JPS63189484A - Pressure-sensitive adhesive composition for oral mucosal application agent - Google Patents

Abstract

PURPOSE:To obtain the titled composition, containing vinylpyrrolidone (co)polymer, carboxymethyl cellulose having a specific viscosity and a water holding softener, having viscoelastic flexibility as well as excellent tackiness and water resistance. CONSTITUTION:The aimed inexpensive composition, obtained by containing (C) 20-400pts.wt. water holding softener, e.g. at least one of glycerol, diglycerol, triglycerol, sorbitol and maltitol, in 100pts.wt. total amount of (A) vinylpyrrolidone (co)polymer and (B) carboxymethyl cellulose having >=1,000cP viscosity of a 1% aqueous solution at 20 deg.C, preferably at 95:5-60:40 weight ratio, having both water resistance and water solubility, capable of finally dissolving and disappearing in the oral cavity without giving toxicity or irritancy to human bodies.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to an adhesive composition for a thin film-like (film-like or sheet-like) oral mucosal patch, particularly an adhesive composition having viscoelastic flexibility. The present invention also relates to an adhesive composition for oral mucosa patch having excellent adhesiveness and water resistance.

(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 affected areas. 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 hydroxypropylcellulose and polyacrylic acid or its salt (Japanese Patent Publication No. 58
-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, single tablets, troches, granules, and the like have a small application area, resulting in poor drug administration and insufficient mucosal protection. Due to lack of flexibility.

Adhesiveness is also low.

In order to solve these drawbacks, it has been proposed to form bioral mucosal preparations into thin lamellar forms. However, even if the compositions used for tablets, troches, granules, etc. are processed into thin lamellar forms, they cannot be applied to the oral mucosa because they lack flexibility and adhesiveness. It has poor water resistance and dissolves and disperses in a short time. Moreover.

The resulting thin film is likely to be cranked. Even if a softener is added to the composition to impart flexibility and tackiness, although plastic softness increases, viscoelastic flexibility (stretchable flexibility) cannot be obtained.

For this reason, there is a need for an adhesive composition for forming a thin film-like preparation for oral mucosa. For example, in Japanese Patent Application Laid-open No. 59-232553, acrylic acid (co-)
A pressure-sensitive adhesive composition containing a polymer or a water-soluble salt thereof; at least one selected from sodium carboxymethyl cellulose, sodium alginate, and hydroxyethyl cellulose; and glycerin and/or propylene glycol is disclosed. Also, JP-A-5
9-19681/1, gelatin or agar;
Adhesive compositions are disclosed that include gluten; carboxyvinyl polymer; polyhydric alcohol; and vinyl acetate resin or gums. However, neither composition.

Viscoelastic flexibility and adhesion are not sufficient. It also lacks water resistance. Therefore, application to the oral mucosa is not preferred.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional problems, and its purpose is to provide a material that has viscoelastic flexibility and excellent adhesiveness and water resistance. An object of the present invention is to provide an adhesive composition for an oral mucosal patch. Another object of the present invention is to provide an adhesive composition for an oral mucosal patch that can form a thin-film oral mucosal patch. Still another object of the present invention is to provide an adhesive composition for an oral mucosal patch that can control viscoelastic flexibility, adhesiveness, and water resistance over a wide range. Yet another object of the present invention.

An object of the present invention is to provide an adhesive composition for an oral mucosal patch that is sticky when dry or becomes sticky when moisture is absorbed. Still another object of the present invention is to provide an adhesive composition for an oral mucosal patch that can finally dissolve and disappear within the oral cavity. Still another object of the present invention is to provide an adhesive composition for an oral mucosal patch that is not toxic or irritating to the human body. Still another object of the present invention is to provide an adhesive composition for an oral mucosal patch that can be obtained at low cost.

(Means for Solving the Problems) The present invention provides an adhesive composition that has viscoelastic flexibility and excellent adhesiveness by combining a vinylpyrrolidone (co)polymer and a water-retaining softener. Furthermore, this composition has a viscosity of 1% aqueous solution at 20°C of 1.
If carboxymethylcellulose or a salt thereof having a cell diameter of 0,000 centivoids or more is blended, the water resistance of the adhesive composition is improved.

It was completed based on the inventor's knowledge.

The adhesive composition for oral mucosal patch of the present invention is as follows.

The above object is achieved by containing a vinylpyrrolidone (co)polymer, carboxymethylcellulose or a salt thereof having a viscosity of 1% aqueous solution at 20°C of 1000 centivoise or more, and a water-retaining softener.

The weight ratio of the vinylpyrrolidone (co)polymer and the above carboxymethyl cellulose or its salt is 95:5 to 60
: 40. Preferably 90:10 to 65:
35, and 1 for the total amount of 100 parts by weight of both,
The water retention softener is 20 to 400 parts by weight, preferably 50 to 400 parts by weight.
It is contained in a range of 300 parts by weight. The upper limit of the water retention softener is 200% in the case of glycerin or diglycerin.
The parts by weight are 250 parts by weight in the case of triglycerin, 300 parts by weight in the case of sorbitol, and 400 parts by weight in the case of maltitol. Vinylpyrrolidone (
If the amount of the co)polymer is less than the above range, the viscoelastic flexibility and adhesiveness of the resulting pressure-sensitive adhesive composition will decrease. On the other hand, if the amount of vinylpyrrolidone (co)polymer is excessive and the amount of carboxymethylcellulose or its salt is too little, water resistance will be insufficient and it will easily dissolve and disappear in water. The amount of the water-retaining softener is determined based on the total amount of the vinylpyrrolidone (co)polymer and the carboxymethyl cellulose or its salt. If the water retention softener has too few stars, the desired flexibility and adhesiveness cannot be obtained. If the amount of water-retaining softener is excessive, water resistance will decrease.

Vinylpyrrolidone (co)polymers include polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, and the like. This copolymer has one example.

The acrylic ester may be contained in a proportion of 20% by weight or less.

If carboxymethylcellulose is used alone, the resulting oral mucosal patch tends to disintegrate5, so it is usually converted into a salt form or used in combination with a salt of carboxymethylcellulose. Examples of salts of carboxymethylcellulose include sodium carboxymethylcellulose.

Water retention softeners include, for example, glycerin, diglycerin, triglycerin, sorbitol, and maltitol. This softener imparts flexibility and tackiness to the resulting pressure-sensitive adhesive composition, and is also used to adjust water solubility.

This tackifying effect is thought to be due to the direct effect of the liquid softener and the effect of water absorbed by the softener from the air.

Commercially available vinylpyrrolidone (co)polymers include:

For example, Koliton-90 (polyvinylpyrrolidone).

Koliton ni'to (polyvinylpyrrolidone, medium viscosity pore), Koliton -25 (polyvinylpyrrolidone, low viscosity product), Koliton VA-64 (vinylpyrrolidone-vinyl acetate (6/4) copolymer) ) (Both are B
(manufactured by ASF).

Commercially available carboxymethylcellulose or its salts include 9, for example, Cellogen-F-3H (sodium carboxymethylcellulose, manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.).

The viscosity of a 1% aqueous solution is approximately 1300 cps at 20°C),
Celogen-FBSII-6 (sodium carboxymethyl cellulose, manufactured by Daiichi Kogyo Seiyaku Co., Ltd. The viscosity of a 1% aqueous solution is approximately 3500 cps at 20°C), Celogen-FBSH
-10 (sodium carboxymethyl cellulose, manufactured by Daiichi Kogyo Seiyaku Co., Ltd. The viscosity of a 1% aqueous solution is approximately 5000 at 20°C.
cps), Celogen-FBSH-12 (sodium carboxymethylcellulose, manufactured by Daiichi Kogyo Seiyaku Co., Ltd. 1%
The viscosity of the aqueous solution is approximately 8000 cps at 20°C), C
MC-Daicel-2100 (carboxymethylcellulose sodium, manufactured by Daicel Chemical Co., Ltd., viscosity of 1% aqueous solution is about 3000 cps at 20°C).

CMC-Daicel-2260 (sodium carboxymethyl cellulose, manufactured by Daicel Chemical Co., Ltd., viscosity of 1% aqueous solution is approximately 5000 cps at 20°C), CMC-Daicel-2170 (sodium carboxymethyl cellulose, manufactured by Daicel Chemical Company, viscosity of 1% aqueous solution is approximately 20 cps) Approximately 7 degrees Celsius
000cps).

The adhesive composition of the present invention includes, in addition to vinylpyrrolidone (co)polymer, carboxymethylcellulose or a salt thereof having a viscosity of 1% aqueous solution at 20°C of 1000 centipoise or more, and a water-retaining softener.

Water-soluble polymer, organic filler, inorganic filler, crosslinking agent 1 coloring agent, preservative, stabilizer, fragrance, if necessary.

Flavoring agents etc. are added. These additives are added in a proportion of 20% or less of the total components.

If it exceeds 20%, the physical properties of the adhesive composition (viscoelastic softness, softness, adhesiveness, water resistance, etc.) will be impaired.

The adhesive composition of the present invention is manufactured into an oral mucosal patch in the following manner, for example.

Vinylpyrrolidone (co)polymer, carboxymethyl cellulose or its salt having a viscosity of 1% aqueous solution at 20°C of 1000 centiboise or more, and a water-retention softener are separately dissolved in water, alcohol, etc., and the desired components are dissolved. A pressure-sensitive adhesive composition solution is prepared by mixing each solution in a proportionate manner.

This solution is cast onto the release side of a silicone release polyethylene terephthalate (PUT) film on one side and dried. Furthermore, a silicone release layer is layered on the surface for protection. By peeling off the PET film,
A Wj leaflet-shaped oral mucosa patch is obtained. Instead of PET film, use engineered paper (a laminate of OPP film and kraft paper).

The adhesive composition solution may be cast on the surface of the polyether-based polyurethane film that has been temporarily bonded onto the OPP surface and dried. In this case, the oral mucosa patch is obtained by peeling off the process paper. There is no particular limit to the thickness of the thin film, and it is from 50 to
500 μm is preferable, and 100 to 200 μm is more preferable.

(Function) According to the present invention, an adhesive composition for an oral mucosa patch having viscoelastic flexibility and excellent adhesiveness and water resistance can be obtained. This pressure-sensitive adhesive composition has viscoelastic flexibility and excellent adhesiveness due to the vinylpyrrolidone (co)polymer and the water-retaining softener. Water resistance is improved by adding carboxymethyl cellulose or a salt thereof having a viscosity of 1000 centipoise or more at C. Water resistance is due to the synergistic effect of vinylpyrrolidone (co)polymer and carboxymethylcellulose or its salt.

Further improvements will be made.

In the present invention, vinylpyrrolidone (co)polymer.

Carboxymethylcellulose or a salt thereof having a viscosity of 1000 centipoise or more at 20°C in a 1% aqueous solution,
By varying the ratio of water-retaining softeners, viscoelastic flexibility, tackiness, and water resistance can be adjusted over a wide range.

The higher the proportion of vinylpyrrolidone (co)polymer, the higher the tackiness. On the other hand.

If the amount of carboxymethyl cellulose or its salt is increased, water resistance will be improved. In order to obtain viscoelastic flexibility and tackiness, a water-retaining softener is added depending on the ratio of the vinylpyrrolidone (co)polymer to the carboxymethyl cellulose or its salt. Depending on the amount of the water-retaining softener added, it is also determined whether the adhesive becomes sticky upon drying or becomes sticky upon absorption of moisture. If the amount of water-retaining softener is large, it will become sticky even when dry. However, water resistance decreases and water solubility increases. If there is less water retention softener, the tackiness will be reduced.

The adhesive composition of the present invention can also finally dissolve and disappear within one oral cavity. Therefore, there is no need to peel it off after application.

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

(1) Preparation of adhesive composition Polyvinylpyrrolidone (Koriton-90, manufactured by BASF) 90 parts by weight Sodium carboxymethyl cellulose (Celogen-F
BS11-12. (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) 10 parts by weight Maltitol 200 parts by weight The above formulations were mixed to prepare an adhesive composition solution. However, polyvinylpyrrolidone was dissolved separately as a 25% aqueous solution, sodium carboxymethylcellulose was dissolved as a 4% solution in a mixed solvent of water/ethyl alcohol (9515 weight ratio), and maltitol was dissolved as an 80% aqueous solution to obtain the above composition. Each solution was mixed.

Since this adhesive composition has tackiness when dry, it can be bonded immediately.

(2) Preparation of oral mucosal patch 8% of 40 parts by weight of ethyl cellulose (Ethocel 45 cps, manufactured by Dow Chemical Company) and 60 parts by weight of hydroxypropyl cellulose (Nisso HPC-M, manufactured by Nippon Soda Company)
An ethyl alcohol solution was prepared. This solution was applied to 9 polyethylene terephthalate (PE) with silicone releasable surface on one side.
T) 30 μm on the peelable side of the film (thickness: 50 μm)
It was coated thickly. on this coated surface.

(The adhesive composition solution obtained in step 11 was cast and dried to a dry thickness of 150 μm, and a silicone release paper was layered on the surface for protection. The resulting laminate also had adhesive properties.
By peeling off the film.

An oral mucosal patch was prepared. This patch may be impregnated with a medicinal ingredient if necessary, for example.

Cut to 10m x 2CI11. The product is supplied in a suitable moisture-proof packaging bag, and the silicone release paper is peeled off at the time of application.

(3) Evaluation of oral mucosal patch The oral mucosal patch obtained in (2) was placed in a 1 cm x 1
It was cut into cm pieces and pasted on the buccal mucosal surface of one oral cavity. the result.

This patch was kept for about 140 minutes and eventually disappeared naturally due to dissolution.

Tip 1 (1) Preparation of adhesive composition 80 parts by weight of polyvinylpyrrolidone (Koriton-90, manufactured by BASF) Sodium carboxymethyl cellulose (Celogen F-
BSI+-6. (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) 20 parts Glycerin 30 parts Maltitol 50 parts by weight The above formulations were mixed to prepare an adhesive composition solution. However, polyvinylpyrrolidone was dissolved as a 25% aqueous solution, sodium carboxymethyl cellulose was dissolved as an 8% solution in a water/ethyl alcohol mixed solvent (9515 weight ratio), and maltitol was dissolved as an 80% aqueous solution, and glycerin was added to these. Each solution was mixed to obtain the above composition.

This adhesive composition is slightly tacky when dry and increases in tackiness upon absorption of moisture.

When a patch using this composition is applied to the oral mucosa, it gives a retention time comparable to that of the patch prepared in Example 1,
Eventually, it will disappear naturally through dissolution.

Fruit patch main (1) Preparation of adhesive composition Polyvinylpyrrolidone (Koriton-90, manufactured by BASF) 70 parts by weight Sodium carboxymethyl cellulose (CMC-Daicel 2170, manufactured by Daicel Chemical Co., Ltd.) 30 parts by weight Sorbitol 20 parts by weight Maltitol
60 parts by weight of the above formulation was mixed to prepare an adhesive composition solution. However, polyvinylpyrrolidone is a 25% aqueous solution, and carboxymethylcellulose sodium is a water/ethyl alcohol mixed solvent (951
5% by weight) and maltitol as a 6% solution of 8
Each was dissolved separately as a 0% aqueous solution, and each solution was mixed to give the above composition.

Although this adhesive composition is flexible, it does not have tackiness when dry, and becomes tackiness by absorbing moisture.

If a patch using this composition is applied to the oral mucosa, it will last approximately 1.5 to 2 times as long as the patch prepared in Example 1, and will eventually disappear naturally by dissolution.

(2) Production process of oral mucosal adhesive patch On the surface of the polyether-based polyurethane film (thickness 50 μm) that is temporarily adhered to the OPP surface of the paper (laminate of OPP film and kraft paper),
The adhesive composition solution obtained in step 11 was dried to a thickness of 1
It was cast and dried to a thickness of 30 μm.

Next, one oral mucosa patch was prepared by peeling off the processing paper from the obtained laminate. This patch is easy to handle because it is not sticky when dry. Adhesiveness develops by absorbing moisture. This patch is cut into an appropriate size and suitably used for protecting an injured part of the oral cavity or for local fixation of transmucosal tablets.

(3) Evaluation of oral mucosal patch The oral mucosal patch obtained in (2) was
It was cut into crn pieces and pasted on the buccal mucosal surface of one oral cavity. the result.

This patch was kept for about 300 minutes, and finally a polyether-based polyurethane film remained, which peeled off naturally.

Polyvinyl pyrrolidone (Koriton-30, manufactured by BASF) 35 heavy feet Vinyl pyrrolidone-vinyl acetate copolymer (Koridoor VA
-64, manufactured by BASF) 30 parts by weight Sodium carboxymethylcellulose (CMC Daicel-2260, manufactured by Daicel Chemical) 35 parts by weight Maltitol
300 parts by weight of the above formulation was mixed to prepare an adhesive composition solution. However, polyvinylpyrrolidone is 40%
As aqueous solutions, vinylpyrrolidone-vinyl acetate copolymer is used as a 30% aqueous solution, sodium carboxymethylcellulose is used as a 12% solution in a water/ethyl alcohol mixed solvent (9515 weight ratio), and maltitol is used as a 80% aqueous solution.
% aqueous solution, and the solutions were mixed to give the above composition.

This adhesive composition was very flexible and showed strong tack even when dry.

(2) Preparation of oral mucosal patch 1 An oral mucosal patch was produced in the same manner as in Example 1 using the adhesive composition solution obtained in (1). However, 30 parts by weight of ethyl cellulose and 70 parts by weight of hydroxypropyl cellulose were blended, and these ethyl alcohols were used for coating.

(3) Evaluation of oral mucosal patch The oral mucosal patch obtained in (2) was 1 cm x 1
It was cut into cm pieces and pasted on the buccal mucosal surface of the oral cavity. the result.

This patch was retained for about 90 minutes and eventually disappeared naturally due to rock debris.

(Effect of the invention) The adhesive composition for oral mucosal patch of the present invention is as follows.

As described above, it has viscoelastic flexibility and is excellent in adhesiveness and water resistance. Therefore, according to this composition. A lamellar oral mucosa patch can be formed.

Because it has excellent water resistance, it can be retained in the oral cavity for a certain period of time.

The viscoelastic flexibility, adhesiveness, and water resistance of the adhesive composition.
Adjustment is possible over a wide range.

Therefore, the retention time of the obtained oral mucosal patch in the oral cavity can be adjusted. This adhesive composition has tackiness when dry or becomes tackiness by absorbing moisture. Moreover, this composition has both water resistance and water solubility. It may eventually dissolve and disappear in the oral cavity. It is not toxic or irritating to the human body, and can be obtained at low cost.

For this reason, the adhesive composition for the oral mucosal patch of the present invention can be used to treat localized areas of the oral mucosa and diseases (stomatitis, lochitis, glossitis, wisdom teeth periodontitis, alveolar pyorrhea).

It can be effectively used as a preparation to be applied to areas (such as gingivitis) to protect and treat the area; and a preparation to absorb drugs through the oral mucosa to obtain a systemic therapeutic effect.

Claims (1)

[Claims] 1. Vinylpyrrolidone (co)polymer, 1% aqueous solution of 20
An adhesive composition for an oral mucosal patch containing carboxymethyl cellulose or a salt thereof having a viscosity of 1000 centipoise or more at °C, and a water-retaining softener. 2. The weight ratio of the vinylpyrrolidone (co)polymer and the carboxymethyl cellulose or its salt is 95:5.
The oral mucosa patch according to claim 1, wherein the water-retaining softener is contained in an amount of 20 to 400 parts by weight based on 100 parts by weight of the total amount of both. Adhesive composition for. 3. The water retention softener is glycerin, diglycerin,
The adhesive composition for an oral mucosal patch according to claim 1, which is at least one of triglycerin, sorbitol, and maltitol.