JP2010138124A - Oral mucosal patch - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral mucosal patch which allows a drug to be efficiently absorbed in the blood and mitigates an uncomfortable feeling such as bitterness and stimulation due to the drug on taking. <P>SOLUTION: The oral mucosal patch 10 has a mucous membrane attaching layer 1 which attaches to the oral mucous membrane and contains a flavoring agent and an edible water soluble polymer, a support layer 2 which is arranged at an outermost layer on the side opposite to the mucous membrane attaching layer 1 and contains an edible water sparingly soluble polymer, at least two drug layers 3 which are arranged in between the mucous membrane attaching layer 1 and the support layer 2 and contain a drug, a flavoring agent, and an edible water soluble polymer, and an intermediate layer 4 which is arranged in between the drug layers 3 and contains an edible water soluble polymer and a flavoring agent. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to an intraoral mucosa patch preparation, and more particularly to a film preparation having a multilayer structure that can be applied to the oral mucosa and efficiently absorb a drug in blood.

Various drug delivery systems have been proposed for the purpose of controlled release (controlled release), one of which is a sustained drug release technique. As this sustained-release preparation, for example, there is a nicotine-containing chewing gum in which a chewing gum core prepared by uniformly mixing nicotine and various additives is coated with a coating composition containing nicotine and various additives (Patent Document 1). ).
The route of administration of this nicotine-containing chewing gum is continuous oral administration, and since the drug is absorbed not only from the oral mucosa but also from the digestive tract, the drug absorbed from the digestive tract is metabolized and decomposed by the first-pass effect in the liver. End up. Moreover, the drug etc. which couple | bonded with the polymer | macromolecule remain easily in the chewing gum which has finished chewing. Therefore, in order to obtain an effect of increasing the blood concentration of nicotine equivalent to that during smoking, it is necessary to further increase the amount of the drug in the preparation.

  In addition, an oral administration agent having a drug-containing layer, a water-swellable gel-forming layer, and an intermediate layer provided between the drug-containing layer and the water-swellable gel-forming layer has been proposed (Patent Document 2). In this preparation, the water-swellable gel-forming layer provided in the outermost layer is gelled by moisture such as saliva in the oral cavity, and the drug is likely to remain in an enclosed form. A masking effect can be expected. However, similarly to the above-mentioned chewing gum, since the drug stays in the polymer gel in the oral cavity, the drug is not sufficiently absorbed from the oral mucosa. In addition, since the route of administration is continuous oral administration, most of it is absorbed in the gastrointestinal tract, and it is impossible to increase the blood concentration of the drug in a short period of time and reduce the drug content to maintain the effective therapeutic concentration range It is.

  Furthermore, a nicotine-containing film preparation having a three-layer structure in which a coating layer that can be applied to the oral mucosa is provided on both sides of the nicotine-containing layer has been proposed (Patent Document 3). This film preparation has an appropriate sustained release property and does not feel uncomfortable at the time of application, and can be easily applied to the oral mucosa, but after being applied to the oral maxillary mucosa, the coating layer is extremely short due to moisture such as saliva. Since the drug is dissolved and released in time (0.5 to 3 minutes), the drug may not be efficiently absorbed by the oral mucosa.

Special table 2005-500206 gazette JP 2006-160617 A JP 2003-95947 A

  Thus, in the conventional sustained-release preparation, it cannot be said that the drug is efficiently absorbed from the oral mucosa, and there is room for improvement. In addition, there is a need for a formulation technique that alleviates the bitterness and irritation of the drug, but no technique that can sufficiently satisfy such a demand has yet been found.

  Therefore, the present invention has been made in view of such a situation, and the problem to be solved is to absorb the drug efficiently into the blood and to have a discomfort such as bitterness and irritation caused by the drug at the time of taking. It is to provide a relaxed intraoral mucosa patch preparation.

  As a result of diligent research to solve the above-mentioned problems, the present inventors have intervened an intermediate layer between at least two drug layers, and an outermost layer includes a mucosal adhesion layer and a support layer that adhere to the oral mucosa. Adopting the arranged structure and further configuring the drug layer, intermediate layer, mucoadhesive layer and support layer with specific components, so that the drug can be absorbed efficiently into the blood and the bitterness and irritation caused by the drug at the time of taking It was found that an oral mucosal patch preparation with reduced discomfort was obtained.

That is, the present invention
A mucoadhesive layer that adheres to the oral mucosa and contains a corrigent and an edible water-soluble polymer;
A support layer disposed on the outermost layer on the opposite side of the mucosa-adhering layer and containing an edible poorly water-soluble polymer;
At least two drug layers disposed between the mucoadhesive layer and the support layer and containing a drug, a corrigent and an edible water-soluble polymer;
An intermediate layer disposed between the drug layers and containing an edible water-soluble polymer and a corrigent;
An oral mucosal patch preparation is provided.

  The intraoral mucosa patch preparation of the present invention preferably has a five-layer structure in which a mucoadhesive layer, a drug layer, an intermediate layer, a drug layer and a support layer are sequentially laminated, and at least one drug layer is porous. Also good. As a result, the absorbability of the drug into the blood can be further enhanced, and unpleasant feelings such as bitterness and irritation caused by the drug at the time of taking can be more reliably alleviated.

  In the present invention, from the viewpoint of alleviating discomfort such as bitterness and irritation caused by drugs, it is preferable to use at least one selected from the group consisting of a sour agent, a high sweetness sweetener and a refreshing agent as a corrigent. The sour agent is preferably at least one selected from the group consisting of ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof, and the high-sweetness sweetener is aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, At least one selected from the group consisting of acesulfame potassium, saccharin and salts thereof is preferred, and the refreshing agent is at least one selected from the group consisting of fennel oil, camphor, mint oil, mint water, mint, peppermint and menthol. preferable.

The edible water-soluble polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, polyvinylpyrrolidone and sodium alginate. It is preferable that it is at least one kind. Thereby, control of dissolution or disintegration by moisture such as saliva in the oral cavity becomes easy, and strength can be increased.
On the other hand, the edible poorly water-soluble polymer includes starch, gelatin, tragacanth gum, crystalline cellulose, ethyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetal diethylaminoacetate, and polyacrylate. It is preferable that it is at least one selected from more. Thereby, dissolution or disintegration of the support layer due to moisture such as saliva in the oral cavity can be suppressed, and the absorbability of the drug from the oral mucosa can be increased. The support layer may further contain the edible water-soluble polymer described above.

  The intraoral mucosa patch preparation of the present invention preferably disintegrates in the oral cavity in 2 to 15 minutes, and the disintegration time for water is preferably 5 to 25 minutes. As a result, the drug can be released continuously with an appropriate release rate to increase the absorbability of the drug in the blood, and the unpleasant feeling such as bitterness and irritation caused by the drug can be more reliably reduced. it can. In such an intraoral mucosal patch preparation, nicotine is preferably used as a drug because it can be quickly increased to a nicotine blood concentration equivalent to that at the time of smoking.

  In the oral mucosa patch preparation of the present invention, since the release of the drug into the saliva is suppressed in the oral cavity by providing a support layer in the outermost layer, the drug is continuously released while having an appropriate release rate. be able to. As a result, the drug can be efficiently absorbed into the blood through the oral mucosa, and further, the unpleasant feeling such as bitterness and irritation caused by the drug can be alleviated.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. For the convenience of illustration, the dimensional ratios in the drawings do not necessarily match those described.

FIG. 1 is a diagram showing an embodiment of an intraoral mucosa patch preparation (hereinafter also simply referred to as “preparation”) of the present invention.
1A is a plan view of the preparation 10, and FIG. 1B is a cross-sectional view taken along the line II of the preparation 10. FIG.
A formulation 10 shown in FIG. 1 includes a mucosal adhesion layer 1 that adheres to the mucous membrane in the oral cavity, a support layer 2 that is disposed on the outermost layer on the opposite side of the mucosa adhesion layer 1, and between the mucosa adhesion layer 1 and the support layer 2. It is composed of two arranged drug layers (first drug layer 3a, second drug layer 3b) and an intermediate layer 4 arranged between these drug layers 3, and has a five-layer structure. is there.

When the mucosa-adhering layer 1 is pressed against the mucous membrane in the oral cavity, the adherend surface is quickly dissolved (0.1 minutes to 1 minute) by moisture such as saliva, and is not easily peeled off. Here, the oral mucosa is not particularly limited as long as it is a mucosa covered with mucus in the oral cavity. For example, the maxillary mucosa, sublingual mucosa, cheek mucosa, gingival mucosa, palatal mucosa, lip mucosa Line mucosa is illustrated.
On the other hand, the support layer 2 functions as a support and has a function of suppressing dissolution or disintegration due to moisture such as saliva in the oral cavity. Therefore, the formulation 10 first begins to dissolve from the mucosa-adhering layer 1 adhered to the oral mucosa, and then the first drug layer 3a, the intermediate layer 4 and the second drug layer 3b are sequentially dissolved. Thus, since the contact with the moisture in the oral cavity is blocked by the support layer 2, the release of the drug into the saliva is suppressed. As a result, it is difficult to receive the first-pass effect due to gastrointestinal absorption, the blood concentration of the drug can be increased in a short period of time, the drug release time is adjusted, and the drug content to maintain the effective therapeutic concentration range Reduction is possible. In combination with the corrigent contained in the mucoadhesive layer 1, the first drug layer 3a, the intermediate layer 4, and the second drug layer 3b, unpleasant feeling such as bitterness and irritation caused by the drug released into the oral cavity is obtained. Can be relaxed. In addition, the support layer 2 also provides effects such as avoiding blocking properties of the preparation, improving visual value on appearance, and handling properties. Such an effect can be obtained more reliably by adopting a five-layer structure in which the mucoadhesive layer, the first drug layer, the intermediate layer, the second drug layer, and the support layer are sequentially laminated.

  The preparation of the present invention disintegrates in the oral cavity in 2 to 15 minutes, further 4 to 12 minutes, particularly 5 to 8 minutes, or 5 to 25 minutes, further 6 to 20 minutes, particularly 7 to 15 with respect to water. It preferably disintegrates in minutes, and particularly preferably has both of these characteristics. Thereby, it is possible to release the drug continuously while having an appropriate release rate, and to alleviate discomfort.

  In the present specification, “disintegration time in the oral cavity” means that measured by the following oral disintegration test, and “disintegration time for water” means that measured by the following water disintegration test. .

Oral Disintegration Test A test piece cut into a size of a circular φ12 mm is collected, and after sticking it on the oral mucosa of a healthy adult, the time until the test piece is completely disintegrated with only saliva in the oral cavity is measured. In the test, the time taken for taking 6 panelists was averaged, and the average value was taken as the oral disintegration time.

Water disintegration test A test piece cut into a circular φ12 mm size was collected, put into a test solution (purified water 900 mL), and the 15th revised Japanese Pharmacopoeia [B] General Test Method. Formulation Test Method 6.10 Dissolution Test Method According to the paddle method (p. 587), the test is performed at 50 revolutions per minute using a sinker. The test solution is collected every 5 minutes until 60 minutes after the start of the test, and the time when the drug elution rate becomes 95% by mass or more by liquid chromatography is defined as the water disintegration time.

Factors affecting the water disintegration time of the preparation of the present invention include the edible poorly water-soluble polymer constituting the support layer and the thickness of the preparation. In order to obtain a preparation that disintegrates within 15 minutes in the oral cavity and disintegrates in water within 25 minutes, the thickness of the whole preparation is preferably 100 to 300 μm, particularly preferably 110 to 200 μm. Thereby, it gradually disintegrates from the mucosal adhesion layer in the oral cavity, and the oral mucosal absorption of the drug and the release of the corrigent can be efficiently advanced. From this viewpoint, the thickness of the mucosal adhesion layer is preferably 20 to 60 μm, particularly preferably 22 to 40 μm, the thickness of each of the first and second drug layers is preferably 20 to 60 μm, particularly preferably 22 to 40 μm, and the thickness of the intermediate layer is 20 The thickness of the support layer is preferably 20 to 60 μm, particularly preferably 22 to 40 μm.
The size of the preparation is not particularly limited as long as it is a size suitable for application in the oral cavity. For example, when the planar shape is circular, the diameter is preferably about 10 to 30 mm. In addition, the shape is not particularly limited as long as it is suitable for application in the oral cavity. For example, a shape such as a circle, an ellipse, and a rectangle can be appropriately selected, and the surface of the preparation is flat. Is preferred.

  The mucoadhesive layer contains a corrigent and an edible water-soluble polymer, and the support layer contains an edible poorly water-soluble polymer, but the support layer may further contain an edible water-soluble polymer. Good. The drug layer contains a drug, a corrigent, and an edible water-soluble polymer, and the intermediate layer contains an edible water-soluble polymer and a corrigent.

Examples of the corrigent used in the present invention include sour agents, high sweetness sweeteners, and refreshing agents. These can be used alone or in combination.
Examples of sour agents include ascorbic acid, tartaric acid, citric acid, malic acid, or salts thereof. These can be used alone or in combination. Among them, tartaric acid and citric acid are particularly preferable from the viewpoint of alleviating the unpleasant feeling such as the bitterness and irritation of the drug and the pH stability of the preparation. Examples of the salt form include alkali metal salts and alkaline earth metal salts. In addition, tartaric acid, citric acid and malic acid may be in the form of an acid anhydride.
A high-intensity sweetener is a synthetic or natural sugar substitute whose sweetness compared with the sweetness of sucrose is 50 times that of sucrose, but xylitol, sorbitol, mannitol, trehalose In addition, the sweetness of sugar alcohols such as maltitol is smaller than that of sucrose, and a large amount of addition is required to obtain the expected sweetness. Since the preparation of the present invention has a small mass, it is difficult to use a sugar alcohol for the purpose of obtaining sweetness even though it can be used as an excipient or a disintegrant for obtaining fast solubility. It is. Therefore, sugar alcohol is not included in the high-sweetness sweetener according to the present invention.
Examples of the high sweetness sweetener include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and salts thereof. These can be used alone or in combination. Among them, saccharin sodium and sucralose are particularly preferable from the viewpoint of alleviating discomfort such as the bitterness and irritation of drugs. Examples of the salt form include alkali metal salts.
Examples of the refreshing agent include fennel oil, camphor, peppermint oil, peppermint water, mint, peppermint, menthol and the like. These can be used alone or in combination. Among these, menthol is particularly preferable from the viewpoint of alleviating discomfort such as the bitterness and irritation of the drug. The menthol may be a single optically active substance or a mixture thereof (for example, racemate), but a single optically active substance, particularly l-menthol is preferred.

The content of the corrigent in the mucosal adhesion layer is preferably 5 to 50% by mass, more preferably 7 to 40% by mass, and particularly preferably 10 to 30% by mass.
Each content of the corrigent in the first and second drug layers is preferably 5 to 40% by mass, more preferably 7 to 30% by mass, and particularly preferably 10 to 20% by mass.
The content of the corrigent in the intermediate layer is preferably 3 to 50% by mass, more preferably 7 to 40% by mass, and particularly preferably 10 to 30% by mass.

In addition, the content of the corrigent in the unit preparation is preferably 1.5 to 10 mg, more preferably 2 to 8 mg, and particularly preferably 2.5 to 6 mg per 1 mg of the drug from the viewpoint of alleviating unpleasant feelings such as bitterness and irritation.
The content of the sour agent in the unit preparation is 0.5 to 3 mg, more preferably 0.75 to 2.75 mg per 1 mg from the viewpoint of alleviation of unpleasantness such as bitterness and irritation and pH stability of the preparation. -2.5 mg is preferred. The content of the high-intensity sweetener in the unit preparation is preferably 0.5 to 5 mg, more preferably 0.75 to 4 mg, and particularly preferably 1 to 3 mg per 1 mg from the viewpoint of alleviating unpleasant feelings such as bitterness and irritation. The content of the refreshing agent in the unit preparation is preferably 0.1 to 2 mg, more preferably 0.2 to 1.5 mg, and particularly preferably 0.3 to 1 mg per 1 mg from the viewpoint of alleviating unpleasant feelings such as bitterness and irritation. .
Here, in this specification, the “unit preparation” means the minimum unit of preparations to be taken, for example, in the case of preparations individually packaged, it is one preparation and defines the shape. In the case of a film-form preparation in which a plurality of preparations provided with cutting lines to be arranged are arranged in a matrix, the preparations are separated along the cutting line.

  Examples of the edible water-soluble polymer used in the present invention include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, also known as hypromellose), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (CMC-Na, also known as : Carmellose sodium), carboxymethylcellulose calcium (CMC-Ca, also known as carmellose calcium), carboxymethylcellulose potassium (CMC-K, also known as carmellose potassium), carboxymethylcellulose (CMC, also known as carmellose), polyvinylpyrrolidone (PVP), sodium alginate and the like are exemplified. These can be used alone or in combination. Among these, HPC and HPMC are particularly preferable from the viewpoint of controlling dissolution or disintegration by moisture such as saliva in the oral cavity and imparting strength. The viscosity of HPC and HPMC is not particularly limited. For example, in the case of HPC, the kinematic viscosity of a 2% aqueous solution at 20 ° C. is 2.0 to 10 mPa · s, particularly 3.0 to 10 mPa · s. Some are preferable, and in the case of HPMC, the kinematic viscosity of a 2% aqueous solution at 20 ° C. is 3.0 to 10 mPa · s, particularly 3.0 to 6 mPa · s. Such kinematic viscosity is a value based on the test method described in the 15th revision Japanese Pharmacopoeia.

The content of the edible water-soluble polymer in the mucoadhesive layer is preferably 60 to 85% by mass, more preferably 65 to 80% by mass, and particularly preferably 65 to 75% by mass.
Each content of the edible water-soluble polymer in the first and second drug layers is preferably 60 to 85% by mass, more preferably 65 to 80% by mass, and particularly preferably 70 to 80% by mass.
The content of the edible water-soluble polymer in the intermediate layer is preferably 60 to 95% by mass, more preferably 65 to 93% by mass, particularly 70 to 90% by mass.
The content of the edible water-soluble polymer in the support layer is preferably 5 to 30% by mass, more preferably 7 to 25% by mass, and particularly 9 to 20% by mass.
The content of the edible water-soluble polymer in the unit preparation is preferably 50 to 80% by mass, more preferably 55 to 75% by mass, and particularly preferably 60 to 70% by mass.

  The drug used in the present invention is not particularly limited as long as mucosal administration is possible in the oral cavity. Specific examples include allantoin, nicotine, nitroglycerin, isosorbide nitrate, dihydroergotoxin mesylate, zolpidem tartrate, phenobarbital, amobarbital, buprenorphine, nifedipine, nisoldipine, indomethacin, loxoprofen sodium, diclofenac sodium, labetalol, pentoxy Examples include filin, pyridostigrin, terbutaline, verapamil, atenolol, acyclovir, hydralazine, prochlorperazine, sertraline, ziprasidone, itraconazole, fentanyl compounds and the like. Among these, nicotine is preferable because the preparation of the present invention can rapidly increase the blood concentration of nicotine equivalent to that at the time of smoking.

  As nicotine, those usually used in the art can be used without particular limitation, but commercially available products may also be used. Specific examples include nicotine oil, nicotine ditartrate, nicotine citrate, nicotine salicylate, nicotine complex of nicotine and cyclodextrin or polymer resin (for example, nicotine polacrilex), etc. Is done. These can be used alone or in combination. Among these, at least one selected from the group consisting of nicotine oil, nicotine / tartrate, nicotine / citrate and nicotine / salicylate is preferable, and nicotine oil is particularly preferable.

  Nicotine can be used in either the free base form or the ionized form. In the case of the free base form, the effective nicotine amount can be regarded as 100% by mass. Nicotine oil is a pharmaceutical grade that conforms to the standards defined by the US Pharmacopoeia (USP28) and contains 99% by mass or more of nicotine free base, and does not need to be converted as in the nicotine ionized form described below. It can be used as it is as an active ingredient amount.

The nicotine ionized form is a pharmaceutically acceptable salt or metal salt. “Pharmaceutically acceptable salts for acid addition” are ionic compounds formed with inorganic salts such as sulfuric acid, nitric acid, and phosphoric acid, and organic salts such as citric acid, tartaric acid, and salicylic acid. Is an ionic compound formed by metal ions such as zinc ions in addition to alkali metal ions such as sodium ions and potassium ions, alkaline earth metal ions such as calcium ions and magnesium ions.
In the case of an ionized form, the amount used must be corrected using a conversion factor calculated from the molecular weight. For example, when nicotine / tartrate is used, the conversion coefficient is nicotine molecular weight / nicotine / tartrate molecular weight = 162.23 / 498.44 = 0.325 ... ≈0.325. Therefore, 1 mg of nicotine ditartrate corresponds to 0.325 mg of nicotine.

  The content of the drug in the unit preparation can be appropriately set depending on the type of the drug. For example, when the drug is nicotine, it is preferably 0.1 to 5 mg, more preferably 0.3 to 4 mg, particularly The content is preferably 0.4 to 2 mg, and the content of nicotine in the drug layer is preferably 1 to 40% by mass, more preferably 3 to 35% by mass, and particularly preferably 4 to 20% by mass.

  The edible poorly water-soluble polymer used in the present invention is not particularly limited as long as it has a pH range equivalent to that in the oral cavity and is hardly soluble in water. For example, starch, gelatin, tragacanth gum, Examples include crystalline cellulose, ethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate, polyvinyl acetal diethylaminoacetate and polyacrylate. These can be used alone or in combination. Among them, HPMCP is particularly preferable from the viewpoint of suppressing dissolution or disintegration due to moisture such as saliva in the oral cavity.

The content of the edible poorly water-soluble polymer in the unit preparation is preferably 5 to 20% by mass, more preferably 6 to 18% by mass, and particularly preferably 7 to 15% by mass.
The content of the edible poorly water-soluble polymer in the support layer is preferably 50 to 80% by mass, more preferably 55 to 75% by mass, and particularly preferably 60 to 70% by mass.

  The mucoadhesive layer, drug layer, and support layer according to the present invention can contain various additives such as a disintegrant, an excipient, a colorant, a plasticizer, an antioxidant, an essential oil, and a fragrance, if necessary.

  The disintegrant is not particularly limited as long as it is commonly used in the technical field and is edible. For example, sugars, carmellose and salts thereof, cellulose, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate , Dextrin, dehydroacetic acid and its salts, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monooleate (eg, polysorbate), polyethylene glycol (eg, macrogol), anhydrous citric acid An acid etc. are illustrated. These can be used alone or in combination. Among these, saccharides and macrogol are preferably used from the viewpoint of improving disintegration of the preparation and imparting plasticity. Here, the saccharide refers to a synthetic or natural sugar substitute having a sweetness level less than 50 times that of sucrose. For example, mannitol, maltose, trehalose, reduced maltose starch syrup, maltitol, erythritol, xylitol, sucrose. Examples include sugar, fructose, sorbitol, sucrose, lactose and the like. These can be used alone or in combination. Among these, mannitol, maltose, maltitol, trehalose, and reduced maltose starch syrup are preferably used from the viewpoint of improving the disintegration property of the preparation.

The excipient is not particularly limited as long as it is commonly used in the art and is edible. For example, candy powder, starch, fructose, caramel, agar, xylitol, citric acid, glycerin, paraffin, Examples include cellulose, titanium oxide, tartaric acid, sorbitol, lactose, sucrose, glucose, pullulan, propylene glycol, polyoxyethylene hydrogenated castor oil, polyethylene glycol (eg, macrogol), maltitol, maltose, mannitol, trehalose, malic acid, etc. Is done. These can be used alone or in combination. Among these, titanium oxide, mannitol, trehalose, and macrogol are preferably used from the viewpoint of improving the appearance of the product and workability during production.
The colorant is not particularly limited as long as it is commonly used in the technical field and is edible. However, yellow iron sesquioxide, brown iron oxide, caramel, black iron oxide, titanium oxide, iron sesquioxide, tar Examples thereof include a dye, an aluminum lake dye, and copper chlorophyllin sodium. These can be used alone or in combination. Of these, titanium oxide and aluminum lake dye are preferably used from the viewpoint of improving the appearance of the product and the product image.

  The plasticizer is not particularly limited as long as it is commonly used in the art and is edible. For example, glycerin, sesame oil, sorbitol, castor oil, propylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate 80 [polyoxyethylene sorbitan monooleate (20EO)], polyethylene glycol [especially Macrogol 400 (polymerization degree n of oxyethylene units is 7 to 9, the same applies hereinafter), Macrogol 600 (n is 11 to 13) , Macrogol 1500 (n is an equal mixture of 5 to 6 and n is 28 to 36), Macrogol 4000 (n is 59 to 84), Macrogol 6000 (n is 165 to 210)], etc. The These can be used alone or in combination. Among these, glycerin, propylene glycol, and macrogol 400 are preferably used from the viewpoint of improving the adhesion between film layers by pressurization during production and imparting flexibility to the product.

  Antioxidants are not particularly limited as long as they are commonly used in the art and are edible. For example, ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, citric acid, Examples include tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole and the like. These can be used alone or in combination. Among these, ascorbic acid, sodium bisulfite, sodium edetate, tocopherol acetate, dibutylhydroxytoluene, and butylhydroxyanisole are preferably used from the viewpoint of improving the stability of the drug.

  Examples of the essential oil include anise oil, eucalyptus oil, orange oil, sage oil, thyme oil, lemon oil and the like excluding the above-mentioned refreshing agent, and can be appropriately added as necessary. These can be used alone or in combination.

  As a fragrance, for example, vanilla flavor, orange flavor, orange peel flavor, strawberry flavor, raspberry flavor, chocolate flavor, grapefruit flavor, cranberry flavor, ume flavor, coconut flavor, herbal flavor, coffee flavor, tea flavor, cinnamon flavor, Honey lemon flavor etc. are illustrated. These can be used alone or in combination. Among these, orange flavor and grapefruit flavor are preferable from the viewpoint of improving the refreshing feeling and the refreshing feeling when dissolving the preparation.

  In the present invention, the content of various additives can be appropriately set within a range that does not impair the object of the present invention. For example, the content of the disintegrant and the excipient in the unit preparation is 0 to 0 in total. 49 mass% is preferable. Furthermore, the content of the plasticizer in the unit preparation is preferably 0 to 10% by mass, and the content of the antioxidant in the unit preparation is preferably 0 to 10% by mass.

  In this embodiment, for convenience of explanation, the case where the oral mucosa patch preparation has a five-layer structure has been described. However, the oral mucosa patch preparation of the present invention is not limited to this and has a laminated structure exceeding five layers. It may be. For example, another functional layer can be provided adjacent to the first drug layer and / or the second drug layer on the inside and / or outside. An example of such a layer is a moisture-proof layer mainly composed of ethyl cellulose and moisture-proof. In addition, when the same kind of layers are stacked adjacent to each other, they are in close contact with each other and perform the same function, and therefore, in the present invention, they are handled as substantially one layer. Moreover, the composition of the first drug layer and the second drug layer may be the same or different.

Next, the manufacturing method of the intraoral mucosa patch preparation of this invention is demonstrated.
The preparation of the present invention can be produced by employing a known method. For example, as described in JP-A No. 2004-196784, JP-A No. 2004-043450, JP-A No. 11-116469, etc. A method is illustrated.

In the present invention, a production method including the following steps (1) to (11) is preferably employed.
(1) a step of directly applying a coating liquid containing a corrigent and an edible water-soluble polymer on a resin film to form a mucoadhesive layer having a predetermined thickness;
(2) A coating liquid containing a drug, a flavoring agent and an edible water-soluble polymer is applied on the mucosal adhesion layer formed in step (1) to have a first drug layer having a predetermined thickness. Obtaining an intermediate product A;
(3) forming a support layer having a predetermined thickness by directly applying a coating liquid containing an edible water-insoluble polymer onto a resin film;
(4) An intermediate having a second drug layer having a predetermined thickness by applying a coating liquid containing a drug, a flavoring agent and an edible water-soluble polymer on the support layer formed in step (3) Obtaining product B;
(5) a step of directly forming a coating liquid containing an edible water-soluble polymer and a corrigent on a resin film to form an intermediate layer having a predetermined thickness;
(6) The intermediate layer obtained in the step (5) and the intermediate product A obtained in the step (2) are stacked so as to face each other and pressed from the back surface of the resin film, thereby bringing them into close contact with each other. A step of obtaining an intermediate product C,
(7) A step of peeling off only the resin film on the intermediate layer side of the intermediate product C obtained in the step (6) to obtain an intermediate product D,
(8) By superposing the intermediate layer obtained in step (5) and the second drug layer of intermediate product B obtained in step (4) so as to face each other and pressing from the back surface of the resin film , A process for obtaining an intermediate product E by bringing them into close contact with each other,
(9) A step of peeling off only the resin film on the intermediate layer side of the intermediate product E obtained in step (8) to obtain an intermediate product F;
(10) The intermediate layer of the intermediate product D obtained in the step (7) and the intermediate layer of the intermediate product F obtained in the step (9) are stacked so as to face each other and pressed from the back surface of the resin film. To obtain an intermediate product G by bringing them into close contact with each other,
(11) A step of peeling at least one of the resin films on both sides of the intermediate product G obtained in the step (10).

In the above-described steps (1) to (5), the coating liquid can be formed on the resin film and dried. In that case, for example, the coating described in JP-A-2004-196784 is possible. Construction equipment can be used. Examples of resin films include polyethylene terephthalate, polyethylene naphthalate, copolymer polyester, polyimide, polypropylene, cellulose triacetate, vinyl acetate resin, ethylene-vinyl acetate copolymer, polyethylene, polyvinyl chloride, polycarbonate, polypropylene, triacetate, and fluororesin ( ETFE, PFA, FEP) and other films made of a resin can be appropriately selected for use. Among these, polyethylene terephthalate (PET) is particularly preferable.
As a solvent used for the preparation of the coating liquid, water, alcohol, ketone, ether, ester, hydrocarbon, halogenated hydrocarbon, amide, or a mixture thereof can be used without particular limitation. In particular, ethanol), esters (especially ethyl acetate) or a combination of these solvents (for example, ethanol-water mixture, ethanol-ethyl acetate mixture) are preferably used.
In the steps (6) to (11), a crimping device described in JP-A No. 2004-196784 and JP-A No. 2005-80838 can be used. In this case, the pressure is adjusted to 0.05 to 1.5 MPa, the temperature of the layer to be pressure-bonded is adjusted to 30 to 70 ° C., and then pressure-bonded. It is preferable to cool to a lower temperature.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated more concretely, this invention is not restrict | limited to the following Example.

  The thicknesses of the oral mucosa patch preparations of Examples 1-2 and Comparative Examples 1-3 are unified at 138 μm.

[Example 1]
It has a five-layer structure in which a mucoadhesive layer, a first drug layer, an intermediate layer, a second drug layer and a support layer are sequentially laminated, and all layers other than the support layer are anhydrous citric acid, saccharin sodium and l-menthol. Oral mucosa patch preparation (I)
In 15 g of water, 0.6 g of anhydrous citric acid, 0.6 g of sodium saccharin, and 0.6 g of D-mannitol were dissolved. Next, after adding a solution in which 0.2 g of l-menthol was dissolved in 15 g of ethanol, 1 g of titanium oxide was added to this solution. Then, 7 g of hydroxypropylmethylcellulose was added to this solution to obtain a mucoadhesive layer preparation solution.
2.5 g of macrogol was mixed with 5 g of water. Subsequently, after adding a solution in which 0.06 g of iron sesquioxide was dispersed in 20 g of ethanol, 0.3 g of titanium oxide was added to this solution. Then, 6.2 g of hydroxypropylmethylcellulose phthalate and 1 g of hydroxypropylmethylcellulose were added to this solution to obtain a support layer preparation solution.
In 30 g of water, 2 g of nicotine oil, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 0.6 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.4 g of l-menthol in 30 g of ethanol was added to this solution. Then, 7.3 g of hydroxypropyl methylcellulose and 7.3 g of hydroxypropylcellulose were added to this solution to obtain a drug layer preparation solution.
In 30 g of water, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 3 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.4 g of l-menthol in 30 g of ethanol was added to this solution. Then, 14.2 g of hydroxypropylmethylcellulose was added to this solution to obtain an intermediate layer preparation solution.

An oral mucosa patch preparation was prepared by the following procedure using each preparation solution.
1) Production process of edible intermediate product 11 A polyethylene terephthalate film (PET film) subjected to silicone release treatment is set on the unwinding shaft of the coating machine, the mucoadhesive layer preparation liquid is supplied to the dam part, and the surface of the PET film ( After applying the mucoadhesive layer preparation solution to the surface not subjected to the silicone release treatment, it was dried with warm air to form an edible mucoadhesive layer having a thickness of 23 μm. Next, the PET film on which the mucoadhesive layer is formed is set again on the unwinding shaft, and after the drug layer preparation liquid is applied onto the mucoadhesive layer, it is dried with warm air and the edible intermediate product 11 having a thickness of 46 μm is obtained. Obtained.
2) Manufacturing process of edible intermediate layer PET film with both sides of silicone peeled is set on the unwinding shaft of the coating machine, the intermediate layer preparation liquid is supplied to the dam part, and the intermediate layer preparation liquid is applied to the surface of the PET film. Was applied. Subsequently, it dried with warm air and formed the edible intermediate | middle layer of thickness 23 micrometers.

3) Manufacturing process of edible intermediate product 12 Polyethylene terephthalate film (PET film) subjected to silicone release treatment is set on the unwinding shaft of the coating machine, the support layer preparation liquid is supplied to the dam part, and the surface of the PET film (silicone) The support layer preparation solution was applied to the surface not subjected to the peeling treatment, and then dried with warm air to form an edible support layer having a thickness of 23 μm. Next, the PET film on which the support layer was formed was set again on the unwinding shaft, and after the drug layer preparation solution was applied on the support layer, it was dried with warm air to obtain an edible intermediate product 12 having a thickness of 46 μm. .
4) Pressure bonding step The drug layer of the intermediate product 11 and the intermediate layer obtained in step 2) are bonded together so as to face each other and pressure bonded at a pressure bonding temperature of 70 ° C., and the mucoadhesive layer is sandwiched between the two PET films. An intermediate product 13 having a three-layer structure of a drug layer and an intermediate layer was obtained.

5) Resin film peeling step Only the PET film on the intermediate layer side of the intermediate product 13 was peeled off to obtain an intermediate product 14.
6) Pressure bonding step The drug layer of the intermediate product 12 and the intermediate layer obtained in step 2) are bonded together so as to face each other and pressure bonded at a pressure bonding temperature of 70 ° C., and between the two PET films, An intermediate product 15 consisting of three layers, a drug layer and an intermediate layer, was obtained.
7) Resin film peeling step Only the PET film on the intermediate layer side of the intermediate product 15 was peeled to obtain an intermediate product 16.

8) Pressure bonding step The intermediate layer 14 of the intermediate product 14 and the intermediate layer 16 of the intermediate product 16 are bonded so as to face each other, and both are pressure bonded at a pressure bonding temperature of 70 ° C. Between the two PET films, the mucosal adhesion layer and the drug layer An intermediate product 17 having a five-layer structure including the intermediate layer, the drug layer, and the support layer was obtained.
9) Resin film peeling step Only the PET film on the support layer side of the intermediate product 17 was peeled off to obtain an intermediate product 18.
10) Punching process The intermediate product 18 was punched using a circular φ12 mm cutter so as not to reach the back surface of the PET film to obtain an oral mucosa patch preparation (I) having a thickness of 138 μm.

[Example 2]
It has a five-layer structure in which a mucoadhesive layer, a first drug layer, an intermediate layer, a second drug layer and a support layer are sequentially laminated, and all layers other than the support layer are anhydrous citric acid, saccharin sodium and l-menthol. Oral mucosal patch preparation (II)
In 15 g of water, 0.6 g of anhydrous citric acid, 0.6 g of sodium saccharin, and 0.6 g of trehalose were dissolved. Next, after adding a solution in which 0.2 g of l-menthol was dissolved in 15 g of ethanol, 1 g of titanium oxide was added to this solution. Then, 7 g of hydroxypropylmethylcellulose was added to this solution to obtain a mucoadhesive layer preparation solution.
2.5 g of macrogol was mixed with 5 g of water. Subsequently, after adding a solution in which 0.06 g of iron sesquioxide was dispersed in 20 g of ethanol, 0.3 g of titanium oxide was added to this solution. Then, 6.2 g of hydroxypropylmethylcellulose phthalate and 1 g of hydroxypropylmethylcellulose were added to this solution to obtain a support layer preparation solution.
In 30 g of water, 2 g of nicotine oil, 1.2 g of anhydrous citric acid, and 1.2 g of sodium saccharin were dissolved. Next, a solution prepared by dissolving 0.4 g of l-menthol in 30 g of ethanol was added to this solution. Then, 7.3 g of hydroxypropyl methylcellulose and 7.3 g of hydroxypropylcellulose were added to this solution to obtain a drug layer preparation solution.
1.2 g of anhydrous citric acid and 1.2 g of saccharin sodium were dissolved in 30 g of water. Next, a solution prepared by dissolving 0.4 g of l-menthol in 30 g of ethanol was added to this solution. Then, 14.2 g of hydroxypropylmethylcellulose was added to this solution to obtain an intermediate layer preparation solution.
An oral mucosa patch preparation (II) was obtained by the same operation as in Example 1 using each preparation solution.

  Tables 1 and 2 show the composition per unit preparation (one oral mucosa patch preparation) in the Examples group.

[Comparative Example 1]
It has a three-layer structure in which a mucoadhesive layer, a drug layer, and a support layer are sequentially laminated. All layers other than the support layer contain anhydrous citric acid, sodium saccharin and l-menthol. 1.5 g of acid, 1.5 g of sodium saccharin, and 1.5 g of D-mannitol were dissolved. Next, a solution in which 0.5 g of l-menthol was dissolved in 15 g of ethanol was added to this solution, and then 2.5 g of titanium oxide was added. Then, 17.5 g of hydroxypropylmethylcellulose was added to this solution to obtain a mucoadhesive layer preparation solution.
2.5 g of macrogol was mixed with 5 g of water. Next, after adding a solution in which 0.06 g of iron sesquioxide was dispersed in 20 g of ethanol, 0.3 g of titanium oxide was added to this solution. Then, 6.2 g of hydroxypropylmethylcellulose phthalate and 1 g of hydroxypropylmethylcellulose were added to this solution to obtain a support layer preparation solution.
In 30 g of water, 2.0 g of nicotine oil, 1.5 g of anhydrous citric acid, 1.5 g of sodium saccharin, and 0.75 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.5 g of l-menthol in 30 g of ethanol was added to this solution. Then, 9.38 g of hydroxypropylmethylcellulose and 9.38 g of hydroxypropylcellulose were added to this solution to obtain a drug layer preparation solution.

An oral mucosa patch preparation was prepared by the following procedure using each preparation solution.
1) Production process of edible intermediate product 101 A polyethylene terephthalate film (PET film) subjected to silicone release treatment is set on the unwinding shaft of the coating machine, a mucoadhesive layer preparation solution is supplied to the dam part, and the surface of the PET film ( The mucoadhesive layer preparation solution was applied to the surface not subjected to the silicone release treatment. Next, it was dried with warm air to form an edible mucosal adhesion layer having a thickness of 58 μm. Next, the PET film on which the mucoadhesive layer was formed was set again on the unwinding shaft, and the drug layer preparation solution was applied onto the mucoadhesive layer. Next, it was dried with warm air to form an edible intermediate product 101 having a thickness of 86 μm.
2) Manufacturing process of edible intermediate product 102 Polyethylene terephthalate film (PET film) subjected to silicone release treatment is set on the unwinding shaft of the coating machine, the support layer preparation liquid is supplied to the dam part, and the surface of the PET film (silicone) The support layer preparation solution was applied to the surface not subjected to the peeling treatment, and then dried with warm air to form an edible support layer having a thickness of 23 μm. Next, the PET film on which the support layer was formed was set again on the unwinding shaft, and after the drug layer preparation solution was applied onto the support layer, it was dried with warm air to form an edible intermediate product 102 having a thickness of 52 μm. .

3) Pressure bonding process The intermediate product 101 and the intermediate product 102 are bonded so that the drug layers face each other, and both are bonded at a pressure bonding temperature of 70 ° C., and between the two PET films, the mucoadhesive layer, the drug layer, and the support An intermediate product 103 having a three-layer structure was obtained.
4) Resin film peeling step Only the PET film on the support layer side of the intermediate product 103 was peeled off to obtain an intermediate product 104.
5) Punching process The intermediate product 104 was punched out using a circular φ12 mm cutter so as not to reach the back surface of the PET film, thereby obtaining an oral mucosal patch preparation having a thickness of 138 μm.

[Comparative Example 2]
Mucoadhesive layer, drug layer, and support layer have a three-layer structure sequentially laminated. Oral mucosa patch preparation containing anhydrous citric acid, sodium saccharin and l-menthol only in the drug layer 1.5 g of D-mannitol in 15 g of water Was dissolved. Next, 15 g of ethanol was added to this solution, and then 2.5 g of titanium oxide was added. Then, 21 g of hydroxypropylmethylcellulose was added to this solution to obtain a mucoadhesive layer preparation solution.
In 30 g of water, 2.0 g of nicotine oil, 3 g of anhydrous citric acid, 3 g of sodium saccharin, and 0.75 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 1 g of l-menthol in 30 g of ethanol was added to this solution. Then, 7.63 g of hydroxypropylmethylcellulose and 7.63 g of hydroxypropylcellulose were added to this solution to obtain a drug layer preparation solution.
2.5 g of macrogol was mixed with 5 g of water. Next, after adding a solution in which 0.06 g of iron sesquioxide was dispersed in 20 g of ethanol, 0.3 g of titanium oxide was added to this solution. Then, 6.2 g of hydroxypropylmethylcellulose phthalate and 1 g of hydroxypropylmethylcellulose were added to this solution to obtain a support layer preparation solution.
An oral mucosa patch preparation was obtained by the same operation as in Comparative Example 1 using each preparation solution.

[Comparative Example 3]
It has a five-layer structure in which a mucoadhesive layer, a first drug layer, an intermediate layer, a second drug layer and a support layer are sequentially laminated, and all layers other than the support layer are anhydrous citric acid, saccharin sodium and l-menthol. The support layer was prepared by dissolving 0.6 g of anhydrous citric acid, 0.6 g of sodium saccharin, and 0.6 g of D-mannitol in 15 g of water. Next, after adding a solution in which 0.2 g of l-menthol was dissolved in 15 g of ethanol, 1 g of titanium oxide was added to this solution. Then, 7 g of hydroxypropylmethylcellulose was added to this solution to obtain a mucoadhesive layer preparation solution.
2.5 g of macrogol was mixed with 5 g of water. Subsequently, after adding a solution in which 0.06 g of iron sesquioxide was dispersed in 20 g of ethanol, 0.3 g of titanium oxide was added to this solution. Then, 7.2 g of hydroxypropylmethylcellulose was added to this solution to obtain a support layer preparation solution.
In 30 g of water, 2 g of nicotine oil, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 0.6 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.4 g of l-menthol in 30 g of ethanol was added to this solution. Then, 7.3 g of hydroxypropyl methylcellulose and 7.3 g of hydroxypropylcellulose were added to this solution to obtain a drug layer preparation solution.
In 30 g of water, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 3 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.4 g of l-menthol in 30 g of ethanol was added to this solution. Then, 14.2 g of hydroxypropylmethylcellulose was added to this solution to obtain an intermediate layer preparation solution.

An oral mucosa patch preparation was prepared by the following procedure using each preparation solution.
1) Manufacturing process of edible intermediate product 201 A polyethylene terephthalate film (PET film) subjected to silicone release treatment is set on the unwinding shaft of the coating machine, a mucoadhesive layer preparation solution is supplied to the dam part, and the surface of the PET film ( After applying the mucoadhesive layer preparation solution to the surface not subjected to the silicone release treatment, it was dried with warm air to form an edible mucoadhesive layer having a thickness of 23 μm. Next, the PET film on which the mucoadhesive layer is formed is set again on the unwinding shaft, the drug layer preparation liquid is applied onto the mucoadhesive layer, and then dried with warm air to produce an edible intermediate product 201 having a thickness of 46 μm. Obtained.
2) Manufacturing process of edible intermediate layer PET film with silicone release treatment on both sides is set on the unwinding shaft of the coating machine, the intermediate layer preparation solution is supplied to the dam part, and the intermediate layer is prepared on the surface of the PET film. The liquid was applied. Subsequently, it dried with warm air and formed the edible intermediate | middle layer of thickness 23 micrometers.

3) Manufacturing process of edible intermediate product 202 Polyethylene terephthalate film (PET film) subjected to silicone release treatment is set on the unwinding shaft of the coating machine, the support layer preparation liquid is supplied to the dam part, and the surface of the PET film (silicone) The support layer preparation solution was applied to the surface not subjected to the peeling treatment, and then dried with warm air to form an edible support layer having a thickness of 23 μm. Next, the PET film on which the support layer was formed was set again on the unwinding shaft, and after the drug layer preparation solution was applied onto the support layer, it was dried with warm air to obtain an edible intermediate product 202 having a thickness of 46 μm. .
4) Pressure bonding step The drug layer of the intermediate product 201 and the intermediate layer obtained in step 2) are bonded together so as to face each other, pressure bonded at a pressure temperature of 70 ° C., and the mucosal adhesion layer between the two PET films. An intermediate product 203 having a three-layer structure of a drug layer and an intermediate layer was obtained.

5) Resin film peeling step Only the PET film on the intermediate layer side of the intermediate product 203 was peeled off to obtain an intermediate product 204.
6) Pressure bonding step The drug layer of the intermediate product 202 and the intermediate layer obtained in step 2) are bonded together so as to face each other and pressure bonded at a pressure bonding temperature of 70 ° C., and between the two PET films, the support layer and An intermediate product 205 consisting of three layers, a drug layer and an intermediate layer, was obtained.
7) Resin film peeling step Only the PET film on the intermediate layer side of the intermediate product 205 was peeled off to obtain an intermediate product 206.

8) Pressure bonding step The intermediate layer of the intermediate product 204 and the intermediate layer of the intermediate product 206 are bonded together so as to face each other, and both are pressure bonded at a pressure bonding temperature of 70 ° C., and between the two PET films, the mucosal adhesion layer and the drug layer An intermediate product 207 having a five-layer structure including an intermediate layer, a drug layer, and a support layer was obtained.
9) Resin film peeling step Only the PET film on the support layer side of the intermediate product 207 was peeled off to obtain an intermediate product 208.
10) Punching process The intermediate product 208 was punched using a circular φ12 mm cutter so as not to reach the back surface of the PET film to obtain a 138 μm thick intraoral mucosa patch preparation.

  Table 2 shows the composition per unit preparation (one oral mucosa patch preparation) in the comparative example group.

Taste sensory test regarding throat soaking Six panelists took the preparations obtained in each of the examples and comparative examples, and the throat after taking was evaluated according to the following criteria. The evaluation was performed in five stages, with the formulation having the least irritation in the throat being “1 point” and the formulation having the most irritation in the throat being “5 points”, and the evaluation was made based on the average value of the scores of 6 people. The results are shown in Table 3.

As shown in Table 3, the score of throat after taking is 1.8 points for the five-layer preparations of Examples 1 and 2 each containing a flavoring agent in all layers other than the support layer. Although it was 7 points, it was 3.2 points in the preparation of the comparative example 1 of the three-layer type containing the flavoring agent in all layers other than the support layer, and the comparative example 2 containing the flavoring agent only in the drug layer The score of 4.0 was 4.0. For this reason, having a five-layer structure in which an intermediate layer is provided between drug layers, and containing a flavoring agent in all layers other than the support layer is effective in mitigating drug-derived irritation. it is conceivable that.
In addition, since the support layer has 4.3 points in the preparation of Comparative Example 3 of the five-layer type in which the poorly water-soluble polymer is not contained, the outermost support layer contains the hardly water-soluble polymer in the oral cavity. It is thought that it is effective in effectively promoting intraoral mucosal absorption, in that excessive release of the drug to the skin can be suppressed to alleviate the stimulus derived from the drug.

  The preparations obtained in each Example and Comparative Example were subjected to the following water disintegration test and oral disintegration test. The results are shown in Table 4.

Water disintegration test A test piece cut into a circular φ12 mm size was collected, put into a test solution (purified water 900 mL), and the 15th revised Japanese Pharmacopoeia [B] General Test Method. Formulation Test Method 6.10 Dissolution Test Method According to the paddle method (P587), a test was performed at 50 rpm using a sinker. The test solution was collected every 5 minutes until 60 minutes after the start of the test, and the time when the drug elution rate reached 95% by mass or more by liquid chromatography was defined as the water disintegration time.

Oral Disintegration Test A test piece cut into a size of a circular φ12 mm was collected, and after sticking it on the oral mucosa of a healthy adult, the time until the test piece was completely dissolved only by saliva in the oral cavity was measured. In the test, the time required for taking 6 panelists was averaged, and the value was taken as the oral disintegration time.

  From Tables 3 and 4, the preparation of Comparative Example 1 can absorb the drug into the blood continuously at an appropriate release rate, but it is uncomfortable when taken, and the preparation of Comparative Example 2 Not only was the release rate slow, but there was also discomfort during taking. Further, the preparation of Comparative Example 3 had the fastest drug release rate but the strongest discomfort during taking. In contrast, the preparations of Examples 1 and 2 were able to release the drug continuously while having an appropriate release rate, and the discomfort during taking was alleviated.

1 shows one embodiment of the intraoral mucosa patch preparation of the present invention, FIG. 1 (a) is a plan view of the preparation 10, and FIG. 1 (b) is a cross-sectional view taken along line II of the preparation 10; It is.

Explanation of symbols

1: mucoadhesive layer 2: support layer 3: drug layer (3a: first drug layer, 3b: second drug layer)
4: Intermediate layer 10: Oral mucosa patch preparation

Claims (12)

A mucoadhesive layer that adheres to the oral mucosa and contains a corrigent and an edible water-soluble polymer;
A support layer disposed on the outermost layer on the opposite side of the mucosa-adhering layer and containing an edible poorly water-soluble polymer;
At least two drug layers disposed between the mucoadhesive layer and the support layer and containing a drug, a corrigent and an edible water-soluble polymer;
An intraoral mucosa patch preparation comprising an intermediate layer containing an edible water-soluble polymer and a corrigent disposed between the drug layers.   The oral mucosal patch preparation according to claim 1, which has a five-layer structure in which a mucoadhesive layer, a drug layer, an intermediate layer, a drug layer and a support layer are sequentially laminated.   The oral mucosa patch preparation according to claim 1 or 2, wherein the support layer further contains an edible water-soluble polymer.   The intraoral mucosa patch preparation according to any one of claims 1 to 3, wherein the taste masking agent is at least one selected from the group consisting of a sour agent, a high sweetness sweetener, and a refreshing agent.   The oral mucosal patch preparation according to claim 4, wherein the sour agent is at least one selected from the group consisting of ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof.   The oral mucosal patch preparation according to claim 4, wherein the high-sweetness sweetener is at least one selected from the group consisting of aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and salts thereof.   The oral mucosal patch preparation according to claim 4, wherein the refreshing agent is at least one selected from the group consisting of fennel oil, camphor, peppermint oil, peppermint water, mint, peppermint and menthol.   The edible water-soluble polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, polyvinylpyrrolidone and sodium alginate. The intraoral mucosa patch preparation according to any one of claims 1 to 7, which is a seed.   The edible poorly water-soluble polymer is selected from the group consisting of starch, gelatin, tragacanth gum, crystalline cellulose, ethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetal diethylaminoacetate, and polyacrylate. The intraoral mucosa patch preparation according to any one of claims 1 to 8, which is at least one kind.   The intraoral mucosa patch preparation according to any one of claims 1 to 9, wherein the drug is nicotine.   The intraoral mucosal patch preparation according to any one of claims 1 to 10, which disintegrates in the oral cavity in 2 to 15 minutes.   The intraoral mucosal patch preparation according to any one of claims 1 to 11, wherein the disintegration time for water is 5 to 25 minutes.

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