JPH01113054A - Poultice for mucous membrane of oral cavity - Google Patents

Abstract

PURPOSE:To stick a poultice over a long time without imparting a feeling of physical disorder to the surface of the mucous membrane of the oral cavity, by forming a protective layer having a specific thickness consisting of a specific cellulose derivative and a softening agent to the single surface of a sticking layer having stickiness to the wet surface of the mucous membrane. CONSTITUTION:A poultice for the mucous membrane of the oral cavity is constituted by forming a protective layer to the single surface of a sticking layer having stickiness to the wet surface of the mucous membrane. The protective layer is based on a cellulose derivative and a softening agent and the cellulose derivative is soluble in alcoholic ester and/or ketone type org. solvents and insoluble in water while the softening agent is a compound having an ester bond and/or ether bond in the molecule thereof. The thickness of the protective layer is 1/10 or less that of the sticking layer. As the sticking agent used in the sticking layer, one bondable to the wet surface of the mucous membrane, having flexibility and harmless to a human body is used. This sticking agent is based on a water-soluble polymeric compound, a water-retentive softening agent and a hydrophylic polymeric compound or a hydrophobic rubber substance. This poultice can be stuck to the surface of the mucous membrane of the oral cavity for a relatively long time and imparts no feeling of physical disorder and has no toxity.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a patch for oral mucosa.

(Prior Art) Patches have been manufactured for the purpose of protecting damaged areas of oral mucosa and promoting healing 1 for local or systemic administration of medicinal ingredients through oral mucosa.

Since the oral mucosal surface is wet or becomes wet over time, the patch used needs to have hydrophilicity and good adhesiveness, and is also desired to have a certain degree of water resistance.

As a patch that can be applied to the oral mucosal surface, a preparation whose main component is a relatively highly hydrophilic polymer is known. For example, Japanese Patent Publication No. 58-7605 discloses an oral adhesive sustained-release preparation containing a drug, which is made of hydroxypropyl cellulose and an acrylic acid (co)polymer or a salt thereof. Japanese Patent Publication No. 59-196813
The publication contains gelatin or agar, gluten, and carboxyvinyl polymer.

Adhesive compositions based on polyhydric alcohols and vinyl acetate or gums are disclosed.

The above-mentioned preparations are prepared, for example, in the form of tablets or troches. Such preparations are hard and non-adhesive when dry, but when wet with water, they soften and become adhesive, allowing them to be applied to the oral mucosal surface, etc. but,
These preparations have the following drawbacks: ■ They are hard and lack flexibility when not containing water, giving a strange sensation when applied to mucous membranes until the base softens; When absorbed, its strength decreases and it disintegrates or dissolves;
■Since the base has a high degree of water solubility, it dissolves or disintegrates within a short period of time (less than 2 hours) when applied to the oral mucosal surface.

An example where these shortcomings have been improved to some extent.

For example, there is a formulation disclosed in JP-A-59-232553. This preparation is a sheet-like or film-like mucosal dressing whose main ingredients are acrylic acid (co)polymer or its salt; sodium carboxymethyl cellulose, sodium alginate, or hydroxyethyl cellulose; and glycerin or propylene glycol.

This formulation is relatively flexible compared to the above formulations. but.

The degree of flexibility is still insufficient, and like the above formulations, the water resistance is also poor, so it cannot be applied to the surface of the oral mucosa for a long period of time.

Japanese Utility Model Publication No. 60-905 discloses a patch in which a sponge-like adhesive layer is formed on the surface of a support that is insoluble or poorly soluble in water. This sponge-like adhesive layer is hard when dry, but when water is applied, it quickly absorbs water and becomes sticky. The adhesive has the property of being soluble in water. In this preparation, water resistance is improved because a water-insoluble or sparingly soluble sheet, such as a nonwoven fabric sheet, is used as a support, but since the support is hard, it gives a strange feeling when applied to the oral mucosal surface. It also has the disadvantage of being easy to peel off.

(Problem that the invention attempts to solve) The present invention solves the above-mentioned conventional problems.

The purpose is to provide a patch that has the following properties: (1) It can be easily applied to the oral mucosal surface and has appropriate water resistance for a relatively long period of time. (2) A patch that is in the form of a flexible sheet and does not cause discomfort when applied to the surface of the oral mucosa; (3) A patch that can be applied to the human body for more than 2 hours; A patch made of non-toxic material.

(Means and effects for solving the problem) The patch for oral mucosa of the present invention is a patch for oral mucosa in which a protective layer is formed on one side of an adhesive layer that has adhesive properties on the wet mucosal surface. The protective layer.

Mainly composed of a cellulose derivative and a softener; the cellulose derivative is soluble in alcohol-based, ester-based and/or ketone-based organic solvents, and insoluble in water;
The softener is a compound having an ester bond and/or an ether bond in the molecule; and the thickness of the protective layer is 1710 mm or less than that of the adhesive layer; thereby, the above object is achieved.

The adhesive used in the adhesive layer forming the adhesive patch of the present invention may be any adhesive that can adhere to a moist mucosal surface, has flexibility, and is harmless to the human body. A material having viscoelastic properties is more preferred. Such adhesives have as main components: (1) a water-soluble polymer compound and a water-retaining softener; or (2) a hydrophilic polymer compound and a hydrophobic rubber-like substance.

The water-soluble polymer compound used in the adhesive mentioned above is α-1,6-linked polymaltotriose (pullulan).
, polyvinylpyrrolidone or vinylpyrrolidone copolymer, carboxymethylated sodium starch, methyl vinyl ether-maleic anhydride copolymer, its half-esterified product or its sodium neutralized salt, polyacrylic acid or copolymer mainly composed of acrylic acid There is such a thing as merging. Among the above compounds, polyacrylic acid and a copolymer containing acrylic acid as a main component are preferably used in combination with other above compounds.

As a water-retaining softener used in adhesives (2).

A compound that is compatible with the above-mentioned water-soluble polymer compound and can soften it to develop tackiness is used.

Glycerin and jigvaseline. These include triglycerin, polyglycerin, sorbitol, maltitol, polyethylene glycol, polypropylene glycol, polyoxyethylene/polyoxypropylene glycol, acetylethanolamine, and magnesium chloride. This water-retaining softener is made of the above-mentioned water-soluble polymer compound 100.
It is contained in the adhesive in a proportion of 30 to 200 parts by weight.

As the hydrophilic polymer compound used in the above adhesive, any of the water-soluble polymer compounds used in the above adhesive may be used, and the following compounds may also be used: sodium nyalginate, Gelatin, sodium carboxymethyl cellulose, gum arabic, guar gum, gum tragacanth, gum karaya, pectin, dextran.

Cyclodextrin or its derivatives, chitosan or its derivatives, polyvinyl alcohol, polymers of 2-hydroxyalkyl (e.g. ethyl, propyl) (meth)acrylates or copolymers based thereon, diacetone acrylamide as the main component. copolymer, poly(
Sodium meth)acrylate, methylol crosslinked starch, phosphoric acid crosslinked starch, polyacrylamide grafted starch, etc.

Hydrophobic rubber-like substances used in the adhesive (2) include natural rubber, polyisoprene, polybutadiene, polyisobutylene, styrene-isoprene copolymer, styrene-butadiene copolymer, ethylene-styrene-butadiene copolymer, ethylene -vinyl acetate copolymer, (meth)acrylic acid ester copolymer, polyvinylethyl ether,
Examples include polyvinyl isobutyl ether. This hydrophobic rubbery substance is contained in the adhesive in a proportion of 50 to 300 parts by weight based on 100 parts by weight of the hydrophilic polymer compound.

The adhesive of (1) or (2) above may contain medicinal ingredients and various additives. As the medicinal ingredient, any drug that can be absorbed through the oral mucosa can be used. Additives include absorption aids for medicinal ingredients, surfactants, neutralizing agents or buffering agents, bactericidal and fungicidal agents, odor component absorbers, fragrances, flavoring agents, coloring agents, fillers, thickeners, etc. be. These are contained in a total proportion of 30% by weight or less. The thickness of the adhesive layer varies depending on the purpose of use of the patch, but is usually 10
A range of 0 to 1000 μm is suitable.

As mentioned above, the cellulose derivatives contained in the protective layer of the adhesive patch of the present invention are alcohol-based, ester-based and/or
Or, it is soluble in ketone-based organic solvents and insoluble in water. Suitable examples of such compounds include cellulose ethers and/or cellulose esters. Examples of cellulose ethers include cellulose alkyl ethers such as ethyl cellulose, propyl cellulose, and butyl cellulose. As cellulose ester,
Cellulose acetate, cellulose propionate.

Cellulose acetate, cellulose valerate, cellulose acetate/butyrate, cellulose acetate/phthalate, etc. Among the above compounds, ethylcellulose, cellulose acetate, cellulose acetate/butyrate, cellulose acetate/phthalate, etc. are produced on an industrial scale.

Moreover, it is suitable because it is supplied with stable quality.

The softening agent contained in the protective layer is compatible with the cellulose derivative and imparts flexibility and tenacity (
It is a compound that can impart toughness).

A compound that is also harmless to the human body is selected. Such compounds include compounds having ester bonds and ether bonds in their molecules (for example.

acid esters, glycol ethers) are used.

For example, citric acid esters such as triethyl citrate; glycerin esters such as glycerin triacetate (triacetin); polyalkylene glycols such as polyethylene glycol, polypropylene glycol, copolymers containing them, or their terminal Alkyl etherified products: Glycolic acid ester derivatives such as butyl phthalyl butyl glycolate, and phthalic acid esters such as diethyl phthalate and dibutyl phthalate.

The above softening agent is 20% per 100 parts by weight of the cellulose derivative.
It is contained in the protective layer in a proportion of ~120 parts by weight.

If there is too little softener, the protective layer will lack flexibility and toughness. If it is excessive, the water resistance of the protective layer will be poor.

The thickness of the protective layer is 171 degrees or less of the thickness of the adhesive layer.

It is usually 1 to 20 μl. If the protective layer is too thin, the patch obtained will lack water resistance, and if it is too thick, the patch will lack flexibility as a whole.

Components constituting the patch of the present invention (for example).

The polymers, softeners, cellulose derivatives forming the protective layer, etc. contained in the adhesive patch may be used in combination of two or more.

To prepare the adhesive patch of the present invention, for example, the following methods may be adopted: (a) preparing a sheet-like adhesive;
A method of applying and drying a solution containing a component forming the above-mentioned protective layer on the surface thereof; (c) applying and drying a solution containing a component forming the above-mentioned protective layer on a release paper (release film);
Further, a method of applying and drying a solution or suspension containing the above-mentioned adhesive on the surface; (C) A method of applying and drying a solution containing the components that form the above-mentioned protective layer on a release paper, and then adhering it on another release paper. A method in which a solution or suspension containing the agent is applied, dried, and then laminated.

In the method (a) above, the sheet-like adhesive is:

For example, in the case of the above-mentioned pressure-sensitive adhesive containing a water-soluble polymer compound and a water-retaining softener, an aqueous solution (or an alcohol solution or a water-alcohol mixture solution) containing the pressure-sensitive adhesive is prepared, and this is spread on a release paper. Prepared by coating, wiping, and drying. For the adhesive (2) containing a hydrophilic polymerized metal material and a hydrophobic rubbery substance, the hydrophobic rubbery substance is mixed in a suitable kneader (such as a Dar mixer, a Banbury mixer, or a 22-roll kneader). The mixture was kneaded under heat, and a hydrophilic polymer compound was added little by little to obtain a kneaded product.

It is prepared by molding this into a sheet.

To obtain a sheet-like adhesive using the adhesive described in (2).

Another method may also be adopted in which a hydrophobic rubbery substance is dissolved in an organic solvent such as toluene, a hydrophilic polymer compound is added thereto to suspend it, and this is applied onto a release paper and dried. The components forming the protective layer (cellulose derivative and softener) are used as a solution dissolved in an organic solvent such as ethyl alcohol. In methods (b) and (C), the adhesive solution or suspension and the solution containing the protective layer components are prepared in the same manner as in method (a) above.

The adhesive of the patch thus obtained has appropriate viscoelastic properties and flexibility, and is excellent in hydrophilicity. Therefore, this patch exhibits good adhesion to the moist oral mucosal surface.The adhesive of the patch has excellent hydrophilic properties, so it gradually absorbs water, swells and softens, and eventually Dissolve or disintegrate. In the adhesive patch of the present invention, a protective layer with relatively excellent water resistance is formed on the surface of the adhesive layer, so that the adhesive layer is less likely to be eroded by moisture. Even if the adhesive layer absorbs moisture and softens, the protective layer prevents it from becoming fluid.

In other words, this protective layer improves the water resistance of the adhesive patch, allowing it to be applied over a long period of time. Although the protective layer of the patch is relatively less flexible than the adhesive layer, since its thickness is 1710 mm or less than the adhesive layer, the overall flexibility is not impaired. Furthermore, since the patch is prepared to have a thin overall thickness, it fits well on the surface of the oral mucosa and does not cause any discomfort. In this way, the protective layer functions in the same way as a conventional support to increase water resistance and maintain the shape of the patch, but has the advantage that it does not give a strange feeling unlike the conventional support. Furthermore, the protective layer itself is not adhesive.

It is easy to apply and does not stick to other mucous membrane surfaces during application.

The adhesive composition of the present invention can be changed depending on the purpose,
A desired patch for oral mucosa can be prepared by containing a drug inside the adhesive layer. Each component constituting this adhesive patch is non-irritating to the human body and does not exhibit toxicity. Since each component is inexpensive and the preparation method is easy, a patch for oral mucosa can be provided at low cost.

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

Daiarashi Ban (A) Preparation of patch: 15% protective layer composition consisting of 100 parts by weight of ethyl cellulose (Dow Chemical Company: 5TD-100cps) and 60 parts by weight of triethyl citrate.
was made into an ethyl alcohol solution. This solution was applied onto a silicone release paper and dried to form a protective layer with a thickness of 7 μm. Separately, 97 parts by weight of pullulan, 3 parts by weight of heat-crosslinked polyacrylic acid (Junron pw-1xO, manufactured by Nippon Pure Chemical Industries, Ltd.),
30 parts of an adhesive composition consisting of 90 parts by weight of maltitol and 20 parts by weight of polyethylene glycol (molecular weight 400)
An aqueous solution (adhesive solution) was prepared containing the following:

This adhesive solution was cast on the surface of the above-mentioned retainer II layer and dried to form an adhesive layer with a thickness of about 300 μm.

(B) Performance evaluation of patch: It was confirmed by a finger touch test that the adhesive layer of the patch obtained in section (A) had good adhesiveness. On the other hand, the surface of the protective layer had no tackiness at all. When the flexibility of the adhesive patch was tested using the following method, no cracks were observed, and it was confirmed that it had sufficient flexibility.

Flexibility test: thickness 200-500 am, 1cmX
A 3 cm specimen is prepared and left to equilibrate under standard conditions (20° C., 60% RH). Next, both ends of the test piece in the longitudinal direction are bent so that they overlap each other up to at least 0.5 cm from the ends. At this time, observe whether or not cracks occur in the test piece.

Next, from the patch obtained in section (A), 6 mm x 12 mm
A rectangular test piece was obtained. When this test piece was pressed so that the adhesive layer side was in close contact with the mucous membrane of the anterior maxillary gums,
It adhered to the mucosal surface in about 10 seconds. The patch was flexible, so it blended well with the mucous membranes and did not cause any discomfort to the subjects. The time required for this patch to dissolve (disintegrate) or peel off was measured. The results are shown in Table 1.

A patch having a typical composition described in the prior art was prepared and evaluated.

(A) Preparation of patch: Hydroxypropylcellulose (
The viscosity of a 2% aqueous solution at 20°C is approximately 5000 cps
An aqueous solution containing 50 parts by weight of polyacrylic acid (0.2% aqueous solution having a viscosity of about 15,000 cps at 20° C.) was prepared. This was cast on release paper and dried to obtain a sheet-like patch with a thickness of 307 μm.

(B) Performance Evaluation of Patch: Two Comparative Examples The surface of the patch obtained in section (A) was moistened with an appropriate amount of water and pressed against the mucosal surface in the same manner as in Example 1. It took about 1 minute for this patch to adhere to the mucosal surface.

Since this patch was relatively hard, it gave subjects an uncomfortable feeling when it was applied. As in Example 1, the time required for the patch to dissolve (disintegrate) was measured. The results are shown in Table 1.

Comparison 1 According to the method of Example 1, 2 thickness 30 consisting of adhesive layer only
A 7 μm sheet-like patch was prepared. When this patch was pressed against the mucosal surface in accordance with Example 1, it adhered to the mucosal surface in about 10 seconds. Because this patch is flexible, it blends well with the mucous membranes and did not cause any discomfort to the subjects. However, since both sides of the adhesive patch were sticky, the application process was troublesome. As in Example 1, the time required for the patch to dissolve (disintegrate) was measured. Table 1 shows the results.
Shown below.

(Left below) Table 1 (A) Preparation of patch: Polyvinylpyrrolidone (BASP)
Co., Ltd.: Kollidon K-90) 70 parts by weight, Eudragit S-100 (methyl methacrylate-methacrylic acid (weight ratio 70:30) copolymer; R6hn
+Pharma) 30 parts by weight.

An ethyl alcohol solution containing a 25% adhesive composition consisting of 40 parts by weight of glycerin triacetate and 70 parts by weight of polypropylene glycol (molecular weight 1500) was prepared. This adhesive solution was cast on a silicone release paper and dried to form an adhesive layer with a thickness of 300 μm. Separately, cellulose acetate (acetation degree: 55%) 10
An acetone solution containing 18% of a protective layer composition consisting of 0 parts by weight and 50 parts by weight of glycerin triacetate was prepared. This solution was applied to the surface of the adhesive layer and dried to form a protective layer with a thickness of about 10 μm.

(B) Performance evaluation of patch: It was confirmed by a finger touch test that the adhesive layer of the patch obtained in Section (A) of this example had good adhesiveness. On the other hand, the surface of the protective layer had no tackiness.
When tested in the same manner as described in Section 1, no cracks were observed, and it was confirmed that the material had sufficient flexibility.

Next, when this patch was pressed against the mucosal surface in the same manner as in Example 1, it adhered to the mucosal surface in about 10 seconds. Because the patch is flexible, it blends into the mucous membranes and does not cause any discomfort to the subjects.The patch dissolves (disintegrates).
The time until it peeled off or peeled off was measured. The results are shown in Table 2.

le comparator According to the method of Example 2, it consists of only an adhesive layer.

A sheet-like patch with a thickness of 310 μm was prepared. When this patch was pressed against the mucosal surface according to Example 1,
It adhered to the mucosal surface in about 10 seconds. Because this patch is flexible, it blends well with the mucous membranes and did not cause any discomfort to the subjects. However, since both sides of the adhesive patch were sticky, the application process was troublesome. As in Example 1, the time required for the patch to dissolve (disintegrate) was measured. The results are shown in Table 2.

Table 2 (8) Preparation of patch: 100 parts by weight of polyisobutylene rubber was put into a kneader mixer, and while kneading at about 110°C, 20 parts by weight of liquid paraffin was added, and kneaded for about 8 minutes to sufficiently soften it. . Separately, 40 parts by weight of sodium alginate and 60 parts by weight of gum arabic.

30 parts by weight of carboxymethylated starch sodium salt (Nippon Starch Chemical: Kibrogum F-500) and 2 parts by weight of butyl p-oxybenzoate were mixed. This mixture was gradually added to the above-mentioned kneaded material over about 20 minutes, and after kneading for an additional 5 minutes, it was cooled and the lumps were taken out.

An appropriate amount of the adhesive layer was placed between a pair of smooth plate-shaped molds whose surfaces had been subjected to silicone release treatment.

A spacer with a thickness of 300 μI was placed around the mold. After pressing with a press at 80°C, it was cooled.

A pressure-sensitive adhesive sheet with a thickness of about 400 μm was obtained.

Separately, cellulose acetate/butyrate (degree of acetate 25%).

A protective layer composition consisting of 100 parts by weight (butyric acid degree 25%) and 60 parts by weight of diethyl phthalate was dissolved in an acetone-methyl ethyl ketone mixture (50:50) at a ratio of 20%. Apply this solution on release paper and dry it.
A protective layer with a thickness of 13 μl was formed. next.

The pressure-sensitive adhesive sheet obtained by the above-mentioned press processing was laminated on the surface of this protective layer, and another release paper was further laminated thereon, and then passed between a pair of pressing rollers and pressed.

In this way, a patch with a total thickness of about 380 μm was obtained.

(B) Performance evaluation of adhesive patch 2 When the adhesive layer side of the adhesive patch obtained in Example (A) was brought into close contact with a wet surface, it adhered in a relatively short time. On the contrary.

The surface of the protective layer had no tackiness at all. When the flexibility of the adhesive patch was tested in the same manner as in Example 1, no cracks or fissures were observed, confirming that it had sufficient flexibility. Additionally, keep the humidity below 50% RH and 70%
Similar results were obtained when the test was conducted at RH or above. Next, when this patch was pressed against the mucosal surface in the same manner as in Example 1, it adhered to the mucosal surface in about 20 seconds. The patch was flexible, so it blended well with the mucous membranes and did not cause any discomfort to the subjects. The time required for this patch to dissolve (disintegrate) or peel off was measured. The results are shown in Table 3.

comparative mottled soil According to the method of Example 3, it consists of only an adhesive layer.

A sheet-like patch with a thickness of 380 μm was prepared. When this patch was pressed against the mucosal surface according to Example 1,
It adhered to the mucosal surface in about 20 seconds. Because this patch is flexible, it blends well with the mucous membranes and did not cause any discomfort to the subjects. However, since both sides of the adhesive patch were sticky, the application process was troublesome. As in Example 1, the time required for the patch to dissolve (disintegrate) was measured. The results are shown in Table 3.

Table 1 (Effects of the Invention) According to the present invention, a patch can be obtained that can be easily applied to the surface of the mucous membrane of the oral cavity and has water resistance. The base of this adhesive patch is flexible and relatively thin, so it can be applied for a long period of time without causing discomfort to the oral mucosal surface. Because it is water resistant, it can be maintained for a relatively long time without peeling or dissolving. All materials used for the patch are safe for the human body. Such patches can be widely used for the protection of intraoral trauma or as oral mucosal patches for transmucosal absorption.

that's all

Claims (1)

[Scope of Claims] 1. A patch for oral mucosa, which has a protective layer formed on one side of an adhesive layer that has adhesive properties on a moist mucosal surface, the protective layer comprising a cellulose derivative and a softening agent. The cellulose derivative is mainly soluble in alcohol-based, ester-based, and/or ketone-based organic solvents and insoluble in water, and the softening agent is a compound having an ester bond and/or an ether bond in the molecule. A patch for oral mucosa, wherein the thickness of the protective layer is 1/10 or less of the thickness of the adhesive layer. 2. The patch according to claim 1, wherein the cellulose derivative is a cellulose alkyl ether and/or a cellulose fatty acid ester. 3. The patch according to claim 1, wherein the softener is an acid ester and/or a glycol ether. 4. The patch according to claim 1, wherein the softener is contained in a proportion of 20 to 120 parts by weight based on 100 parts by weight of the cellulose derivative. 5. The adhesive according to claim 1, wherein the adhesive constituting the adhesive layer mainly contains a water-soluble polymer compound and a water-retaining softener, or a hydrophilic polymer compound and a hydrophobic rubbery substance. patch. 6. The adhesive patch according to claim 1, wherein the adhesive layer has a thickness of 100 to 1000 μm.