JPS61186309A - Composition applicable to mucosa of oral cavity - Google Patents

Abstract

PURPOSE:The titled composition having long duration time of effects, comprising a layer containing a specific amount of a specified polymer, prolonging in a middle degree elution of bacterial plaque decomposing enzyme and a layer comprising the polymer and a polyacrylic acid in a specific ratio, prolonging highly elution of the enzyme. CONSTITUTION:The titled composition for preventing effectively diseases in the oral cavity, bondable easily to the mucosa in the oral cavity for a long time, prolonging elution of bacterial plaque decomposing enzyme into the spittle for a long time, comprising at least two layers of the layer I consisting of (A) one or more selected from polyvinyl pyrrolidone, polyvinyl alcohol, and an alternating copolymer of alginic acid, its pharmaceutically acceptable salt, and/or maleic anhydride and methyl vinyl ether, (B) a bacterial plaque decomposing enzyme and (C) an excipient as essential components, containing 20-50wt% component A based on the total composition of the layer I, prolonging in a middle degree elution of the enzyme B, and the layer II consisting of the components A and B, and (D) a polyacrylic acid and/or its pharmaceutically acceptable salt as essential components in a weight ratio of the component A:D=70:30-95:5, prolonging highly elution of the enzyme B.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a composition that has the effect of suppressing the decomposition of dental plaque and the formation and adhesion of dental plaque. , dextranase, mutanase, and other plaque-degrading enzymes elute into saliva for a long time, so oral diseases such as caries, gingivitis, and alveolar pyorrhea can be effectively prevented by application to the oral mucosa. Regarding the composition.

(Prior Art) Conventionally, studies have been made on gums, toothpastes, etc. to prevent oral diseases such as dental caries, gingivitis, and alveolar pyorrhea.

(Problem that the invention attempts to solve) However, both gum and toothpaste have a short duration of effectiveness.

Furthermore, in toothpaste, there are problems such as deactivation of the active ingredient by other ingredients, and there are restrictions on the formulation.

(Ninth Means for Solving the Problems) In view of the above-mentioned drawbacks of conventional products for preventing oral diseases such as dental caries, gingivitis, and alveolar pyorrhea, the purpose of the present invention is to Glue to food and drink.

The object of the present invention is to provide a new type of oral mucosal composition that does not peel off during normal activities such as conversation, does not give a foreign body sensation, and maintains the elution of plaque-degrading enzymes such as degistranase and mutanase into saliva for a long time. .

As a result of intensive efforts to obtain the desired product, the present inventors discovered a layer (1) that moderately retards the elution of plaque-degrading enzymes such as dextranase and mutanase, and a layer (1) that highly retards the elution of plaque-degrading enzymes such as dextranase and mutanase. ) is a product consisting of two layers.

A friend who found that that purpose could be achieved.

That is, the present invention consists of at least two layers, one layer (I) and one layer (II), and the layer (I) is composed of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salt, maleic anhydride and methyl vinyl ether. One or more polymer components selected from the group consisting of alternating copolymers of

The layer (II) contains a plaque-degrading enzyme, an excipient, and other additives if necessary, and the polymer component is 20 to 50% by weight based on the total composition of the layer (I). One or more polymer components (A) selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, alternating copolymers of maleic anhydride and methyl vinyl ether, and polyacrylic Contains one or more polymer components (B) selected from the group consisting of acids and pharmaceutically acceptable salts thereof, a plaque-degrading enzyme, and if necessary excipients and other additives, and the polymer component This is a composition for application to oral mucosa, characterized in that the weight ratio of component (A) to polymer component (B) is 70=30 to 95:5.

Polyvinyl pyrrolidone, polyvinyl alcohol used in the above layers (I) and (I[).

Alginic acid and its pharmaceutically acceptable salts, alternating copolymers of maleic anhydride and methyl vinyl ether are copolymers of two or more elements with one or more other monomers, as long as they do not affect their physicochemical properties; Also included are crosslinked polymers crosslinked with suitable crosslinking agents. In order not to affect the physicochemical properties.

It is desirable that the copolymerization ratio of other heptamers is 30 mo/I/% or less. The pharmaceutically acceptable salts herein include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts, and the like.

Other polymer components used in layer (I[), Polyac I
)) In the case of acid and its pharmaceutically acceptable salts, homopolymers, copolymers of two or more elements with one or more other monomers, crosslinked polymers crosslinked with a suitable crosslinking agent, etc. In the case of a copolymer, it is preferable that other monomers are copolymerized in an amount of 30 moles or less so that it is included in this and does not affect the physicochemical properties of the homopolymer.

Suitable examples include Carbopol 934■ and Carpopol 1v.
Commercially available products such as 940■ and CABOPO/L'941■ can be used.

The plaque-degrading enzyme used in the present invention refers to an enzyme that has the ability to decompose dental plaque and inhibit its formation and adhesion. Examples include dextranase, mutanase, and the like. It is reasonable to include 200 to 100,000 units of plaque-degrading enzyme per 1f of the total composition of layer (I) or layer (II).

The excipient used in the present invention is starch.

Crystalline cellulose, dextrin, am, mannide,
Examples include sorbitol and anhydrous calcium phosphate.

The oral mucosal application composition provided by the present invention is manufactured using polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, and a pharmaceutically acceptable salt thereof.

One or more selected from the group consisting of alternating copolymers of maleic anhydride and methyl vinyl ether may contain two or more polymer components, plaque-degrading enzymes, excipients, and, if necessary, to improve appearance or odor. For this purpose, lubricants, binders,
A method in which a flavoring agent and one or more coloring agents are sufficiently mixed to form a uniform mixture, and an appropriate amount of the mixture is directly pressure-molded using a punch, die, or press.

Alternatively, υ can be formed by pressure molding through an appropriate granulation process.
After forming the layer (1), one or two selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, and alternating copolymers of maleic anhydride and methyl vinyl ether are added. One type selected from the group consisting of the above polymer component (A), polyacrylic acid, and a pharmaceutically acceptable salt thereof is two or more types of polymer component (B) and a plaque-degrading enzyme, and furthermore, necessary Lubricants, binders, excipients, flavorings, 1M coloring agent, depending on the requirements
It can be easily produced by placing a species or a mixture of two or more species uniformly on the layer (1) and applying further application.

Another method for producing the composition for oral mucosa provided by the present invention is to separately dissolve the components constituting each of layers (I) and (II) in a suitable solvent, and then cast the solution and undergo a transfer step. Form it on a thin film and paste it with a suitable adhesive, or
Bilayer tablets can be obtained either by moistening with water or other solvents and pressing, or by applying heat.

Examples of lubricants that may be used as necessary include talc, stearic acid and its salts, and waxes, and examples of binders include starch, dextrin, tofugant, and gelatin.

Examples of excipients include starch, crystalline cellulose, dextrin, milk fas mannitol, sorbitol, anhydrous calcium phosphate, etc., and flavoring agents include citric acid, tumatric acid, tartaric acid, and menthol. , citrus flavor, etc.

In the present invention, layer (I) or layer (I[) contains a bactericidal agent or an antibacterial agent.

Preservatives etc. may be included.

Application of the product of the present invention is not particularly limited, and the layer (I[) side is applied to the gums and inner cheek mucosa. The layer (1) side of the product of the present invention also has adhesive properties to the mucous membrane due to the presence of the adhesive polymer, but if this is applied, for example, by adhering the layer (n) side to the outside of the gums, then one layer ( I
) side may adhere to the buccal mucosa, but this does not pose any problem.

Layer (I) is one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, and alternating copolymers of maleic anhydride and methyl vinyl ether. ta is two or more polymer components. ,
It contains a plaque-degrading enzyme and an excipient as essential components, and the effect of moderately delaying the release of the plaque-degrading enzyme is brought about by the polymer component. In addition to the above-mentioned polymer components, plaque-degrading enzymes, and excipients, this layer can contain other additives as necessary, but in order to appropriately delay the elution of the drug, It is necessary that the above polymer component constitutes 20% to 50% by weight of the total composition in layer (1). If the above polymer component is less than 20% by weight, the elution of the plaque-degrading enzyme is too fast and the elution cannot be sustained for a long time even when combined with a layer that highly retards elution. Because of this delay, it cannot serve as a layer that moderately delays elution.

On the other hand, the first layer (I[) is selected from the group consisting of polyvinylpyrrolidone, polyvinylalco-1v% alginic acid, and pharmaceutically acceptable salts thereof; one or two selected from the group consisting of acrylic acid and its pharmaceutically acceptable salts;
More than one polymer component (B).

The three components of the plaque-degrading enzyme are essential components, and the effect of highly delaying the release of the plaque-degrading enzyme is brought about by the combination of the polymer component (A) and the polymer component (B). The polymer component (A) alone does not have a sufficient release retardation effect, and the (B) component alone exhibits a sufficient release retardation effect, but the swelling property is too strong, resulting in a strong foreign body sensation. From this point of view, it is necessary that the weight ratio of the polymer component (A) and the polymer component (B) is 70=30 to 95:5. Excipients and other additives can be added to the layer (II) as necessary, but in order to fully demonstrate their effects, (A), (B), and plaque-degrading enzymes are required. Additives other than 20% by weight or less of the food composition in layer (I[), especially 1
It is preferably 0% by weight or less. The nine-layer (If) has strong adhesion to the oral mucosa due to the presence of both the adhesive polymer components (A) and (B).

(Effects of the Invention) As mentioned above, the present invention provides a composition for application to oral mucosa comprising at least two layers: a layer (I) that moderately retards the release of plaque-degrading enzymes and a layer (I[) that highly retards the release of plaque-degrading enzymes. It is a thing,
A new type of oral mucosal composition that exhibits long-term release of plaque-degrading enzymes, easily adheres to the oral mucosa, does not come off easily during normal activities such as eating, drinking, and talking, and does not give any foreign body sensation. It is.

The greatest feature of the product of the present invention is that the rate of elution of plaque-degrading enzymes into saliva is sustained over a long period of time. It is expected that the prevention efficiency of internal diseases can be greatly improved.

The second feature of the product of the present invention is that it easily adheres to the oral mucosa and remains adhesive for 4 to 24 hours.

It is about sustaining. Moreover, this adhesiveness is drunk.

It is not affected by daily oral movements such as smoking, drinking coffee, eating, and talking.

The feature of 1g3 of the product of the present invention is that the molded product swells with saliva in the mouth and becomes extremely soft, so there is almost no foreign body sensation.

The fourth feature of the product of the invention is that it moderately retards the elution of plaque-degrading enzymes! fj (I) and /m by changing the composition in the highly retarded layer (π).

Adhesion and durability can be adjusted arbitrarily, and the layer (I
) and layer (II), it is possible to arbitrarily obtain the next optimum elution performance depending on the action of the plaque-degrading enzyme.

(Examples) Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. In the examples, parts or q indicate parts by weight or % by weight.

Test method 1. Elution test of dental plaque degrading enzyme After slightly wetting the π-layer side of a Trackfield-type tablet prepared in the same manner as shown in Example 1 with water, 100 g/
Press the tablet from the bottom of the beaker so that the center of the tablet is located on the wall of 3cf11, and fix it so that the short axis is parallel to the water surface. Then, 0.2M acetate buffer (pH
5,5) Pour 100 liters into a beaker and start stirring. While keeping the test solution at 40°C with a stirring speed of 100 rpm, sample 3 ml at a time, and for each sampling, add the same amount of 0.2 M acetate buffer (pH 5,
5) and keep the content at 100 g/l at all times. The collected sample was filtered with a membrane filter (pore size: 5 μm), and 1 ml of solution F was used as a test solution.

In the case of dextranase, add dextran, and in the case of mutanase, add a high unit of dextran degrading enzyme (commercial product) to the suspension of mutan, and at 400% α-1,6 in mutan.
- Dissolve or suspend mutan whose glucoside bond has been cleaved in a 0.2 M acetate buffer to a concentration of 0.5%.

After reacting 1 ml of this solution with the test solution at 400° C. for 10 minutes, the released subreducing sugar was quantified by the Somogyi-Nerlan method and the elution rate was determined with the theoretical value as 100%.

Example 1゜(I) layer polyvinylpyrrolidone (molecular weight 40,000) 28.6
5% d-mannido/L'
66.85 Tidextowonase (500,000 units/P)
3% vanilla powder
1% Magnesium Stearate
0.5% food red No. 3
0.002% After uniformly mixing the above composition, it was compressed to form (1) a layer.

(I[) layer polyacrylic acid 6.6
9% polyvinylpyrrolidone (molecular weight 360,000) 88
．． 8: 2% dextranase (500,000 units/P)
3% vanilla powder
1% Magnesium Stearate
0.5% After uniformly mixing the above (I[) layer composition, it was placed on the above (I) layer and compressed into tablets with a weight of 70 cm and a thickness of 1.5%.
A track field type two-layer tablet with a length of 75 cod, a major axis of B, a bar, and a minor axis of 4.4H was obtained.

Perform a dissolution test using the obtained product according to Test Method 1. The results are shown in FIG.

Example 2゜(I) layer polyvinylpyrrolidone (molecular weight 40,000) 29.2
5% d-mannitol 68.
25% mutanase (100,000 single tears/2)
1 Chipanilla powder
1% Magnesium Stearate 0
．． 5% food red No. 3 0.
02% (II) layer polyacrylic acid 6.
83% polyvinylpyrrolidone (molecular weight 360,000) 9
0.68% mutanase (100,000 units/2)
1 vanilla powder
1% Magnesium Stearate
A two-layer tablet similar to 0.5% Example 1 was obtained.

A dissolution test was conducted using the obtained product according to Test Method 1. The results are shown in FIG.

Comparative example 1. Monolayer tablet consisting of layer (I) of the present invention polyvinylpyrrolidone (molecular weight 40,000) 29%d
- Mannitol 68.5 Ti Vanilla Powder 1 Ti Magnesium Stearate 00
5% dextranase (1 million unit m/P)
1% After uniformly mixing the above composition, it was compressed into tablets, weight 70kg, thickness 1.751+1, major axis 8.8ff, minor axis 4.4M.
A truck field type single layer tablet was obtained.

A dissolution test was conducted using the obtained product according to Test Method 1. The results are shown in FIG.

Example 3 The two-layer tablet formulation of Example 1.2 was evaluated for foreign body sensation and adhesiveness on two subjects per type, and both showed adhesiveness for 8 hours or more. None of the subjects complained of foreign body sensation.

[Brief explanation of the drawing]

FIG. 1 shows the elution test results of the products of Example 1 and Comparative Example 1 containing dextranase. In FIG. 1, - by - indicates Example 1. The first one is Comparative Example 1
shows. Figure 2 shows the elution test results for the product of Example 2 containing mutanase. 1st day B'rP? (hrs,) 2nd @ 1 interval (hrs)

Claims (1)

[Claims] Consisting of at least two layers, layer (I) and layer (II),
The layer (I) is polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and a pharmaceutically acceptable salt thereof,
Contains one or more polymer components selected from the group consisting of alternating copolymers of maleic anhydride and methyl vinyl ether, a plaque-degrading enzyme, an excipient, and other additives if necessary, and the polymer component is 20 to 50% by weight based on the total composition of the layer (I), and the layer (II) contains polyvinylpyrrolidone, polyvinyl alcohol, alginic acid and its pharmaceutically acceptable salts, maleic anhydride and methyl vinyl ether. One or more polymer components selected from the group consisting of alternating copolymers of (A) and one or more polymer components selected from the group consisting of polyacrylic acid and pharmaceutically acceptable salts thereof. contains polymer component (B), plaque-degrading enzyme, and if necessary, excipients and other additives, and the weight ratio of polymer component (A) and polymer component (B) is 70:30 to 95:5. A composition for application to oral mucosa.