JPH01113056A - Poultice composition 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, by combining two sets of specific polymers and softening agents different from each other as main components. CONSTITUTION:A polymer A soluble in both of alcohol and water, a water- retentive softening agent A compatible with said polymer A and soluble in alcohol, a polymer B soluble in alcohol but substantially insoluble in water and a softening agent B compatible with said polymer B and soluble in alcohol but substantially insoluble in water are contained as main components. For example, as the polymer A, a copolymer based on polyacrylic acid and acrylic acid is designated and, as the softening agent A, there are glycerine, acetylethanolamine or the like. For example, as the polymer B, there is a copolymer of alkyl (meth)acrylate and/or vinyl acetate and a vinyl monomer having a hydrophylic group. As the softening agent B, there are triethyl citrate, phosphoric triester or the like. This poultice is easily to the surface of the mucous membrane of the oral cavity and imparts no feeling of physical disorder even in use over a long time.

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 9. Administering medicinal ingredients locally or systemically 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, preparations with a composition mainly composed of relatively highly hydrophilic polymers are known. For example, Japanese Patent Publication No. 5B-7605 discloses that An oral adhesive sustained-release preparation containing a drug is disclosed, which is composed of an acid (co)polymer or a salt thereof. Japanese Patent Publication No. 55-118414
The publication discloses a nasal mucosa-adhesive sustained-release preparation containing a drug, which is composed of cellulose ether (excluding hydroxypropyl cellulose) and an acrylic acid (co)polymer or a salt thereof. Japanese Patent Publication No. 59-19681
No. 3 discloses a patch preparation based on four main ingredients: gelatin or agar, gluten, carboxyvinyl polymer, polyhydric alcohol, and vinyl acetate or gums.

JP-A-59-232553 discloses a sheet-like or film-like mucous membrane containing as a main component an acrylic acid (co)polymer or its salt; sodium carboxymethyl cellulose, sodium alginate, or hydroxyethyl cellulose; and glycerin or propylene glycol. A bandage is disclosed. Japanese Patent Publication No. 60-215622
In the bulletin.

Polyvinylpyrrolidone, polyvinyl alcohol.

polyethylene glycol, alginic acid or its salt, maleic anhydride-methyl vinyl ether copolymer, etc.
A patch preparation comprising an acrylic acid (co)polymer is 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 formulations have the following disadvantages: ■ They are hard and brittle in the absence of water, while their strength decreases and they disintegrate or dissolve easily when they contain water; Because it does not have an elastic physical property range9, it cannot be used, for example, by forming it into a flexible sheet-like preparation; ■Because the base has a high degree of water solubility2
When applied to the oral mucosal surface, it dissolves or disintegrates within a short period of time.

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

The purpose is to provide a composition capable of forming an oral mucosal patch having the following properties: (
1) A patch that can be easily applied to the surface of the oral mucosa and has appropriate water resistance so that it can be applied for a relatively long period of time (for example, 2 hours or more); (2) It has flexibility. (3) A patch that is in sheet form and is easy to apply to the surface of the oral mucosa and does not cause discomfort; (3) A patch that is made of a material that is non-toxic to the human body.

(Means for Solving the Problems) The oral mucosa adhesive composition of the present invention comprises a polymer A that is soluble in both alcohol and water; Softener A; Polymer B that is soluble in alcohol and substantially insoluble in water; and Softener B that is compatible with the polymer B and soluble in alcohol and substantially insoluble in water. as the main component, thereby achieving the above objective.

As mentioned above, the polymer A contained in the composition of the present invention is a polymer that is soluble in both alcohol and water. Examples of such polymer A include the following compounds: polyacrylic acid, a copolymer mainly composed of acrylic acid; polyvinylpyrrolidone, vinylpyrrolidone containing vinylpyrrolidone in a proportion of 50% by weight or more; Copolymer with vinyl acetate, vinylpyrrolidone and 2
= hydroxyalkyl (e.g. ethyl, propyl) (
Copolymer with meth)acrylate; Copolymer containing 30% by weight or more of (meth)acrylamide having a quaternary ammonium salt (ammonio group) in the side chain; ) has (meta)
A copolymer containing 30% by weight or more of an acrylic ester, a (meth)acrylamide having an ammonio group or 10% by weight or more of a (meth)acrylic ester, and a hydroxyl group-containing (meth)acrylate (for example).

A copolymer containing 50% by weight or more of hydroxypropyl acrylate) as a copolymerization component. Among the above-mentioned compounds, compounds that can form salts (eg, sodium salts, potassium salts), such as polyacrylic acid, are also included.

The softener A is compatible with the polymer A, and the softener A is compatible with the polymer A.
It is a water-retaining softener that develops stickiness. This softener A has the property of being soluble in alcohol. Compounds used for softener A include:

Examples include glycerin, diglycerin, triglycerin, polyglycerin, sorbitol, maltitol, liquid polyethylene glycol, polypropylene glycol, polyoxyethylene/polyoxypropylene glycol, and acetylethanolamine. The amount of softener A is based on polymer A.

The smaller the amount, the greater the water resistance of the resulting composition, but the lower the initial tack. If the amount of softener A is 50 parts by weight or less based on 100 parts by weight of polymer A, the composition will not have tackiness when dried. As the amount of softener A increases, the water resistance and adhesive strength of the composition decrease. In the composition of the present invention, the softener A is 2 parts by weight per 100 parts by weight of the polymer A.
It is suitably contained in a proportion of 0 to 200 parts by weight.

Polymer B is contained mainly for the purpose of imparting water resistance to the composition. This polymer B is soluble in alcohol and substantially insoluble in water.

It has the property of being compatible with the above polymer A in an alcohol solution. As such polymer B.

For example, (meth)acrylic acid alkyl ester and/or
Alternatively, there is a copolymer of vinyl acetate and a vinyl monomer having a hydrophilic group. The alkyl group of the above (meth)acrylic acid alkyl ester has 3 or less carbon atoms, and the above hydrophilic group includes 10000 groups, -0H groups, secondary amino groups, tertiary amino groups, etc. say. The above (meth)acrylic acid alkyl ester and/or vinyl acetate are contained in the copolymer in a proportion of 40% or more. As polymer B.

In addition, a copolymer containing a predetermined amount of a monomer such as an alkyl (meth)acrylate or vinyl acetate as a copolymerization component in the composition of the polymer A may be used. Since such a copolymer contains a predetermined amount of the above monomer as a copolymerization component, it loses its water-soluble properties.
It has only alcohol-soluble properties. Polymer B is
It is contained in a proportion of 20 to 200 parts by weight per 100 parts by weight of polymer A. Too little polymer B and polymer A
If it is excessive, it will have excellent adhesion to wet mucosal surfaces, but will have poor water resistance. Conversely, if Polymer B is present in excess, the water resistance will increase, but the adhesiveness to wet mucosal surfaces will be poor.

Softener B is compatible with polymer B and has the function of softening it and imparting water resistance. Examples of the softening agent B include triethyl citrate, glycerin triacetate, polyalkylene glycol monoether, diethyl phthalate dibutyl phthalate, butylphthalyl butyl glycolate, and phosphoric triesters. Softener B is contained in a proportion of 30 to 200 parts by weight based on 100 parts by weight of polymer B. If the amount of softener B is too small, the composition as a whole will not exhibit water resistance. When the softener B is in excess, the state of the entire composition varies depending on the content of the polymer B. Polymer B is present in the composition in a relatively large amount (for example, 50 parts by weight of Polymer B based on 100 parts by weight of Polymer A).
(parts by weight or more), the entire composition softens.

When the amount of polymer B is relatively small, for example, the softening agent oozes out over time from the inside of a patch obtained by molding the composition.

The composition of the present invention further contains medicinal ingredients and additives as necessary. As the drug, any drug commonly used in transmucosal preparations can be used, in addition to drugs commonly used in the treatment of external wounds, such as bactericidal agents and antibacterial agents. As an additive other than drugs.

Drug absorption (transfer) enhancer, surfactant, crosslinking agent.

Neutralizing or buffering agents, bactericidal and fungicidal agents, odor component absorbers,
There are 1 filler, 1 coloring agent, and 1 flavoring agent.

The amount of drugs and various additives added depends on their type, but usually a total of 30 parts by weight per 100 parts by weight of the polymer component.
The proportion is less than % by weight.

Each component used in the present invention (polymer A, B; softener A
, B: the above additives, etc.) may be used in combination of two or more.

Although the shape of the oral mucosal preparation using the composition of the present invention is not particularly limited, it is preferably formed into a sheet-like patch. Examples of sheet-like patches include: (1) A patch in which a layer of the above composition is provided on the surface of an insoluble film or sheet made of plastic or the like to a thickness of about 50 to 500 μm; 〉Sheet of the above composition alone (
A patch with a thickness of approximately 100 to 1000 μl11); <3
> Sheet of the above composition alone (thickness approximately 100 tttra
-1000 am) with a protective layer of about 2 to 20 μm thick on one side. Among these, the protective layer of the patch <3> is provided for the purpose of further increasing water resistance, and is made of a relatively water resistant and flexible resin composition. The resin composition is composed of, for example, a cellulose derivative and/or acrylate-based (co)weight, and a softener.

As the above cellulose derivative, cellulose ether and/or cellulose ester are suitable. Examples of cellulose ethers include cellulose alkyl ethers such as ethyl cellulose, propyl cellulose, and butyl cellulose. Cellulose esters include cellulose acetate, cellulose propionate, and cellulose butyrate.

Examples include cellulose valerate, cellulose 7acetate/butyrate, and cellulose acetate/phthalate.

As the acrylate-based (co)polymer, a polymer containing a (meth)acrylic acid alkyl ester as a (co)weight component in a proportion of 40% by weight or more is used. Here, the average number of carbon atoms in the alkyl group of the (meth)acrylic acid alkyl ester is preferably 8 or less, and the number of carbon atoms in the alkyl group is preferably in the range of 1 to 8. For example, propyl acrylate, butyl acrylate, etc. are used.

A softening agent that can soften the polymer for such a protective layer and impart flexibility and toughness (softening agent for the protective layer)
As such, compounds having ester bonds and/or ether bonds in their molecules (eg, 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 alkyls. Etherified product: Glycolic acid ester derivatives such as butylphthalyl butyl glycolate.

There are phthalate esters such as diethyl phthalate and diptylphthalate. These softeners are contained in the protective layer in an amount of 20 to 120 parts by weight per 100 parts by weight of the polymer used in the protective layer.

A patch using the composition of the present invention is prepared by the following method. A patch having a support according to <1> above.

For example, a method of casting (coating) a solution of the composition of the present invention dissolved on a support such as a plastic film and drying; casting a solution of the composition dissolved on a suitable release paper;
It is prepared by drying and adhering a support to the surface of the support. As the solvent for the composition solution, alcohol or hydrous alcohol (20% or less water) is usually used, although it depends on the types of components in the composition used.

Similar solvents are also used in other methods described below.

, <2> A patch consisting of a sheet of the composition alone is prepared by casting a composition solution onto a release paper and drying it. <3> A patch having a protective layer is prepared by a method in which, for example, a composition solution is cast on a release paper and dried, and a solution containing the protective layer composition is applied and dried on the surface; A method of forming a protective layer and forming a composition layer thereon;
It is prepared by forming a composition layer and a protective layer on each of two pieces of release paper and bringing them into close contact with each other. The release paper used in the above method can be peeled off and another protective sheet attached to it for further processing such as cutting or individual packaging.9 Usually, the release paper is used as is as a protective sheet. .

(Function) The patch for oral mucosa using the composition of the present invention thus obtained has appropriate viscoelastic properties and hydrophilicity, and therefore easily adheres to +Y* moistened oral mucosal surfaces. do. This is mainly due to the properties of the combination of polymer A and softener A. Furthermore, this patch has appropriate water resistance.

It is possible to apply it for a long time (usually 2 hours or more). This water resistance is due to the properties of the combination of Polymer B and Softener B in the composition.

A composition consisting only of a combination of polymer B and softener B is soluble in organic solvents such as alcohol, but is substantially insoluble in water. Although polymer A and polymer B have different solubility in water, they can be mixed uniformly in an alcoholic solvent, and even when the solvent is removed, both components remain homogeneously compatible. Therefore, the two properties are expressed together without canceling each other out, and in this way,
The composition of the present invention is obtained which has hydrophilicity and excellent water resistance.

In the composition of the present invention, the softener A softens the polymer A,
Because softener B softens polymer B.

It is flexible as a whole, and therefore can be easily prepared into a sheet-like (thin-like) shape suitable for oral mucosa. Because it is flexible, the patch does not cause any discomfort when used.

The patch of the present invention can be made into a desired patch for oral mucosa by changing the adhesive composition to change the adhesive properties or by incorporating a drug into the adhesive layer. Each component that makes up this patch is non-irritating to the human body, does not exhibit toxicity, and each component is inexpensive.
Moreover, since 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.

(A) Preparation of patch: polyacrylic acid (average degree of polymerization 10
,000; 100 parts by weight of polymer A), 100 parts by weight of glycerin (softener A), 50 parts by weight of methyl methacrylate-meccrylic acid (55:45) copolymer (polymer B; Eudragit L: R7ihm Phara+a), An ethyl alcohol solution containing 15% of a composition consisting of 40 parts by weight of polyoxyethylene (50), polyoxybupropylene (26) glycol monobutyl ether (Uniloop 50MB26: NOF) was prepared. Separately, as a backing base material, the thickness is 80tI1
An internally plasticized vinyl chloride resin film (Nismezoica V: Sekisui Chemical @) of No. 1 was prepared. The above ethyl alcohol solution was cast onto this base material and dried to form an adhesive sheet (patch) with a thickness of 400 μm.

(B) Performance evaluation of patch: The adhesive layer of the patch obtained in section (A) has slight tackiness. When water is applied to this adhesive layer, good adhesiveness is developed. 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 200-500μ-, 1c! 1X
Thirty specimens are 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 at least to a position of 0.5 C11 from the ends. At this time, observe whether or not cracks occur in the test piece.

Next, a rectangular test piece of 6 nn*×12 sizes was obtained from the patch obtained in section (A). 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 30 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 Kitakami's prior art was prepared and evaluated.

(A) Preparation of patch; hydroxypropyl cellulose (viscosity of 2% aqueous solution at 20'C is approximately 5000 cp)
50 parts by weight of polyacrylic acid (20°
The viscosity of a 0.2% aqueous solution in C is approximately 15,000 cps
An aqueous solution containing 50 parts by weight of O. This was cast onto the same base material as in Example 1 and dried.
A sheet-like patch with a thickness of am was obtained.

(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 the adhesive layer of this adhesive patch was relatively hard, it gave the test subject an uncomfortable feeling when applied. As in Example 1, the time required for the patch to dissolve (disintegrate) or peel off was measured. The results are shown in Table 1.

Table 1 (A) Preparation of patch: polyvinylpyrrolidone (BASF
Company: Kolltdon K-90; Polymer A) 10
0 parts by weight, polyoxyethylene (30) polyoxypropylene (33) glycol (softener A) 60 parts by weight, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer (28: 28:
44) (Eudragit E-100: Rijhm
An ethyl alcohol solution containing 45% of a composition consisting of 70 parts by weight of polymer B) and 30 parts by weight of triethyl citrate (softener B) was prepared. This ethyl alcohol solution was cast on release paper and dried to form an adhesive sheet (patch) with a thickness of about 400 μm.

(B) Performance evaluation of patch: The adhesive layer of the patch obtained in Section (A) of this example has slight tackiness.

This patch is a little harder than the adhesive layer of the patch in Example, but when tested in the same manner as shown in Example 1 (B), no cracks were observed and it was sufficiently flexible. It was confirmed that it has sex. 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 30 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 2.

Construction Basis 1 According to the method of Example 2, only Polymer A and Softener A were used. A sheet-like patch with a thickness of 400 μm was prepared. When this patch was pressed against the mucosal surface in accordance with Example 1, it adhered to the mucosal surface in about 30 seconds. Because this patch is flexible, it blends well with the mucous membranes and did not cause any discomfort to the subjects. As in Example 1, the time required for the patch to dissolve (disintegrate) was measured. Table 2 shows the results.
Shown below.

Table 2 (A) Preparation of Polymer A: 30 parts by weight of 3(methacrylamido)propyltrimethylammonium chloride, 2
- An alcoholic solution containing a copolymer having a zero weight average molecular weight of about 320.000 obtained by polymerizing monomers consisting of 40 parts by weight of hydroxypropyl acrylate and 30 parts by weight of butyl acrylate in ethyl alcohol using azobisisobutyronitrile as a catalyst. was gotten. Adjust this alcohol solution to 35%.

It was used to prepare a patch described below.

(B) Preparation of Polymer B: Monomers consisting of 40 parts by weight of vinylpyrrolidone, 20 parts by weight of 2-hydroxypropyl acrylate, 10 parts by weight of vinyl acetate and 30 parts by weight of butyl acrylate in ethyl alcohol.

Polymerization was carried out using azobisisobutyronitrile as a catalyst.

An alcoholic solution containing a copolymer having a weight average molecular weight of 450,000 was obtained. This alcohol solution is 30%
and used for the preparation of the patch described below.

(C) Preparation of patch: Methyl methacrylate-methacrylic acid copolymer (7,1:29) (Eudragit S:
T? ohm Pharma) and 50 parts by weight of triethyl citrate.
An ethyl alcohol solution was prepared containing %.

This was applied to one side of release paper and dried to form a protective layer with a thickness of about 4 μm.

Separately, a solution of polymer A obtained in the above (A) (containing 100 parts by weight of polymer A), diglycerin (softening agent A)
30 parts by weight, N-acetylethanolamine (softener A
) 20 parts by weight, solution of polymer B obtained in section (B) (
(containing 840 parts by weight of polymer) and 40 parts by weight of polyoxyethylene (50) polyoxypropylene (26) glycol monobutyl ether (softener B) were mixed to adjust the solid content to 34%. This was cast onto the above protective layer and dried.

An adhesive layer having a thickness of about 400 μm was formed.

(D) Performance evaluation of patch 2 It was confirmed that the adhesive layer of the patch obtained in Example (C) had good adhesiveness. When the flexibility of the patch was tested in the same manner as shown in Example 1, no cracks were observed, and it was confirmed that it had sufficient flexibility. This patch is Example 1
Although it was softer than the patches obtained in 2 and 2, it was confirmed that it had sufficient shape retention. For example, this patch is cut into a size suitable for practical use (for example, 2 cm x 1 cm), and the longitudinal ends of this test piece are held.

Even when the test piece was held vertically with this holding portion located at the bottom, it did not bend.

Next, when this patch was pressed against the mucosal surface in the same manner as in Example 1, it adhered to the mucosal surface within 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 3.

According to the method of Example 2, only polymer A and softener A were used. A sheet-like patch having a thickness of 404 μm was prepared. When this patch was pressed against the mucosal surface in accordance with Example 1, it adhered to the mucosal surface within about 10 seconds. Because this patch is flexible, it blends well with the mucous membranes and did not cause any discomfort to the subjects. As in Example 1, the time required for the patch to dissolve (disintegrate) was measured. The results are shown in Table 3.

Table 3 (Effects of the Invention) According to the present invention, a composition can be obtained that can be easily applied to the surface of the two oral mucosa and can be used to prepare a patch having water resistance. Since this composition has flexibility, it can be easily prepared into a sheet-like patch. The resulting patch can be applied for a long period of time without causing any discomfort to the surface of the oral mucosa. Because it is water resistant, it can be maintained for a relatively long time without peeling or dissolving.

All components contained in the composition are safe for the human body. Patch preparations prepared using the composition can be widely used for protection of oral trauma or as preparations for transmucosal absorption.

that's all

Claims (1)

[Claims] 1. Polymer A soluble in both alcohol and water
a water-retaining softener A that is compatible with the polymer A and soluble in alcohol; a polymer B that is soluble in alcohol and substantially insoluble in water; a softening agent B that is soluble and substantially insoluble in water;
An oral mucosal patch composition containing as the main ingredient. 2. The polymer A is polyacrylic acid, a salt of polyacrylic acid, a copolymer containing acrylic acid as a main component, a salt of a copolymer containing acrylic acid as a main component, polyvinylpyrrolidone, or vinylpyrrolidone as a main component. copolymer with 4 in the side chain
The claimed invention is at least one polymer selected from the group consisting of a (meth)acrylamide copolymer having a quaternary ammonium salt and a (meth)acrylic acid ester copolymer having a quaternary ammonium salt in its side chain. Range 1
The composition described in Section. 3. The polymer B is a copolymer of a (meth)acrylic acid alkyl ester and a vinyl monomer having a hydrophilic group; and/or a copolymer of vinyl acetate and a vinyl monomer having a hydrophilic group. A composition according to claim 1. 4. With respect to 100 parts by weight of the polymer A, the polymer B is 20 to 200 parts by weight, and the softener A is 20 parts by weight.
~200 parts by weight, and polymer B10
The composition according to claim 1, wherein the softener B is contained in a ratio of 30 to 200 parts by weight based on 0 parts by weight.