JPS63171565A - Constitutional body for adhesion of mucous membrane of oral cavity and its production - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a thin film-like (film-like or sheet-like) oral mucosal adhesive composition and a method for producing the same.

The present invention relates to a structure for applying to oral mucosa that is easily constructed, has flexibility, and whose water solubility can be easily adjusted, and a method for producing the same.

(Prior technology) A preparation that is applied to uneven areas of the oral mucosa or diseased areas (stomatitis, lipitis, glossitis, periodontitis, alveolar pyorrhea, gingivitis, etc.) to protect and treat the area. and preparations for absorbing drugs through the oral mucosa to obtain a systemic therapeutic effect include tablets, troches, granules, powders, and thin sheets.

For preparations such as tablets, troches, and granules, for example, sustained-release preparations consisting of a mixture containing hydroxypropyl cellulose and polyacrylic acid or its salt (Japanese Patent Publication No. 5B
-7605), polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof.

and an oral mucosal sustained-release preparation (specially Kaisho 60-21
(disclosed in Japanese Patent No. 5622).

However, tablets, troches, granules, and the like have a small area of application, resulting in poor drug administration and insufficient mucosal protection. Due to lack of flexibility.

Adhesiveness is also low.

In order to solve these drawbacks, oral mucosal preparations in the form of thin sheets have been proposed. for example.

JP-A-59-232553 discloses an acrylic acid (co)polymer or a water-soluble salt thereof: at least one of sodium carboxymethyl cellulose, sodium alginate, and hydroxyethyl cellulose; and glycerin and/or propylene glycol as main components. A film mucosal dressing is disclosed comprising a mixture of: This mucosal bandage is formed by applying the above mixture onto the surface of a plastic film such as a polyester film and drying it. In use, the mucosal bandage is peeled off from the plastic film and applied to the application site on the oral mucosa. However, since plastic films do not have surface peeling properties, it is difficult to peel off mucosal bandages formed on the film surface. The more flexible the mucosal bandage is to be applied to the oral mucosa, the more difficult it will be to peel off.If a mount with a silicone releasable surface is used instead of a plastic film, it will be impossible to apply or cast the mixture, A bandage cannot form.

For this reason, a structure for application to oral mucosa in which an adhesive layer is formed on a support has been proposed.

For example, JP-A-59-196814 discloses a sheet-like nifedipine preparation in which an adhesive layer containing nifedipine as a drug is formed on a support. Adhesives used in this drug include gelatin or agar; gluten; carboxyvinyl polymer; polyhydric alcohol;
and vinyl acetate resin or gums. Nylon is used as a support.

Non-woven fabrics such as vinylon; vinyl chloride resin films.

Plastic films such as polyurethane film and ethylene-vinyl acetate resin film are used. However, since this construct uses nonwoven fabric or plastic as a support, when applied to the mucous membrane of the oral cavity, it may not blend well with the mucous membrane and may give a sense of discomfort. The support has no flexibility and is easily peeled off due to mechanical strain. Since the peeled support does not dissolve, it is dangerous if accidentally swallowed.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional problems, and its purpose is to provide an oral mucosal patch that is flexible and can be retained on the oral mucosa for a long time. An object of the present invention is to provide a structure for use in the present invention and a method for manufacturing the same. Another object of the invention is to
It is an object of the present invention to provide a composition for application to oral mucosa whose water solubility can be easily adjusted, and a method for producing the same. Yet another object of the present invention.

It is an object of the present invention to provide an oral mucosal adhesive composition and a method for producing the same, which is water-soluble and therefore poses no danger even if it is peeled off and swallowed. Still another object of the present invention is to provide a structure for applying to oral mucosa that can be easily constructed and a method for manufacturing the same. Still another object of the present invention is to provide a composition for application to oral mucosa that is neither toxic nor irritating to the human body, and a method for producing the same. Still another object of the present invention is to provide a structure for applying to oral mucosa that can be obtained at low cost and a method for producing the same. Still another object of the present invention is to provide an oral mucosal adhesive composition capable of releasing a drug also from the side opposite to the adhesive side, and a method for producing the same.

(Means for Solving the Problems) The present invention provides a two-layer structure for applying to oral mucosa having a support and an adhesive layer, in which ethyl cellulose and hydroxy By using propylcellulose, flexibility and water solubility can be imparted to the construct. Water solubility can be easily adjusted by changing the ratio of ethylcellulose and hydroxypropylcellulose. Furthermore, since ethylcellulose and hydroxypropylcellulose are soluble in alcoholic solvents, such compositions for oral mucosal application are made by casting and drying an alcoholic solution onto a silicone releasable surface, and then forming an adhesive layer on top of this. It can be easily constructed by forming a . It was completed based on the inventor's knowledge.

The oral mucosal patch composition of the present invention has a surface layer containing ethyl cellulose and hydroxypropyl cellulose;
and an adhesive layer laminated on the surface layer, thereby achieving the above object.

A method for producing a composition for application to oral mucosa according to the present invention.

A method for producing an oral mucosal adhesive composition having a surface layer containing ethyl cellulose and hydroxypropyl cellulose, and an adhesive layer laminated on the surface layer, the method comprising applying an alcoholic solution of the surface layer forming material onto a silicone releasable surface. The process of casting and drying.

A step of casting and drying an aqueous solution of the adhesive layer forming material on the obtained surface layer, and a step of curing the obtained adhesive layer by heating or the like, if necessary.

, thereby achieving the above objective.

In the surface layer, hydroxypropylcellulose is contained in an amount of 18 to 600 parts by weight, preferably 20 to 400 parts by weight, based on 100 parts by weight of -ethylcellulose. When the amount is less than 18 parts by weight, the water solubility of the second surface layer becomes too low, and the surface layer remains even after the adhesive layer dissolves and disappears, so there is a risk that the surface layer may be swallowed by mistake. Although it dissolves when swallowed, it can be painful if it gets into the bronchial tubes. 6
If it exceeds 0.00 parts by weight, the water solubility of the first surface layer is too high and it dissolves and disappears before the adhesive layer dissolves. Therefore, only the adhesive layer remains in the oral cavity and the adhesive surface is exposed to the oral cavity.

Therefore, there is a risk that the sticker may be pasted at a location other than the pasting location.

The adhesive layer also tends to dissolve and disappear, resulting in a shorter holding time.

The adhesive layer is made of 2, for example, polyacrylic acid, sodium polyacrylate, sodium carboxymethylated starch, or sodium carboxymethyl cellulose.

It contains at least one of α-1,6-linked polymaltotriose, polyvinylpyrrolidone, sodium alginate, methyl vinyl ether-maleic anhydride copolymer, maltitol, glycerin, diglycerin, triglycerin, and sorbitol.

Commercial products of ethyl cellulose include 2, for example, Ethocel 5T.
D-7,10,20,45, Etcel MED-50,7
0°100 (all manufactured by Dow Chemical Company). Commercially available hydroxypropylcellulose contains 2g HP
C-5L (viscosity of 2% aqueous solution is 3 to 5 cps at 20°C,
98 Soda HP
C-M (The viscosity of a 2% aqueous solution is 150-400 at 20℃
cps, manufactured by Nippon Soda Co., Ltd.) 2nd Soda HPC-H (viscosity of 2% aqueous solution is 1000 to 4000 cps at 20°C, manufactured by Nippon Soda Co., Ltd.).

The composition of the adhesive layer includes the following composition.

(Composition-1) Heat-crosslinked polyacrylic acid (Shunron PW-111).

(manufactured by Nippon Pure Chemical Industries) 60 parts by weight Sodium polyacrylate (Aronbis GL.

(manufactured by Nippon Pure Chemical Industries) 40 parts by weight Maltitol (reduced maltose) 150 parts by weight Glycerin
50 parts by weight (composition-2) Heat-crosslinked polyacrylic acid (Shunron PW-111).

Nippon Pure Chemical Industries, Ltd.) 60 parts by weight carboxymethylated starch sodium (Kyprogum F-5
00. (manufactured by Nippon Star Chemical Co., Ltd.) 40 parts by weight Maltitol
250 parts by weight (composition-3) α-1,6-linked polymaltotriose (pullulan PI-
20, manufactured by Hayashibara Shoji Co., Ltd.) 70 parts by weight Sodium carboxymethyl cellulose (Celogen FBSI+-12. manufactured by Dai-Kogyo Seiyaku Co., Ltd.) 30 parts by weight Maltitol
180 parts by weight glycerin
20 parts by weight (composition-4) Polyvinylpyrrolidone (Koriton-90, manufactured by BASF) 80 parts by weight Sodium alginate 20 parts by weight diglycerin 140 parts by weight (composition-5) Methyl vinyl ether-maleic anhydride copolymer (GA)
NTREZ-AN-119, manufactured by GAF) 40 parts by weight Sodium carboxymethylated starch (Kyprogum F-50
0, manufactured by Nippon Star Chemical Co., Ltd.) 60 parts by weight triglycerin
80 parts by weight sorbitol
The layer thickness of the 50 parts by weight surface layer is preferably in the range of 10 to 100 μm.

On the other hand, the thickness of the adhesive layer is preferably 50 to 500 μm.

A method for producing a composition for application to oral mucosa according to the present invention.

For example, this is done in the first order.

Ethyl cellulose and hydroxypropyl cellulose are dissolved in ethyl alcohol alone or in a mixed solvent mainly composed of ethyl alcohol.

This solution is cast onto a flat surface (such as a mount) having a silicone release surface and dried to form a surface layer. On this surface layer, an aqueous solution or aqueous solution of adhesive layer components is further cast.
Dry to form an adhesive layer.

If necessary, the adhesive layer is cured by heating or the like. By peeling off the plane having the silicone peelable surface, one oral mucosa adhesive construct is obtained.

In addition to the compounds contained in the surface layer and the adhesive layer, the composition for oral mucosa application of the present invention may optionally contain a softening agent,
Filler 9 Colorants, fragrances, medicinal ingredients, etc. are added. These additives are added at a rate of 50% or less for each of the 9 surface layers and the adhesive layer. If it exceeds 50%, physical properties of the surface layer and adhesive layer (flexibility, water solubility, etc.)
is damaged.

(Function) According to the present invention, a structure for application to oral mucosa that has flexibility and whose water solubility can be easily adjusted can be obtained. Due to its flexibility, it can be kept in the oral cavity for a long time. Water solubility is controlled by changing the ratio of ethyl cellulose and hydroxypropyl cellulose contained in the two surface layers. When ethyl cellulose increases,
Water solubility decreases. On the other hand, more hydroxypropylcellulose increases water solubility. The water solubility of the surface layer is usually adjusted to such an extent that the adhesive layer and the surface layer can dissolve and disappear almost simultaneously. If the surface layer dissolves before the adhesive layer,
Only the adhesive layer remains in the oral cavity.

The adhesive surface is exposed to the oral cavity. Therefore, depending on the adhesive surface, there is a possibility that the adhesive may be attached to a place other than the attachment point.

The adhesive layer also tends to dissolve and disappear, resulting in a shorter holding time. On the other hand, if the adhesive layer dissolves first, the surface layer remains even after the adhesive layer dissolves and disappears, and there is a risk that the surface layer may be swallowed by mistake. Although it dissolves when swallowed, it can be painful if it gets into the bronchial tubes.

Water solubility can also be adjusted by the molecular weight of ethylcellulose and the degree of ethyl etherification.

Such a structure for application to oral mucosa can be easily constructed. This is because both ethyl cellulose and hydroxypropyl cellulose are alcohol-soluble and have compatibility, so that an alcohol solution of ethyl cellulose and hydroxypropyl cellulose can be easily coated onto a silicone releasable surface. Conventional adhesive compositions are water soluble but insoluble in solvents outside the water plate (eg, alcohol). Therefore, even if an aqueous solution is attempted to be applied onto a silicone releasable surface, it cannot be applied due to the repellent phenomenon. plastic film CPVC
, PET, etc.), it is difficult to peel off. As an integral part with a plastic film, it has the same drawbacks as the prior art.

In the oral mucosal adhesive composition of the present invention, the surface tackiness of the 9th surface layer is low, and handleability is improved. In order to impart adhesiveness and adhesion to the composition for application to oral mucosa, it is sufficient to increase the water solubility of the 9th surface layer and dissolve and eliminate the 2nd surface layer. For this purpose, the proportion of hydroxypropylcellulose contained in the surface layer 9 may be increased. Also 9 surface layer and adhesive layer (especially adhesive layer).

If necessary, it can be hardened by heating, etc.

Retention time in the oral cavity becomes longer.

(Example) The present invention will be described below with reference to examples.

(1) Production of construct for oral mucosa patch 75 parts by weight of ethyl cellulose (Ethocel Ml!D-70, manufactured by Tau Chemical Co., Ltd.) and 25 parts by weight of hydroxypropyl cellulose (8 Sodium 11Pc-H, manufactured by Nippon Soda Co., Ltd.) Parts by weight were blended to prepare a 11% solution in ethyl alcohol. This solution was applied onto the release side of two 50 μm polyethylene terephthalate (PET) films with silicone release properties on one side.
Apply so that the thickness after drying is 20 μm and dry it.
Formed the surface layer.

(Composition-1) 60 parts by weight of heat-crosslinked polyacrylic acid (Shunron PW-111 manufactured by Nippon Pure Chemical Industries, Ltd.) Sodium polyacrylate (Aronbis GL).

(manufactured by Nippon Pure Chemical Industries) 40 parts by weight Maltitol (reduced maltose) 150 parts by weight Glycerin
50 parts by weight of the above formulation is blended,
It was made into an approximately 10% aqueous solution. This was applied to the above surface layer so that the thickness after drying was 80 μm and dried to form an adhesive layer. The adhesive layer is non-tacky when dry, but becomes tacky by absorbing moisture or becoming wet with water. Adhesion to oral mucosa etc. is achieved within a short time of one minute. This adhesive layer exhibits a medicinal effect by incorporating a medicinal ingredient into Composition-1 as necessary.

After forming the surface layer and the adhesive layer in this manner, the PET film is peeled off to obtain a structure for application to oral mucosa. This composition for oral mucosal application is.

Cut into a desired size, for example, 1 cm x 2 aa).

It is appropriately packaged in a moisture-proof packaging bag.

What is the retention time in the oral cavity of this composition for application to oral mucosa?

It is 4 to 6 hours.

(2) Evaluation of the construct for attaching to the oral mucosa obtained in (1) by 1 cffl×
It was cut into pieces 1a11 and one piece was pasted on the left and right buccal inner mucosa of three panelists. The application was repeated six times, and the time until the construct peeled off or dissolved/disappeared was measured.

The average time, maximum and minimum times are shown in the table below. The average time was 360 minutes, the maximum time was 400 minutes, and the minimum time was 280 minutes. The construct is.

The surface layer and adhesive layer dissolved and disappeared almost simultaneously.

Back fat base 1 (1) Production of construct for oral mucosa application 50 parts by weight of ethyl cellulose (Ethocel MED-50, manufactured by Tau Chemical Co., Ltd.) and 50 parts by weight of hydroxypropyl cellulose (Nisso HPC-M, manufactured by Nippon Soda Co., Ltd.). The mixture was mixed to form a 12% solution in ethyl alcohol. Using this solution, a surface layer having a thickness of 40 μm was formed in the same manner as in Example 1.

(Composition-2) Heat-crosslinked polyacrylic acid (Shunron PH-111).

Nippon Soda Co., Ltd.) 60 parts by weight Sodium carboxymethylated starch (Kiprogum F-5
00. (manufactured by Nippon Star Chemical Co., Ltd.) 40 parts by weight Maltitol
250 parts by weight of the above formulation, approximately 20%
An aqueous solution of Apply this to the above surface layer so that the thickness after drying is 1
It was applied to a thickness of 20 μm and dried to form an adhesive layer. The retention time in the oral cavity of this oral mucosal adhesive composition is 3~
It is 4 hours.

(2) Evaluation of construct for application to oral mucosa The construct for application to oral mucosa obtained in (1) was evaluated by the same method as in Example 1. As a result, the average time is 24
0 minutes, maximum time was 280 minutes, and minimum time was 180 minutes. These results are shown in the table below. In the structure, the surface layer and the adhesive layer dissolved and disappeared almost simultaneously.

(1) Production of construct for oral mucosa patch 40 parts by weight of ethyl cellulose (Ethocel MED-50, manufactured by Dow Chemical Company) and 60 parts by weight of hydroxypropyl cellulose (8 Sodium 11Pc-M, manufactured by Nippon Soda Company). A 12% solution in ethyl alcohol was prepared. Using this solution, a surface layer with a thickness of 40 μm was formed in the same manner as in Example 1.

(Composition-3) α-1,6-linked polymaltotriose (pullulan PI-
20, manufactured by Hayashibara Shoji Co., Ltd.) 70 parts by weight Sodium carboxymethyl cellulose (Celogen FBSH-12. manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) 30 parts by weight Maltitol
180 parts by weight glycerin
20 parts by weight of the above formulation was blended to form an approximately 18% aqueous solution. Apply this to the above surface layer to a thickness of 100 μm after drying.
The adhesive layer was formed by coating and drying to form an adhesive layer. The retention time in the oral cavity of this structure for application to oral mucosa is 2 to 3 hours.

(2) Evaluation of construct for application to oral mucosa The construct for application to oral mucosa obtained in (1) was evaluated by the same method as in Example 1. As a result, the average time is 18
The maximum time was 220 minutes and the minimum time was 130 minutes. These results are shown in the table below. In the structure, one surface layer and the adhesive layer dissolved and disappeared almost simultaneously.

(1) Production of construct for application to oral mucosa Ethyl cellulose (Ethocel MED-100, manufactured by Tau Chemical Co., Ltd. > 10 parts by weight, ethyl cellulose (Ethocel 5TD-20, manufactured by Dow Chemical Company) 20 parts by weight, and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) to prepare a 13% solution of ethyl alcohol. using this solution.

A surface layer having a thickness of 60 μm was formed in the same manner as in Example 1.

(Composition-4) Polyvinylpyrrolidone (Koriton-90, BAS
(manufactured by Company F) 80 parts by weight Sodium alginate 20 parts by weight Diglycerin 140 parts by weight The above formulation was blended. It was made into an approximately 17% aqueous solution. Apply this to the surface layer above.
Apply it so that the thickness after drying is 90μ axis, dry it,
An adhesive layer was formed. The retention time in the oral cavity of this structure for application to oral mucosa is 2 to 3 hours.

(2) Evaluation of construct for application to oral mucosa The construct for application to oral mucosa obtained in (1) was evaluated in the same manner as in Example 1. the result. Average time is 15
0 minutes. The maximum time was 200 minutes and the minimum time was 130 minutes. These results are shown in the table below. In the structure, the first surface layer and the adhesive layer dissolved and disappeared almost simultaneously.

1 (1) Production of construct for oral mucosa patch 10 parts by weight of ethyl cellulose (Ethocel MED-100, manufactured by Dow Chemical Company), ethyl cellulose (Ethocel 5)
1 part of TD-7 (manufactured by Dow Chemical Company), 20 parts by weight of hydroxypropyl cellulose (manufactured by Soda Company), and 60 parts by weight of hydroxypropyl cellulose (8-carbon HPC-SL, manufactured by Nippon Soda Company) were blended. A 14% solution in ethyl alcohol was prepared.

Using this solution, a thickness of 50 μm was prepared in the same manner as in Example 1.
formed the surface layer of

(Composition-5) Methyl vinyl ether-maleic anhydride copolymer (GA
NTREZ-AN-119, manufactured by GAF) 40 parts by weight Sodium carboxymethylated starch (Kyprogum F-5
00, Nippon Star Chemical Co., Ltd.) 60 parts by weight triglycerin
80 parts by weight sorbitol
50 parts by weight of the above formulation was blended to form an approximately 30% aqueous solution. Apply this to the above surface layer to a thickness of 130 μm after drying.
The adhesive layer was formed by applying layers in layers and drying. The retention time in the oral cavity of this structure for application to oral mucosa is 1 to 2 hours.

(2) Evaluation of construct for application to oral mucosa The construct for application to oral mucosa obtained in (1) was evaluated in the same manner as in Example 1. As a result, the average time is 12
The maximum time was 140 minutes, and the minimum time was 100 minutes. These results are shown in the table below. In the structure, the surface layer and adhesive layer dissolved and disappeared almost simultaneously.

table (Effect of the invention) The oral mucosal adhesive composition of the present invention is thus prepared.

Because it is flexible, it can be retained in the oral mucosa for a long time. Water solubility can be easily adjusted by adjusting the surface layer components. Because it is water-soluble, there is no danger if the surface layer peels off and is swallowed. Such an oral mucosal adhesive structure includes, for example,
It is easily constructed by forming a surface layer on a silicone releasable surface using an alcohol solution of the surface layer forming material, and then forming an adhesive layer on this surface layer. This oral mucosal adhesive composition is neither toxic nor irritating to the human body.

In addition to being inexpensive, If a drug component is incorporated into the surface layer during the manufacturing process, the drug can be released from the surface opposite to the application surface.

For these reasons, the oral mucosal adhesive composition of the present invention. A preparation that is applied to uneven areas of the oral mucosa or diseased areas (stomatitis, loliitis, glossitis, periodontitis, alveolar pyorrhea, gingivitis, etc.) to protect and treat the area; and oral mucosa. It is useful as a formulation for obtaining systemic therapeutic effects by absorbing drugs through the drug.

that's all

Claims (1)

[Claims] 1. A surface layer containing ethyl cellulose and hydroxypropyl cellulose, and an adhesive layer laminated on the surface layer;
A construct for pasting on oral mucosa. 2. The surface layer contains 18 to 60 parts of the hydroxypropyl cellulose per 100 parts by weight of the ethyl cellulose.
The composition for application to oral mucosa according to claim 1, which contains the composition in the range of 0 parts by weight. 3. The adhesive layer contains polyacrylic acid, sodium polyacrylate, sodium carboxymethylated starch, sodium carboxymethylcellulose, α-1,6-linked polymaltotriose, polyvinylpyrrolidone, sodium alginate, methyl vinyl ether-maleic anhydride, etc. The composition for application to oral mucosa according to claim 1, which contains at least one of a polymer, maltitol, glycerin, diglycerin, triglycerin, and sorbitol. 4. The structure for application to oral mucosa according to claim 1, wherein the thickness of the surface layer is in the range of 10 to 100 μm. 5. The structure for application to oral mucosa according to claim 1, wherein the adhesive layer has a thickness in the range of 50 to 500 μm. 6. The structure for application to oral mucosa according to claim 1, wherein the surface layer and/or the adhesive layer contains a medicinal ingredient. 7. A surface layer containing ethyl cellulose and hydroxypropyl cellulose, and an adhesive layer laminated on the surface layer;
A method for producing a structure for pasting on oral mucosa, comprising: casting an alcoholic solution of the surface layer forming material onto a silicone releasable surface and drying it; A method for producing an oral mucosal adhesive composition comprising the steps of casting and drying an aqueous solution, and, if necessary, curing the obtained adhesive layer by heating or the like. 8. The surface layer contains 18 to 60 parts of the hydroxypropyl cellulose per 100 parts by weight of the ethyl cellulose.
The method for producing a composition for application to oral mucosa according to claim 7, wherein the content is in the range of 0 parts by weight. 9. The adhesive layer contains polyacrylic acid, sodium polyacrylate, sodium carboxymethylated starch, sodium carboxymethyl cellulose, α-1,6-linked polymaltotriose, polyvinylpyrrolidone, sodium alginate, methyl vinyl ether-maleic anhydride, etc. 8. The method for producing a composition for application to oral mucosa according to claim 7, which contains at least one of a polymer, maltitol, glycerin, diglycerin, triglycerin, and sorbitol. 10. The method for producing an oral mucosa adhesive structure according to claim 7, wherein the surface layer has a thickness in the range of 10 to 100 μm. 11. The method for producing an oral mucosal adhesive structure according to claim 7, wherein the adhesive layer has a thickness in the range of 50 to 500 μm. 12. The method for producing an oral mucosal adhesive structure according to claim 7, wherein the surface layer and/or the adhesive layer contains a medicinal ingredient.