JP6842381B2 - Oral mucosa patch - Google Patents

Description

The present invention relates to a film-like patch used by sticking to the oral mucosa.

Several oral mucosal patches are known for the purpose of drug absorption via the oral mucosa, sterilization of the oral cavity, treatment of stomatitis, etc., and a film preparation having excellent usability is particularly effective as a dosage form. .. For example, a three-layer film preparation containing fentanyl, which is an opioid analgesic (Patent Document 1), and a five-layer film preparation containing nicotine, which is a smoking cessation aid (Patent Document 2), are shown. In both cases, the drug is absorbed from the oral mucosa and acts on the whole body. In addition, an oral mucosal patch that protects the affected area of stomatitis from physical irritation and at the same time releases the drug to the affected area is also known, and is a three-layer type containing a steroidal agent or a non-steroidal agent having an anti-inflammatory effect. (Patent Document 3) is shown.

On the other hand, the oral mucosal patch needs to have sufficient adhesiveness to the oral mucosa in order to obtain a reliable medicinal effect because it is exposed to saliva in the oral cavity. From this point of view, Patent Document 4 describes adhesion to the oral mucosa by adding a carboxyvinyl polymer and at least one selected from tragant gum, xanthan gum, gellan gum, carrageenan and sodium alginate to a film preparation based on hypromerose. Film formulations for the treatment of stomatitis with improved sex have been shown. This preparation has a property that a carboxyvinyl polymer easily forms a splinter when it is dissolved in ethanol or water in the process of preparing a coating liquid, and there is a problem that special care is required at the time of preparation. Further, Patent Document 5 describes a film preparation in which the hardness, elasticity, solubility and adhesive strength of the base are controlled by adding tannic acid to a film preparation containing hydroxypropyl cellulose and / or polyvinylpyrrolidone as a base. It is shown.

Japanese Unexamined Patent Publication No. 2010-138123 Japanese Unexamined Patent Publication No. 2010-138124 Japanese Unexamined Patent Publication No. 61-280423 Japanese Unexamined Patent Publication No. 2016-11293 Japanese Unexamined Patent Publication No. 07-187993

Usually, when a film-like patch is applied to the oral mucosa, the patch is taken on the fingertip and attached to the oral mucosa. At this time, if it is not possible to distinguish whether the surface to be taken by the fingertip is the front surface or the back surface, the surface having the drug-containing layer cannot be correctly attached to the mucous membrane, and the desired medicinal effect cannot be obtained. In addition, when the patch attached to the oral mucosa is white or the like, there is a problem that the patient feels uncomfortable.
Therefore, the subject of the present invention is that when the film is attached to the oral mucosa, the front surface and the back surface can be clearly distinguished, the film can be correctly applied, and the desired medicinal effect can be obtained. The purpose is to provide a good film-like intraoral mucosal patch.

Therefore, the present inventor has three layers of the oral mucosal patch, a layer for taking the drug-free transparent support layer of the surface layer as a finger, and a water-soluble polymer as the base of the two drug-containing layers, and the surface side. If the layer has a hue similar to the color of the oral mucosa and the sticking surface contains an opaque agent, the water-soluble polymer provides sufficient adhesiveness of the drug-containing layer, and it is easy to remove with a finger and the surface. It was found that it is possible to distinguish it from the back side. It was also found that the composition of the water-soluble polymer of the drug-containing layer and the addition of tannic acid improve the adhesiveness to the oral mucosa and the feeling of use.

That is, the present invention provides the following [1] to [6].

[1] A film-like oral mucosal patch having the following layers (a), (b) and (c) in order from the surface side after application.
(A) Drug-free transparent support layer,
(B) A drug-containing layer containing a drug, a water-soluble polymer, and one or more colorants selected from yellowish, orange-based and red-based.
(C) A drug-containing layer containing a drug, a water-soluble polymer, and an opacity agent.
[2] The film-like oral mucosal patch according to [1], wherein the support layer contains a water-insoluble polymer.
[3] The film-like oral mucosal patch according to [1] or [2], wherein the opacity agent is one or more selected from titanium oxide, zinc oxide and magnesium oxide.
[4] The film-like oral mucosal patch according to any one of [1] to [3], wherein the layers (b) and (c) further contain 0.5 to 4.5% by mass of tannic acid.
[5] The film-like oral mucosal patch according to any one of [1] to [4], wherein the water-soluble polymer is polyvinylpyrrolidone and hydroxypropyl cellulose.
[6] The film-like oral mucosal patch according to [5], wherein the content mass ratio of polyvinylpyrrolidone to the total amount of polyvinylpyrrolidone and hydroxypropyl cellulose is 0.2 to 0.8.

The film-like oral mucosal patch of the present invention has excellent adhesion to the oral mucosa by a finger, has good distinguishability between the front surface and the back surface, does not cause discomfort in the patch after application, and has an oral mucosa. It also has excellent adhesion to.

An example of the multi-layered form of the patch of the present invention is shown. (A) is a plan view, and (b) is a cross-sectional view taken along the line I-I. It is a figure which shows the adhesive strength test method. It is a figure which shows the relationship between the adhesive force and the PVP ratio. It is a figure which shows the relationship between the adhesive force and the tannic acid concentration.

The film-like oral mucosal patch of the present invention is characterized by having the following layers (a), (b) and (c) in order from the surface side after application.
(A) Drug-free transparent support layer,
(B) A drug-containing layer containing a drug, a water-soluble polymer, and one or more colorants selected from yellowish, orange-based and red-based.
(C) A drug-containing layer containing a drug, a water-soluble polymer, and an opacity agent.

The outermost surface layer after application of the film-like oral mucosal patch of the present invention is (a) a drug-free transparent support layer.
The support layer (a) is a support layer that is taken by a finger when the patch is applied to the oral mucosa and is applied. This (a) support layer does not contain a drug.

(A) The film-forming agent for the support layer preferably contains a water-insoluble polymer because it does not adhere to the oral mucosa. Examples of such water-insoluble polymers include ethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate ester, hypromellose acetate succinate ester, ethyl acrylate copolymer methacrylate, and metaacrylic acid methacrylic acid. Examples thereof include methyl acrylate copolymer, ethyl methacrylate / trimethylammonium ethyl methacrylate copolymer, dimethylaminoethyl methacrylate / methyl methacrylate copolymer and the like.
In addition to the water-insoluble polymer, the support layer (a) can contain a water-soluble polymer as a film-forming agent, a plasticizer, an antioxidant, an opacity agent, a flavoring agent, a fragrance, and the like. Examples of the water-soluble polymer used here include polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, pregelatinized starch, dextrin, gum arabic, and traganth gum. Gelatin, canten, purulan, xanthan gum, sodium alginate, propylene glycol alginate and the like are used. Among them, hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC), which are water-soluble polymers, are easy to adjust the dissolution time of the support layer and improve the wearability when the support layer and the drug layer are bonded to each other. ) And ethyl cellulose (EC) or hypromellose phthalate (HPMCP), which are water-insoluble polymers, are preferably used in combination. Above all, it is preferable to use HPC and EC in combination from the viewpoint that the dissolution time of the support layer can be easily adjusted.
The support layer (a) is preferably transparent, and the content of the opacity agent is preferably small, from the viewpoint of making it possible to distinguish the color of the drug-containing layer containing the colorant (b). Further, for the purpose of suppressing the gloss of the preparation, it is preferable to add 0.05 to 0.9% by mass of an opacity agent to the support layer, more preferably 0.1 to 0.8% by mass, and 0.25 to 0.25 to. 0.75% by mass is more preferable. If the amount is too small, the preparation becomes glossy and the preparation becomes conspicuous when attached to the gums or the like. If the amount is too large, the support layer tends to melt, and the functions required for the support layer cannot be obtained.
As the plasticizer, antioxidant, flavoring agent, fragrance and the like, those described below can be used.

In the lower layer of (a) support layer, a drug-containing layer containing (b) a drug, a water-soluble polymer, and one or more colorants selected from yellow, orange, and red is arranged. In the lower layer thereof, a drug-containing layer containing (c) a drug, a water-soluble polymer, and an opacity agent is arranged.

The drug used in the layer (b) and the layer (c) may be any drug as long as it has a local action on the oral cavity or pharynx, or is absorbed by the oral mucosa and has a systemic action. For example, the following can be mentioned. Examples of the steroidal anti-inflammatory agent include triamcinolone acetonide, cortisone acetate, hydrocortisone, prednisolone, methylprednisolone, betamethasone and the like. Examples of the anti-inflammatory agent include glycyrrhetinic acid, dipotassium glycyrrhizinate, sodium azulene sulfonate, cicon extract and the like. Examples of the disinfectant include chlorhexidine hydrochloride, domiphen bromide, cetylpyridinium chloride hydrate, decalinium chloride, benzethonium chloride and the like. Examples of the antibiotic include tetracycline hydrochloride and the like. Examples of antitussive expectorants include dextromethorphanphenol phthalin salt, potassium guaiacol sulfonate, and the like. Examples of the analgesic include buprenorphine hydrochloride, morphine hydrochloride hydrate, morphine sulfate hydrate, oxycodone hydrochloride hydrate, codeine phosphate hydrate, dihydrocodein phosphate, pethidine hydrochloride, pentazocine hydrochloride and the like. Examples of smoking cessation treatments include nicotine and the like. Examples of migraine therapeutic agents include zolmitriptan, eletriptan hydrobromide, rizatriptan benzoate, naratriptan hydrochloride and the like. For the treatment of schizophrenia, olanzapine, quetiapine fumarate, perospirone hydrochloride hydrate, sultupride hydrochloride, pipamperone hydrochloride, oxyperone, chlorpromazine hydrochloride, spiperone, zotepine, pimozide, fluphenazine maleate, properiazine Examples include chimiperone. Examples of the therapeutic agent for Parkinson's disease include apomorphine hydrochloride, ropinirole hydrochloride, selegiline hydrochloride, rotigotine, and smanilol maleate. Examples of β-blockers include bisoprolol, carvedilol, atenolol and the like. Examples of the therapeutic agent for Alzheimer's disease include rivastigmine, donepezil hydrochloride, memantine hydrochloride, galantamine hydrochloride and the like. Examples of the bronchodilator include tulobuterol, montelukast sodium, pranlukast hydrate, pemirolast potassium and the like. Examples of non-steroidal anti-inflammatory analgesics include meloxicam, celecoxib, loxoprofen sodium hydrate, ketoprofen, indomethacin, felbinac, ibuprofen, diclofenac sodium, flurbiprofen and the like.

The drug content in the total amount (a + b + c layer) of the patch of the present invention is preferably 0.01 to 20 mg, more preferably 0.01 to 15 mg per sheet from the viewpoint of the expressiveness, durability and usability of the drug effect. 0.01 to 10 mg is more preferable. When the drug content is high, the influence of the physical characteristics of the drug on the physical characteristics and usability of the preparation becomes large, and the physical characteristics and usability of the preparation may be impaired. In addition, in order to increase the drug content, the amount of the drug per unit area may increase, causing problems such as oral mucosal irritation.

Water-soluble polymers include polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, pregelatinized starch, dextrin, gum arabic, tragant gum, gelatin, canten, etc. Pluran, xanthan gum, sodium alginate, propylene glycol alginate and the like are used.

Since the drug layer is a layer that comes into contact with the affected part or the application site of the oral mucosa, it is preferable to contain a polymer that absorbs water and exhibits adhesiveness. Among them, polyvinylpyrrolidone (PVP) and hydroxypropyl cellulose (HPC), which are water-soluble polymers, are combined because there are various grades and the dissolution time of the preparation can be easily adjusted, and because they can be dissolved in ethanol. It is good to use it.
The content ratio of polyvinylpyrrolidone to hydroxypropylcellulose is more preferably when the content ratio of polyvinylpyrrolidone is high in terms of improving the adhesive strength, and the mass ratio of polyvinylpyrrolidone to the total amount of polyvinylpyrrolidone and hydroxypropylcellulose is 0.2. It is more preferably ~ 0.8, and even more preferably 0.4 to 0.8.

The content of the water-soluble polymer in the total amount of the patch of the present invention is preferably 50 to 90% by mass, more preferably 60 to 90% by mass, from the viewpoint of adhesion to the oral mucosa and durability. If the amount is too small, it becomes difficult to adjust the adhesiveness and persistence of the drug to the oral mucosa according to the therapeutic purpose. On the other hand, if the amount is too large, a sufficient amount of drug cannot be added for treatment.

(B) Examples of the yellowish, orange or red colorant contained in the layer include the dyes described in the Ministerial Ordinance (Ministry of Health and Welfare Ordinance No. 30) that defines tar dyes that can be used in pharmaceutical products and the like. .. Specifically, Red No. 2 (also known as Amaranth), Red No. 3 (also known as Erythrosine), Red No. 102 (also known as New Coccine), and Red No. 104 (1) (also known as). Floxine B), Red No. 105 (1) (also known as Rose Bengal), Red No. 106 (also known as Acid Red), Yellow No. 4 (also known as Tartrazine), Yellow No. 5 (also known as Sunset Yellow FCF), Red No. 201 (also known as Lithol Rubine B), Red No. 202 (also known as Lithol Rubine BCA), Red No. 203 (also known as Lake Red) C (Lake Red C)), Red No. 204 (also known as Lake Red CBA), Red No. 205 (also known as Lithol Red), Red No. 206 (also known as Lithol Red CA) , Red No. 207 (also known as Lithol Red BA), Red No. 208 (also known as Lithol Red SR), Red No. 213 (also known as Rhodamine B), Red No. 214 (also known as Tartrazine) B Acetate (Rhodamine B Actate), Red No. 215 (also known as Rhodamine B Steate), Red No. 218 (also known as Tetrachlorotetrabromofluorescein), Red No. 219 (also known as Brilliant Tray) Brilliant Lake Red R), Red 220 (also known as Deep Maroon), Red 221 (also known as Tluidine Red), Red 223 (also known as Tartrazinefluorescein), Red 225 (also known as Tetrabromoflorescein). Also known as Sudan III, Red No. 226 (also known as Helindone Pink CN), Red No. 227 (also known as Fast Acid Magenta), Red No. 228 (also known as Permuton Red (also known as Permaton Red)). Perm aton Red)), Red No. 230 (1) (also known as Eosine YS), Red No. 230 (2) (also known as Eosine YScm), Red No. 231 (also known as Fluorescein BK) ), Red No. 232 (also known as Rose Bengal K), Yellow No. 201 (also known as Dibromofluorescein), Yellow No. 203 (also known as Permanent Orange), Yellow No. 204 (also known as Permanent Orange) Benchidine Orange G (Benzidine Orange Gmg), Orange No. 205 (also known as Orange II), Orange No. 206 (also known as Diiofluorescein), Orange No. 207 (also known as Erythrosin Yellow NA) NA)), Yellow 201 (also known as Fluorescein), Yellow 202 (1) (also known as Uranine), Yellow 202 (2) (also known as Uranine K), Yellow 203 (Also known as Fluoresce Yellow WS), Yellow No. 204 (also known as Fluorine Yellow SS), and Yellow No. 205 (also known as Fluorescein Yellow G) can be mentioned. Further, yellow iron sesquioxide, iron sesquioxide and the like can also be used. These colorants can be used alone or in combination of two or more.
The content of these colorants is preferably 0.005 to 0.4% by mass, more preferably 0.01 to 0.3% by mass, and 0.01 to 0.25% by mass in the layer (b). More preferred.

Examples of the opacity agent contained in the layer (c) include titanium oxide, zinc oxide, magnesium oxide and the like, and titanium oxide is more preferable. The content of the opacity agent is preferably 1 to 10% by mass, more preferably 1 to 5% by mass, still more preferably 1 to 3% by mass in the layer (c). If it is too small, it will be difficult to distinguish between the front and back surfaces of the formulation. On the other hand, if the amount is large, the amount of the inorganic powder in the drug layer increases and the preparation becomes easy to dissolve.

By incorporating a yellow to red colorant in the layer (b) and an opaque agent in the layer (c) in this way, the discomfort of the patch in the oral cavity after application is eliminated, and the front and back sides are eliminated. The distinctiveness becomes clear.

Further, it is preferable that the layer (b) and the layer (c) contain tannic acid from the viewpoint of improving the adhesiveness of the patch of the present invention to the oral mucosa. The content of tannic acid in the total amount of the patch of the present invention is preferably 0.5 to 4.5% by mass, more preferably 1 to 4.5% by mass, from the viewpoint of improving adhesiveness and coatability. More preferably, it is 1.5 to 4.5% by mass. By adding tannic acid, the adhesiveness of the patch of the present invention to the oral mucosa is remarkably improved, and the adhesiveness to the oral mucosa is improved, and as a result, a reliable medicinal effect can be obtained. Further, the effect of adding tannic acid is particularly remarkable when polyvinylpyrrolidone and hydroxypropyl cellulose are used in combination as the water-soluble polymer.

In addition to the above components, the layer (b) and the layer (c) may contain a plasticizer, an antioxidant, a flavoring agent, a fragrance, and the like.

The plasticizer has the role of softening the film preparation and reducing the discomfort during application. In addition, it imparts thermoplasticity and has a role of improving wearability when the support layer and the drug layer are bonded. Examples of the plasticizing agent include polyethylene glycol (Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 4000, Macrogol 6000, etc.), triacetin, glycerin, propylene glycol, triethyl citrate, sorbitol, sesame oil, castor oil, and polyoxy. Examples thereof include ethylene polyoxypropylene glycol, polysorbate 80 (polyoxyethylene sorbitan monooleate (20EO)), and glycerin fatty acid ester.
Among them, polyethylene glycol is preferably used because there are grades having different average molecular weights and the flexibility of the film preparation can be adjusted.

Antioxidants have a role of preventing decomposition of the active ingredient contained in the film preparation during storage. Examples of the antioxidant include L-ascorbic acid stearate, ascorbic acid, sodium sulfite, sodium edetate, erythorbic acid, citric acid, tocopherol acetate, dibutylhydroxytoluene, vitamin E, tocopherol, and butylhydroxyanisole.

A flavoring agent can be added to improve the usability of the formulation. In addition, the flavoring agent stimulates the salivary glands and may affect the solubility of the preparation in the oral cavity by saliva. As a flavoring agent, acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid; sweeteners such as aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, sodium saccharin; Examples include sucralose, mint, peppermint, and menthol.

Fragrances can be added to improve the usability of the formulation. In addition, since the fragrance stimulates the salivary glands, it may affect the solubility of the preparation in the oral cavity by saliva. Flavors include vanilla flavor, orange flavor, orange peel flavor, strawberry flavor, raspberry flavor, chocolate flavor, grapefruit flavor, granberry flavor, ume flavor, kokuto flavor, herb flavor, coffee flavor, tea flavor, cinnamon flavor, honey. Lemon flavor and the like can be mentioned.

The oral mucosal patch of the present invention is a multi-layer film preparation having at least a layer (a), a layer (b) and a layer (c). FIG. 1 shows an example of the multilayer film preparation of the present invention. FIG. 1A is a plan view of the oral mucosal patch 10, and FIG. 1B is a cross-sectional view taken along the line I-I of the oral mucosal patch 10.
On one surface of the drug layer 2 (layer (b) + layer (c)) which is sticky and contains a drug, the preparation may adhere to an unintended portion in the oral cavity, or the drug may flow out into saliva. The support layer 1 is provided for the purpose of preventing the above.
The total thickness of the oral mucosal patch of the present invention is preferably 60 to 500 μm, more preferably 60 to 300 μm.
The thickness of the support layer is preferably 5 to 25 μm, more preferably 5 to 15 μm. The thickness of the drug layer ((b) layer + (c) layer) is preferably 55 to 475 μm, and more preferably 55 to 285 μm.
The mass ratio of the (b) layer to the (c) layer of the drug layer is preferably 40:60 to 10:90, more preferably 25:75 to 15:85. When the proportion of the layer (b) to which the colorant is added becomes large, the front surface and the back surface of the preparation cannot be distinguished. On the other hand, when the ratio of the layer (b) becomes small, the thickness of the layer (b) becomes thin, and as will be described later, the handleability of the film in the step of laminating the coated and dried films may deteriorate. is there.
The shape of the oral mucosal patch of the present invention is not particularly limited as long as it has a shape that allows good stickability to the oral mucosa. For example, a circle, an ellipse, a square and the like can be mentioned.
Area of buccal mucosa adhesive preparation of the present invention is preferably 0.5~4cm ^2, more preferably 0.5~2cm ^2, more preferably 0.5 to 1.5 cm ^2. If it is too small, there will be inconveniences such as poor handleability of the preparation at the time of application and inability to add drugs necessary for treatment. If it is large, there is a strong sense of discomfort when pasting.

The oral mucosal patch of the present invention is a film laminate obtained by laminating films obtained by applying and drying a coating solution in which a drug, a water-soluble polymer, or the like is dissolved in a solvent such as ethanol or water. After obtaining, it can be obtained by cutting it into an appropriate size.
Further, it can be obtained by further coating and drying a coating liquid on the film obtained in the above coating / drying step to obtain a film laminate, and then cutting the film into an appropriate size.
Ethanol, water, or a mixed solution thereof can be used as the solvent of the coating liquid. The solvent should be contained in an amount of 5 to 10 times the solid content of the preparation. If the amount is less than 5 times, the variation in coating clearance appears greatly in the variation in the drug content in the formulation. If the amount is more than 10 times, the drying time becomes long and bubbles are likely to be generated in the drying step.

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

(1) Preparation of Oral Mucosa Patch in Test Group A The oral mucosa patch shown in Table 1 was prepared by the following method.
(Preparation of support layer coating liquid)
Macrogol 400 and titanium oxide were added to ethanol (appropriate amount) and dispersed by stirring. Next, HPC and EC were added and stirred and dissolved to obtain a support layer coating liquid.
(Preparation of drug layer I coating solution)
A drug solution was obtained by adding triamcinolone acetonide to ethanol (appropriate amount) and dissolving by stirring. Separately, tannic acid and macrogol 400 were added to ethanol (appropriate amount) and dissolved by stirring to obtain a tannic acid solution. Separately, Red No. 102 was added to purified water (appropriate amount) and dissolved by stirring to obtain a colorant solution.
A drug solution, a tannic acid solution and a colorant solution were added to ethanol (appropriate amount) and stirred, and then HPC and PVP were added and dissolved by stirring to obtain a drug layer I coating solution.
(Preparation of drug layer II coating solution)
A drug solution was obtained by adding triamcinolone acetonide to ethanol (appropriate amount) and dissolving by stirring. Separately, tannic acid and macrogol 400 were added to ethanol (appropriate amount) and dissolved by stirring to obtain a tannic acid solution. Further, separately, titanium oxide was added to ethanol (appropriate amount) and stirred and dispersed to obtain an opaque agent dispersion.
A drug solution, a tannic acid solution and an opaque agent dispersion were added to a mixed solvent (appropriate amount) of ethanol and purified water and stirred, and then HPC and PVP were added and dissolved by stirring to obtain a drug layer II coating solution. ..
(Painting drying and cutting)
The support layer coating liquid was applied onto the silicone-treated surface of polyethylene terephthalate treated with silicone, and dried by applying warm air at 60 ° C. to obtain a support layer film.
The drug layer I coating solution and the drug layer II coating solution were also coated and dried in the same manner to obtain a drug layer I film and a drug layer II film, respectively.
Incidentally, the coating weight mass after drying, the support layer is 11.21 g / m ^2, the drug layer I is 32.05 g / m ^2, the drug layer II were respectively adjusted such that the 32.00 g / m ² ..
The drug layer I film was bonded once on the obtained support layer film, and the drug layer II film was further bonded four times on the drug layer I film to obtain a six-layer film laminate.
The obtained film laminate was punched out with a circular φ12 mm blade to obtain an oral mucosal patch containing a support layer and a drug layer (see FIG. 1).
In Comparative Example 2A, the drug layer I was attached to the support layer 5 times, and in Comparative Example 3A, the drug layer II was attached to the support layer 5 times to obtain a 6-layer film laminate.

(2) Preparation of Oral Mucosal Patches for Test Group B and Test Group The sample coating solutions shown in Tables 2 and 3 were prepared by the following methods.
(Preparation of sample coating liquid)
Tannic acid and Macrogol 400 were added to ethanol (appropriate amount) and dissolved by stirring. Next, HPC and PVP were added and dissolved by stirring to obtain a sample coating solution.
(Painting drying and cutting)
A sample coating solution was applied onto the silicone-treated surface of polyethylene terephthalate treated with silicone, and dried by applying warm air at 60 ° C. to obtain a sample film. The coating amount was adjusted so that the mass after drying was 32.00 g / m ² .
The obtained sample films were laminated four times to form a five-layer film laminate, which was punched out with a circular φ12 mm blade to obtain an oral mucosa patch.

(3) Preparation of Oral Mucosa Patch for Preparation Example The oral mucosa patch shown in Table 4 was prepared as a preparation example.
When hypromerose phthalate (HPMCP) was used for the support layer, an ethanol / water (8: 2) mixed solution was used as the preparation solvent for the support layer coating solution.
The masses of the support layer, the drug layer I, and the drug layer II per preparation were set to the values shown in Table 4, and the amount of coating and the number of times of bonding were adjusted as necessary.

(4) Confirmation of front and back distinctiveness and color tone change of oral mucosal patch (after storage at 60 ° C for 1 week) Confirm visual distinctiveness (front and back distinctiveness) of the support layer side and adhesive layer side of the oral mucosal patch did. In addition, the transferability of the colorant between layers after packaging in an aluminum bag and storing at 60 ° C. for 1 week was also confirmed. Each judgment standard is as follows.
・ Confirmation of front and back distinctiveness ○: The front and back identification of the preparation can be visually confirmed ×: The front and back identification of the preparation cannot be visually confirmed ・ Confirmation of color tone change (after storage at 60 ° C for 1 week) ○: Transfer of colorant between layers ×: The colorant is transferred between layers, making it difficult to visually identify the front and back sides.

(5) Adhesive strength test The adhesive strength of the oral mucosa patch prepared in the A to C test groups is based on the artificial oral mucosa ("EXSURG" (Technocast Co., Ltd.)) as an adherend, and the texture analyzer TA-XT plus. It was measured using (Eiko Seiki Co., Ltd.) by applying the probe tack test method of the adhesive strength test method described in the Japanese Pharmacopoeia mutatis mutandis (see FIG. 2).
(Measurement procedure)
After immersing the artificial oral mucosa 5 in water at 37 ± 2 ° C., the surface water was removed by sandwiching the artificial oral mucosa 5 with filter paper and applying a load of 200 g for 30 seconds. The artificial oral mucosa 5 was placed in the center of the stand 6 and fixed with a plastic plate 8 having a hole of φ16 mm in the center.
Separately, the oral mucosal patch 10 was fixed to the bottom surface of the probe 9 having a diameter of 15 mm with double-sided tape with the adhesive surface 4 facing downward.
By lowering the probe 9 from a height of 10 mm from the stand 6 at a speed of 0.5 mm / sec, the adhesive surface 4 on the bottom surface of the probe 9 is brought into contact with the artificial oral mucosa 5, and a load of 1.0 N is applied for 60 seconds. After that, the probe was raised at a speed of 1.0 mm / sec.
By the above operation, the maximum load generated when the adhesive surface 4 separates from the artificial oral mucosa 5 when the probe 9 is raised was measured and used as the adhesive strength (g).

(6) Test Results As shown in Example 4A of Table 1 (Examples 1A to 6A), a drug layer to which a colorant was added (drug layer I) and a drug layer to which no colorant was added (drug layer II). In the formulation composition of (support layer) / (drug layer with colorant added) / (drug layer without colorant added) in combination with, the front and back distinctiveness of the formulation was good.
On the other hand, as shown in Comparative Example 2A, it was difficult to distinguish the front and back of the preparation in the preparation consisting of (support layer) / (drug layer with colorant added).
Further, as shown in Comparative Example 3A, the preparation composed of the (colorant-added support layer) / (colorant-free drug layer) in which the colorant was added only to the support layer had good front-back distinction immediately after preparation of the preparation. However, it has been shown that when the preparation is stored for a long period of time, the colorant is transferred from the support layer to the drug layer, and the front-back distinction of the preparation deteriorates.

From Table 2, as a result of examining the adhesive strength at each mixing ratio of PVP and HPC, it was confirmed that the adhesive strength was improved by the addition of tannic acid.
From FIG. 3, the improvement in adhesive strength is remarkable when the amount of PVP added is increased, and the preparation having a PVP ratio of 20 to 80% by mass defined by the following formula has good adhesiveness and physical properties as an oral mucosal patch. showed that.

A preparation based only on PVP (Comparative Example 6B) had the highest adhesive strength, but when it absorbed water, it had poor shape retention and showed sticky physical properties, suggesting that it is not preferable as an oral mucosal patch. Was done.

From Table 1, Table 3 and FIG. 4, when 0.5 to 4.5% by mass of tannic acid was added to the preparation in each of the A test group and the C test group, the adhesive strength increased as the amount of tannic acid added increased. It improved and showed good adhesiveness and physical properties as an oral mucosal patch.
In the C test group, the preparation to which 6% by mass of tannic acid was added (Example 5C) had improved adhesive strength as compared with the preparation to which no tannic acid was added (Comparative Example 1C), but the preparation to which 4.5% by mass was added (Example 5C). Compared with Example 4C), a decrease in adhesive strength was observed.
In addition, the preparation solution of the preparation to which 6% by mass of tannic acid was added tended to show astringent property, and there was a tendency that coating unevenness occurred slightly.

1: Support layer 2: Drug layer 2A: Drug layer I
2B: Drug layer II
3: Non-adhesive surface 4: Adhesive surface 5: Artificial oral mucosa 6: Stand 7: Clamp 8: Plastic plate 9: Probe 10: Oral mucosa patch 20: Tensile tester

Claims (3)

A film-like oral mucosal patch having the following layers (a), (b) and (c) in order from the surface side after application.
(A) Drug-free transparent support layer,
(B) A drug-containing layer containing a drug , a water-soluble polymer composed of polyvinylpyrrolidone and hydroxypropyl cellulose , one or more colorants selected from yellowish, orange and reddish colors , and tannic acid.
(C) A drug-containing layer containing a drug, a water-soluble polymer composed of polyvinylpyrrolidone and hydroxypropyl cellulose , 1 to 10% by mass of titanium oxide in the layer (c) , and tannic acid. The content of tannic acid, a film-shaped buccal patch according claim 1 is 0.5 to 4.5 mass% in the patch total amount. The film-like oral mucosal patch according to claim 1 or 2 , wherein the content mass ratio of polyvinylpyrrolidone to the total amount of polyvinylpyrrolidone and hydroxypropyl cellulose is 0.2 to 0.8.