to the obtained suspension. In this process, if the temperature of the mixture rises rapidly, the mixture may solidify rapidly. Therefore, it is preferable to use a suitable method so that the temperature of the mixture does not rise above 15 ° C. The resulting polymer mixture is cast using a doctor blade to form a matrix in the form of a film. That is, the high-viscosity polymer mixture mixed above is placed on one end of the silicone paper, which is a release liner, and then inverted with a doctor blade to form a uniform film having a desired thickness. The resulting film is then warmed at 50 ° C. for 24 hours to crosslink the polymer. The patch of the present invention is prepared by press-coating a non-permeable support film at room temperature on the matrix of the release liner / matrix composite layer thus obtained.

The invention is illustrated in more detail by the following examples.

Example 1

[0.05% Triamcinolone Acetonide Patch]

Matrix Layer Component Content

Karaya rubber 46.6 wt%

Glycerin 46.6 wt%

6.75 wt% citric acid

0.05% by weight of triamcinolone acetonide

Citric acid is added to glycerin and stirred to warm up to 40 ° C. to dissolve, and the resulting solution is cooled to 15 ° C., and triamcinolone acetonide is added thereto while stirring to suspend uniformly. The Karaya rubber is added to the resulting suspension with stirring, taking care not to cause the temperature to rise sharply above 15 ° C. to obtain a homogeneous viscous mixture. The homogeneous viscous mixture is placed on one end of 0.05 mm thick silicone paper and uniformly inverted with a doctor blade to be 1.5 mm thick, then warmed at 50 ° C. for 24 hours to crosslink the Karaya rubber to form a matrix layer. Immediately thereafter, a 0.05 mm triamcinolone acetonide-containing patch according to the present invention is prepared by compressing and coating a pre-prepared 0.3 mm thick Eudragit RS100-based non-permeable support membrane in a matrix layer at room temperature.

The Eudrazyl RS100-based non-permeable support membrane used above is prepared by the following method. 26% by weight of Eudrazyl RS100 was mixed with 5% by weight of triacetin, the resulting mixture was added to 69% by weight of acetone while stirring at room temperature, dissolved and cast in accordance with a conventional solution softening method, followed by stirring at 50 ° C for 24 hours. The solvent is evaporated by drying to obtain a 0.3 mm thick film, which is used as the non-permeable support membrane above.

Example 2

[0.1% Beclomethasone Dipropionate Patch]

Matrix Layer Component Content

46% of karaya rubber

Glycerin 46% by weight

7.9% by weight citric acid

Beclomethasone Dipropionate 0.1% by weight

Using the above components as the matrix layer constituent, and according to the same method as in Example 1 except that the thickness of the non-permeable support membrane was 0.2 mm, the title 0.1% beclomethasone dipropionate-containing Prepare patch.

Example 3

[0.1% Triamcinolone Acetonide Patch]

Matrix Layer Component Content

Karaya rubber 43 wt%

5% by weight of Carbopol 934

45% by weight glycerin

6.9 wt% citric acid

Triamcinolone Acetonide 0.1% by weight

Using the above components as the matrix layer component, the title 0.1% triamcinolone acetonide-containing patch was prepared in the same manner as in Example 1 except that the thickness of the matrix was 1 mm and the thickness of the silicone paper was 0.03 mm. Manufacture.

Example 4

[Release Test of 0.05% Triamcinolone Acetonide Patch]

The release liner of the 0.05% triamcinolone acetonide-containing patch prepared in Example 1 was removed and attached to a cellulose nitrate membrane, which was then fixed in a diffusion chamber to perform a release test at 37 ° C.

40% MeOH / PBS (phosphate buffered saline) and 60% MeOH / PBS were used as the receptor phase. Release results were analyzed by HPLC and shown in FIG. 2.

From the results shown in FIG. 2, it can be seen that the patch of the present invention continuously releases the active ingredient for a long time.

Claims (15)

A drug-containing matrix layer containing a steroid-based anti-inflammatory agent, a hydrophilic polymer, glycerin and citric acid; Impermeable support membrane; And a peeling agent for treating stomatitis, comprising a release liner. The method of claim 1, wherein the steroidal anti-inflammatory agent is triamcinolone acetonide, beclomethasone dipropionate, betamethasone, daxamethasone, fluorcinolone acetonide, fluorinide, flumethasone, hydrocortisone, prednisolone and prednisone Patches selected from the configured group. The patch according to claim 2, wherein the steroidal anti-inflammatory agent is triamcinolone acetonide. The patch according to any one of claims 1 to 3, wherein the steroidal anti-inflammatory agent is contained in an amount of 0.01 to 0.1% by weight based on the total weight of the matrix. The patch of claim 1 wherein the hydrophilic polymer is selected from the group consisting of Karaya rubber, gum arabic, carboxymethylcellulose, hydroxypropylmethylcellulose and polyacrylic acid. The patch according to claim 5, wherein the hydrophilic polymer is karaya rubber. The patch according to any one of claims 1, 5 and 6, wherein the hydrophilic polymer is contained in an amount of 40 to 50% by weight relative to the total weight of the matrix. The patch according to claim 1, wherein the glycerin is contained in an amount of 40 to 50% by weight relative to the total weight of the matrix. The patch according to claim 1, wherein the citric acid is contained in an amount of 10 to 20% by weight based on the weight of the hydrophilic polymer. The patch according to claim 1, wherein the release liner is made of silicone paper. The patch of claim 1 wherein the non-permeable support membrane is a Eudrazyl RS100-based film. 12. The patch of claim 11 wherein the eudrazyl RS100-based film contains 3 to 5 weight percent triacetin. The patch according to claim 1, wherein the release layer liner having a thickness of 0.5 to 2.0 mm and a non-permeable support film having a thickness of 0.05 to 0.3 mm is 0.03 to 0.05 mm. a) a steroidal anti-inflammatory agent is suspended in a mixed solution obtained by dissolving citric acid in glycerin: b) a hydrophilic polymer is added to the resulting suspension to obtain a viscous polymer mixture; c) the resulting viscous mixture is placed on an exfoliated liner and spread out to form a film of uniform thickness; d) heating the formed film to crosslink the polymer; e) a method of producing a patch for treating stomatitis according to any one of claims 1 to 13, characterized by pressing and coating a non-permeable support membrane on the obtained matrix layer of the release liner / matrix composite layer. The method of claim 14, wherein the temperature of the mixture in step b) is maintained at 15 ° C. or less.