JPH05155759A - Preparation for applying to oral cavity mucosa - Google Patents

Abstract

(57) [Summary] [Purpose] It has a mucoadhesive base that is excellent in water resistance and therefore is unlikely to be disintegrated or dissolved by saliva, etc., and can easily adhere to the oral mucosa for a long time. A preparation for oral mucosa is obtained. [Structure] A mucoadhesive base comprises a vinylpyrrolidone (co) polymer that is soluble in water and a water-swellable (meth) acrylic acid-containing water-absorbing polymer as main components, and a vinylpyrrolidone (co) polymer Vinylpyrrolidone content of 70 mol%
The above is the mixing ratio of the vinylpyrrolidone (co) polymer and the acrylic acid-containing water-absorbing polymer in a weight ratio of 95:
Oral mucosa application preparation which is 5 to 70:30.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a preparation for oral mucosa using a vinylpyrrolidone (co) polymer and a (meth) acrylic acid-containing water-absorbing polymer, and in particular, it can be easily adhered to the oral mucosa for a long time. The present invention relates to a preparation for application to oral mucosa suitable for protecting the damaged or diseased part in the oral cavity, which can maintain the release of the active ingredient into the oral mucosa and saliva for a long time.

[0002]

2. Description of the Related Art Conventionally, a preparation for oral mucosa which is adhered to the oral mucosa and administers an active ingredient such as a drug to the oral mucosa and saliva, and an intraoral bandage for protecting the damaged or diseased part of the oral cavity Have been proposed. In this kind of preparation for oral mucosa and intraoral bandage, various mucoadhesive bases are used for adhering to the oral mucosa.
In the present specification, the expression “oral mucosa-applied preparation” is used to include both the above-mentioned preparation for oral mucosa and intraoral bandage.

For example, JP-B-58-7605 discloses a mucoadhesive base having a composition comprising hydroxypropyl cellulose and an acrylic acid (co) polymer or a salt thereof, as disclosed in JP-A-59-186913. JP-A No. 61-249473 discloses a polycarboxylic acid, a polycarboxylic acid anhydride and a vinyl acetate polymer, and JP-A No. 61-249473 discloses a composition comprising gelatin or agar, gluten, a carboxyvinyl polymer and a vinyl acetate resin or gums. A composition comprising is disclosed. Each of the mucoadhesive bases described in these prior arts has a hydrophilic polymer as a main component and is configured to exhibit adhesiveness to the oral mucosa by a small amount of water such as saliva.

However, in the conventional mucoadhesive base comprising the above hydrophilic polymer, it swells with a large amount of water,
Since it disintegrates or dissolves, it has a problem in water resistance. Therefore, in order to enhance the water resistance of the mucoadhesive base, a composition in which a water-insoluble polymer such as vinyl acetate or rubber is blended with the above hydrophilic polymer has been proposed.
However, since the affinity between the hydrophilic polymer and the water-insoluble polymer is not good and the interaction is small, sufficient water resistance cannot be achieved.

Further, in Japanese Patent Laid-Open No. 60-248609,
Water-soluble polyvinylpyrrolidone, alginic acid and pharmaceutically acceptable salts thereof, and one or more polymers selected from the group consisting of maleic anhydride-methyl vinyl ether copolymer, polyacrylic acid and pharmaceutically A composition comprising an acceptable salt has been proposed. However, in the combination of polyacrylic acid and a pharmaceutically acceptable salt thereof, and water-soluble polyvinylpyrrolidone, although water resistance is increased as compared with the case where each is used alone, both components are water-soluble. Therefore, it was still impossible to realize sufficient water resistance.

[0006]

An object of the present invention is to have a mucoadhesive base which has excellent water resistance and is unlikely to be disintegrated or dissolved by saliva or the like, and is easily and long-term adhered to the oral mucosa. Another object of the present invention is to provide a preparation for application to the oral mucosa that can protect the damaged or diseased part in the oral cavity for a long time.

[0007]

The preparation for oral mucosa application according to the present invention comprises a water-soluble vinylpyrrolidone (co) polymer and a water-swellable (meth) acrylic acid-containing water-absorbing agent. It is characterized by containing a polymer as a main component. It was known that vinylpyrrolidone (co) polymer provides a base with excellent adhesiveness to the oral mucosa, but as mentioned above, vinylpyrrolidone (co) polymer alone has a problem of insufficient water resistance. It was As a result of intensive studies to solve this problem, the present inventors have found that the above problem can be achieved by using a vinylpyrrolidone (co) polymer and a (meth) acrylic acid-containing water-absorbing polymer together. The present invention has been completed.

The preparation for oral mucosa application of the present invention is characterized by having the above-mentioned mucoadhesive base, but the mucosa-adhesive base contains various agents described below,
Not only so-called preparations for oral mucosa but also oral cavity bandages used for protecting damaged or diseased parts in the oral cavity are included. The mucoadhesive base containing both the vinylpyrrolidone (co) polymer and the (meth) acrylic acid-containing water-absorbing polymer exhibits the following excellent effects.

It absorbs saliva or secretory fluid and locally adheres to it, and even when it swells, the excellent local adhesive action is maintained.
Therefore, it becomes possible to make the drug act directly and locally on the oral cavity or the peripheral disease site, or to effectively protect the damaged site or affected site in the oral cavity. By absorbing saliva or secretory fluid and gradually releasing the drug, it becomes possible to continue to administer the drug to the diseased site or absorption site to which it is applied for a long time, or to protect the affected area.

Since it has high water resistance even when saliva or secretory fluid is absorbed, it does not dissolve and flow out, and it has excellent shape retention even after swelling. When a drug is included, at least a part of the drug will be dissolved and present in the mucoadhesive base, so compared to the case where the drug is simply dispersed in the mucoadhesive base. , The initial release of the drug is excellent.

However, in order to exert the above-mentioned excellent effects, vinylpyrrolidone (co) polymer and (meth)
The mixing ratio of the acrylic acid-containing water-absorbing polymer is 95: 5.
.About.70: 30% by weight is necessary.
This is because if the compounding ratio of the (meth) acrylic acid-containing water-absorbing polymer is less than 5% by weight, the effect of sufficiently enhancing water resistance cannot be obtained, and if it exceeds 30% by weight, the advantages of the vinylpyrrolidone (co) polymer are exhibited. This is because the adhesiveness to a certain wet surface is impaired. Preferably, the blending ratio of the (meth) acrylic acid-containing water absorbent polymer is in the range of 10 to 20% by weight.

Vinylpyrrolidone (co) polymer Examples of the vinylpyrrolidone (co) polymer used in the present invention include vinylpyrrolidone homopolymer, vinylpyrrolidone and (meth) acrylic acid, (meth) acrylic acid methyl ester, Examples thereof include copolymers with one or more of (meth) acrylic acid ethyl ester, (meth) acrylic acid 2-ethylhexyl ester, maleic anhydride, vinyl alcohol, vinyl acetate and the like. Such a vinylpyrrolidone (co) polymer is required to exhibit tackiness when a small amount of water such as saliva is applied. Therefore, the vinylpyrrolidone (co) polymer used in the present invention needs to be soluble in water.

When a vinylpyrrolidone copolymer is used,
In order to realize excellent properties of vinylpyrrolidone, that is, good sticking property to mucous membrane, non-irritating property to skin, and enhancing water resistance by blending a (meth) acrylic acid-containing water-absorbing polymer, The content of vinylpyrrolidone in the copolymer needs to be 70 mol% or more, and preferably 90 mol% or more.

(Meth) acrylic acid-containing water-absorbing polymer The (meth) acrylic acid-containing water-absorbing polymer used in the present invention rapidly hydrates and swells when contacted with water (pure water),
It is one that weighs about 2 to 1000 times its own weight. However, a salt solution such as saliva has a smaller water absorption amount than pure water. The (meth) acrylic acid-containing water-absorbing polymer used in the present invention includes starch (meth)
Graft-polymerized acrylate; Graft-polymerized carboxymethyl cellulose with (meth) acrylic acid; Neutralized (meth) acrylic acid homopolymer with an alkali metal salt such as Na or K; (meth) acrylic The copolymer of 1 type or 2 types of acid and vinyl alcohol and / or acrylamide is mentioned.

The reason why the water resistance of the preparation for oral mucosa of the present invention is remarkably enhanced by the addition of the (meth) acrylic acid-containing water-absorbing polymer is not always clear, but (meth)
It is considered that the carboxylic acid of (meth) acrylic acid in the water-absorbent polymer containing acrylic acid and the pyrrolidone ring of the vinylpyrrolidone (co) polymer interact unexpectedly.

Production The production method of the preparation for oral mucosa of the present invention is not particularly limited, but the following first and second production methods can be exemplified. The first production method is to dissolve a vinylpyrrolidone (co) polymer in methanol and an appropriate organic solvent,
After the (meth) acrylic acid-containing water-absorbing polymer is uniformly dispersed in the solution, it is provided with respective steps of casting and drying, whereby a thin film mucoadhesive base is obtained. In this case, when it is desired to act the drug on the oral mucosa, saliva and the like, when the vinylpyrrolidone (co) polymer is dissolved in an organic solvent, a drug for exerting a therapeutic effect may be added together. Furthermore, if necessary, a drug absorption promoter, a plasticizer, a flavoring agent, a flavoring agent, or the like may be added. According to the first production method, the (meth) acrylic acid-containing water-absorbing polymer is uniformly dispersed in the vinylpyrrolidone (co) polymer film to form a mucoadhesive base.

On the other hand, in the second production method, the vinylpyrrolidone (co) polymer and the (meth) acrylic acid-containing water-absorbing polymer are sufficiently mixed, and an appropriate amount of the mixture is directly pressed using a punch, a die and a press. It is a molding method, whereby a mucoadhesive base having a desired shape is obtained. Also in the second method, when it is desired to cause the drug to act on the oral mucosa or saliva, a therapeutic effect is obtained by adding the vinylpyrrolidone (co) polymer and the polymer component of the (meth) acrylic acid-containing water-absorbing polymer. It is only necessary to add and mix a drug for exerting the effect. Further, if necessary, in addition to the drug, one or two of a drug absorption enhancer, a lubricant (eg, magnesium stearate), a binder, an excipient (eg, lactose), a flavoring agent, etc. You may mix the above. According to the second production method, a mucoadhesive base comprising a blend polymer of a vinylpyrrolidone (co) polymer and a (meth) acrylic acid-containing water-absorbing polymer can be obtained.

Drug The drug to be contained in the preparation for oral mucosa application of the present invention is not particularly limited. Also, the number of types of drugs is not limited, and one or two or more drugs can be appropriately mixed if necessary. Examples of agents that can be used include antipyretic anti-inflammatory analgesics, analgesics, steroidal anti-inflammatory agents, vasodilators, hypertensive agents, arrhythmic agents, antihypertensive agents, antitussive analgesics, local anesthetics, hormone agents, Asthma / nasal allergy treatment agent, antihistamine, anticoagulant, antispasmodic agent, cerebral circulation / metabolic agent, antidepressant / anxiety agent, vitamin D preparation, oral hypoglycemic agent, antiulcer agent, sleeping pill, antibiotic, antibacterial agent Agents, bactericides and the like.

As antipyretic anti-inflammatory analgesics, indomethacin, salicylic acid, aspirin, acetaminophenone,
Dichlorophenac Na, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid,
Ibufenac, fenbufen, alclofenac, phenylbutazone, mehenamic acid, benzatac, piroxicam, flurbiprofen, pentazocine, buprenorphine hydrochloride, butorphanol tartrate and the like can be mentioned.

Examples of steroidal anti-inflammatory agents include hydrocortisone, prodnisolone, fluorocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, hetamethasone acetate, diflucortron valerate, and propioncloheta. Examples thereof include sol and fluocinonide. Examples of the vasodilator include diltiazem, verapamil, pentaerythritol tetranitrate, dipydamol, isosorbide nitrate, nifedipine, nitroglycerin and the like.

Examples of the hypertensive agent / arrhythmic agent include propanol, atenolol, pindolol, diquinine sulfate, azimarin, alprenolol hydrochloride, metroprolol tartrate, nadolol, timolol maleate, and disopyramide. As an antihypertensive agent, clonidine hydrochloride, captopril, prazosin hydrochloride, penbutrol sulfate, guanabenz acetate, guanfacine hydrochloride, punazosin hydrochloride, enalapril maleate, allotirol hydrochloride,
Bunitrolol hydrochloride etc. are mentioned.

Examples of antitussive agents include procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pirbutyrol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimethoquinol hydrochloride and formoterol fumarate. Can be mentioned. Examples of the anti-ulcer agent include 5-fluorouracil, 1- (2-tetrahydrofuryl) -5-fluorouracil, Maitomato C, and the like. Examples of the local anesthetic include benzocaine, procaine, lidocaine and tetracaine.

The hormonal agents include estrogen, estradiol, testosterone, progesterone, prostaglandins, insulin and the like. Examples of the therapeutic agent for asthma / nasal allergy include ketotifen fumarate, azelastine hydrochloride, Na cromoglycate, and the like, and antihistamines include cyclopeptazine hydrochloride, diphenhydrazine hydrochloride, fenbenzamine, mequitazine, and the like. Examples of anticoagulants include heparin, and examples of antispasmodic agents include scopolamine and clofluperol.

Examples of the cerebral circulatory metabolism improver include pinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, brovincamine fumarate, dihydroergotoxine mesylate, ifenprozirne tartrate, isoxuprine hydrochloride and the like. As antidepressant / anxiety drug, maprotiline hydrochloride,
Examples include etizolam, diazepam, bloazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like. Examples of vitamin D agents include alfacalcidol, ergocasiferol, and the like, and oral hypoglycemic agents include glibenclamide, gliclazide, and the like.

Examples of anti-ulcer agents include grepobride malate, famotidine, glycopyrronium bromide and the like. Examples of sleeping pills include phenobarbital and amobarbital, and examples of antibiotics include tetracycline and chloramphenicol. The blending amount of these drugs varies depending on the type of drug, the purpose of use of the patch, etc., but is usually contained in the oral mucosa preparation in a proportion of 0.1 to 40 wt%.

Form of Preparation for Oral Mucosa The preparation for oral mucosa of the present invention can be used alone as a mucoadhesive base. In that case, the thin film-shaped mucoadhesive base obtained by the first production method is used. The thickness of the agent is preferably 10 μm or more and 5000 μm or less, more preferably 30 μm or more and 500 μm or less. The shape, area, thickness, etc. of the mucoadhesive base obtained by the second production method are appropriately selected.

Further, the preparation for oral mucosa application according to the present invention may have a form in which a support layer is laminated on one side of a mucoadhesive base. As the support layer, a water-insoluble or similar non-mucoadhesive base material layer can be used. Examples of the material forming the support layer as described above include natural polymers, semi-synthetic polymers, synthetic polymers, metal foils, and composites thereof. By laminating the support layer on one side of the preparation for oral mucosa application, when applied to the oral mucosa, it is possible to reduce the permeation amount of saliva per unit time from the surface opposite to the oral mucosa, and the oral cavity Disintegration of the mucoadhesive base due to physical irritation is also suppressed. Therefore, compared with the case where the mucoadhesive base alone is used, the water resistance and durability can be further enhanced, and the adhesive can be adhered to the oral cavity for a longer time.

The support layer does not necessarily have to be water-insoluble or sparingly soluble, and a support layer made of a material that does not exhibit tackiness even when absorbing water may be used. Even when such a water-absorbent support layer is laminated, as long as it does not exhibit adhesiveness when absorbing water, the phenomenon that the preparation for oral mucosa adheres to fingers or the like when stuck in the oral cavity Can be prevented,
Therefore, the sticking work can be facilitated. The thickness of the support layer is preferably 1 μm or more and 100 μm or less, more preferably 5 μm or more and 50 μm or less. As a method for laminating the above-mentioned support layer on a mucoadhesive base, heating,
Pressurization or other suitable mechanical method; method of adhering with an adhesive; dissolution of the polymer of the support layer component in a suitable volatile solvent, application to a mucoadhesive base, and drying to form a support layer A forming method or the like can be adopted.

[0029]

In the preparation for oral mucosa application of the present invention, the vinylpyrrolidone (co) polymer in the mucoadhesive base has a function of absorbing saliva or secretory fluid and adhering it locally to the oral cavity. Therefore, it is possible to act the drug directly or locally on the oral cavity or the peripheral diseased part, or to protect the affected part.

After application, the saliva or secretory fluid is absorbed and the vinylpyrrolidone (co) polymer and the (meth) acrylic acid-containing water-absorbing polymer interact with each other to swell in the form of a gel, which absorbs the drug. Release gradually. Therefore, it becomes possible to continue administration of the drug to the applied disease site or absorption site for a long time and protect the affected site. Furthermore, since the gel-like material has excellent water resistance, it does not dissolve and flow out, has flexibility in a swollen state, and is excellent in shape retention. Therefore, even if the gel-like material remains in the oral mucosa for a long time, the patient does not feel a foreign body.

[0031]

EXAMPLES The present invention will be described in detail below by giving Examples and Comparative Examples of the present invention. Example 1 85 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90) was dissolved in ethanol 2
It was uniformly dissolved in 100 parts by weight to obtain a colorless and transparent pressure-sensitive adhesive solution. After uniformly dissolving 10 parts by weight of isosorbide dinitrate in the pressure-sensitive adhesive solution, a starch-acrylate graft polymer (manufactured by Sanyo Chemical Co., Ltd., trade name; Sunwet IM-10).
5 parts by weight of (00 MPS) was uniformly dispersed while stirring with a dissolver. The adhesive solution in which the starch-acrylate graft polymer is dispersed is applied onto polyethylene terephthalate (hereinafter PET) release paper whose surface is treated with silicone so that the thickness is 75 μm, and the temperature is 60 ° C. After drying for 1 hour, a film-form preparation for oral mucosa was obtained.

Comparative Example 1 Except that the blending amount of vinylpyrrolidone homopolymer was changed from 85 parts by weight to 90 parts by weight and 5 parts by weight of the starch-acrylate graft polymer was not dispersed.
In the same manner as in Example 1, a film-form preparation for oral mucosa was obtained.

Example 2 60 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90) and vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Koll)
15 parts by weight of idon 30) was uniformly dissolved in 300 parts by weight of ethanol to obtain a colorless and transparent pressure-sensitive adhesive solution. After uniformly dissolving 10 parts by weight of indomethacin in the pressure-sensitive adhesive solution, 15 parts by weight of acrylic acid-vinyl alcohol copolymer (Sumitomo Chemical Co., Ltd., trade name; Sumikagel SP-510) was uniformly stirred with a dissolver. Dispersed. The pressure-sensitive adhesive solution in which the acrylic acid-vinyl alcohol copolymer was uniformly dispersed as described above was coated on a PET release paper whose surface was treated with silicone to a thickness of 50 μm.
It was dried at a temperature of 0 ° C. for 1 hour to obtain a film-form preparation for oral mucosa application.

Comparative Example 2 72 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90) and vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Koll).
A film-form preparation for oral mucous membrane application was obtained in the same manner as in Example 2, except that 18 parts by weight of ionic 30) was used and the acrylic acid-vinyl alcohol copolymer was not dispersed.

Example 3 95 parts by weight of vinylpyrrolidone and 5 parts by weight of 2-ethylhexyl acrylate were used, and ethanol was used as a solvent.
0.3 parts by weight of lauroyl peroxide was added as a polymerization catalyst, and polymerization was carried out at 60 ° C. As a result, a solution containing a vinylpyrrolidone-2-ethylhexyl acrylate copolymer having a weight average molecular weight of 5.5 × 10 ⁵ and a solid content of 35% by weight was obtained. After uniformly dissolving 10 parts by weight of estradiol in 228.6 parts by weight of the copolymer solution, polyacrylate (manufactured by Sanyo Kasei Co., Ltd., trade name; Sunwet IM)
= 5000 MPS) 10 parts by weight were uniformly dispersed while stirring with a dissolver. The pressure-sensitive adhesive solution in which the polyacrylic acid salt is dispersed is applied onto a PET release paper whose surface is treated with silicone so as to have a thickness of 70 μm, and 6
It was dried at 0 ° C for 1 hour to obtain a film-form preparation for oral mucosa application.

Comparative Example 3 Vinylpyrrolidone-acrylic acid-2 obtained in Example 3
10 parts by weight of estradiol were uniformly dissolved in 257.1 parts by weight of the ethylhexyl copolymer solution. Then, using this adhesive solution, a film-form preparation for oral mucosa was obtained in the same manner as in Example 3.

Example 4 70 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90) and vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Koll)
15 parts by weight of idon 30) was uniformly dissolved in 300 parts by weight of ethanol to obtain a colorless and transparent pressure-sensitive adhesive solution. After uniformly dissolving 5 parts by weight of nifedipine in the adhesive solution,
5 parts by weight of polyacrylic acid salt (trade name; Sumikagel NP-1010 manufactured by Sumitomo Chemical Co., Ltd.) was uniformly dispersed while stirring with a dissolver. The pressure-sensitive adhesive solution in which the polyacrylic acid salt is dispersed is coated on PET release paper whose surface is treated with silicone so that the thickness is 100 μm, and the temperature is 60 ° C.
It was dried at the temperature of 1 hour for 1 hour to obtain a film-form preparation for oral mucosa application.

Comparative Example 4 Vinyl pyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90) 74.1 parts by weight and vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Ko)
A film-form preparation for oral mucosa was obtained in the same manner as in Example 4 except that 15.9 parts by weight of lidon30) was used and the polyacrylate was not dispersed.

Example 5 Methacrylic Acid-Methyl Methacrylate Copolymer (Ro
hm Pharma Co., trade name; Euidragit
L) 50 parts by weight and polyethylene glycol 600 (manufactured by NOF CORPORATION) 25 parts by weight were uniformly dissolved in 300 parts by weight of ethanol. The resulting solution has a thickness of 20 after drying.
PET whose surface is treated with silicone so that
It was coated on a release paper and dried at a temperature of 60 ° C. for 2 hours to obtain a film-like non-mucoadhesive substrate. The above-mentioned mucous membrane non-sticking base material and the preparation for oral mucosa application of Example 4 were thermocompression bonded to obtain a film-shaped preparation for oral mucosa application.

Example 6 Vinylpyrrolidone homopolymer manufactured by BASF, trade name;
Kollidon 90) 85 parts by weight of ethanol 200
By uniformly dissolving it in parts by weight, a colorless and transparent pressure-sensitive adhesive solution was obtained. Starch-acrylate graft polymer (manufactured by Sanyo Kasei Co., trade name; Sunwet IM-
5 parts by weight of 1000 MPS) were uniformly dispersed with stirring with a dissolver. The adhesive solution in which the starch-acrylate graft polymer was uniformly dispersed was prepared to have a thickness of 5
PE whose surface is treated with silicone so that it has a thickness of 0 μm
Apply on T release paper and dry at 60 ℃ for 1 hour,
A film-form preparation for oral mucosa was obtained.

Comparative Example 5 Vinylpyrrolidone homopolymer manufactured by BASF, trade name;
A film-form preparation for oral mucous membrane application was obtained in the same manner as in Example 6, except that 100 parts by weight of Kollidon 90) was used and the starch-acrylic acid graft polymer was not used.

Example 7 The mucous membrane non-sticking substrate obtained in Example 5 and the preparation for oral mucosa application of Example 6 were thermocompression bonded to obtain a film-form preparation for oral mucosa application. Example 8 Vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90F) 45 parts by weight, polyacrylate (manufactured by Sanyo Kasei, trade name; Sunwet IM-5)
000MPS) 5 parts by weight, lactose 10 parts by weight, magnesium stearate 0.2 parts by weight and isosorbide dinitrate 6 parts by weight are weighed and uniformly mixed, and then tableted to obtain a weight of 90 mg and a thickness of 0.9 mm, A tablet type preparation for oral mucosa having a diameter of 10.0 mm was obtained.

Comparative Example 6 In the same manner as in Example 8 except that 50 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90F) was blended and no polyacrylate was blended. A tablet preparation for oral mucosa was obtained. Comparative Example 7 Other than using 5 parts by weight of polyacrylic acid (manufactured by Sanyo Kasei Co., Ltd., trade name; Sunwet IM-5000MPS), polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd., trade name: Junron 110). In the same manner as in Example 8, a tablet-form preparation for oral mucosa application was obtained.

Example 9 47.5 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90F), starch-acrylate graft copolymer (manufactured by Sanyo Kasei Co., trade name; Sunwet IM-1000MPS) 2.5 parts by weight, lactose 10 parts by weight, magnesium stearate 0.5
1 part by weight and 5 parts by weight of indomethacin were weighed out, mixed evenly, and then tableted to give a weight of 100 mg and a thickness of 1.0 m.
A tablet having a diameter of m and a diameter of 10.0 mm was applied to the oral mucosa. Comparative Example 8 Formulation for oral mucosa application of tablets in the same manner as in Example 9 except that the blending ratio of the vinylpyrrolidone homopolymer was changed to 50 parts by weight and that the starch-acrylate graft copolymer was not blended. Got

Example 10 50 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name; Kollidon 90F), acrylic acid-vinyl alcohol copolymer (manufactured by Sumitomo Chemical Co., trade name;
10 parts by weight of SUMIKAGEL SP-510), 0.5 parts by weight of magnesium stearate and 5 parts by weight of estradiol are weighed and uniformly mixed and then tableted to give a weight of 100 m.
Thus, a preparation for oral mucosa, which was a tablet having a weight of 1.0 g, a thickness of 1.0 mm and a diameter of 10.0 mm was obtained. Comparative Example 9 A preparation for oral mucosa application of tablets was prepared in the same manner as in Example 10 except that the amount of the vinylpyrrolidone homopolymer was 60 parts by weight and the acrylic acid-vinyl alcohol copolymer was not mixed. Obtained.

Example 11 The vinylpyrrolidone-2-ethylhexyl acrylate copolymer solution obtained in Example 3 was diluted with water to a 1% by weight solution, and then fine powder was obtained by a spray drying method. 47.5 parts by weight of the vinylpyrrolidone-2-ethylhexyl acrylate copolymer fine powder, 2.5 parts by weight of starch-acrylate graft copolymer (manufactured by Sanyo Chemical Co., Ltd., trade name: Sunwet IM-1000MPS) , Lactose 5 parts by weight,
0.3 parts by weight of magnesium stearate and 10 parts by weight of nifedipine are weighed and uniformly mixed, and then tabletted to obtain a weight of 105 mg, a thickness of 1.05 mm and a diameter of 10.0 mm.
Thus, a tablet preparation for oral mucosa was obtained. Comparative Example 10 Except that the blending ratio of the vinylpyrrolidone-2-ethylhexyl acrylate copolymer fine powder was 50 parts by weight and that the starch-acrylate graft copolymer was not blended. In the same manner as in Example 11, a tablet preparation for oral mucosa was obtained.

Example 12 45 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90F), polyacrylate (manufactured by Sanyo Kasei Co., trade name: Sunwet IM-5)
000MPS) 5 parts by weight, lactose 10 parts by weight and magnesium stearate 0.2 parts by weight are weighed and uniformly mixed and then tableted to give a tablet having a weight of 90 mg, a thickness of 0.9 mm and a diameter of 10.0 mm. A preparation for mucosal application was obtained.

Example 13 Methacrylic Acid-Methyl Methacrylate Copolymer (Ro
hm Pharma Co., trade name; Euidragit
L) 20 parts by weight and polyethylene glycol 6000
2 parts by weight (manufactured by NOF CORPORATION) were uniformly dissolved in 250 parts by weight of ethanol. The obtained solution was uniformly sprayed on one surface of the tablet obtained in Example 12, and then dried at 60 ° C. for 30 minutes to give a weight of 90 mg, a thickness of 0.9 mm and a diameter of 1.
A 0.0mm tablet oral preparation for oral mucosa was obtained. Example 14 The preparation obtained by applying the tablet obtained in Example 12 to the oral mucosa was taken as Tablet I.
Prepared as On the other hand, lactose (50 parts by weight) and magnesium stearate (0.2 parts by weight) were weighed out and uniformly mixed, and then placed on the above-mentioned tablet I and tableted to give a weight of 100 m.
Thus, a preparation for oral mucosa, which was a tablet having a weight of 1.0 g, a thickness of 1.0 mm and a diameter of 10.0 mm was obtained.

Comparative Example 11 A tablet oral preparation for oral mucosa was obtained in the same manner as in Example 12 except that the vinylpyrrolidone homopolymer was added in an amount of 50 parts by weight and no polyacrylate was added. Comparative Example 12 The amount of vinylpyrrolidone homopolymer blended was 47.5 parts by weight, and polyacrylic acid was used instead of polyacrylic acid salt (Nippon Pure Chemical Co., Ltd., trade name; Junron 110).
A tablet preparation for oral mucosa application was obtained in the same manner as in Example 12 except that 2.5 parts by weight was used.

Evaluation For each oral mucosa-applied preparation obtained in Examples 1 to 4 and Examples 8 to 11 and Comparative Examples 1 to 4 and Comparative Examples 6 to 10, wet pork skin was prepared by the method shown in the following Experiment 1. A sticking test was conducted. Experiment 1 Freeze-dried pig skin (manufactured by Mitsui Pharmaceutical Co., Ltd., trade name: Metaskin) was regenerated with sterile physiological saline, and excess water was removed with gauze to obtain a wet pig skin as an adherend. This moist pork skin was punched into a circle having a diameter of 12 mm. As shown in FIG. 1, the punched wet pig skin 3 was bonded to both a stainless jig 1 having a weight of 10 g and a diameter of 12 mm and a stainless steel stand 2 having a size of 100 × 100 mm with a cyanoacrylate adhesive. The film-form oral mucosa-applied preparation 4 was punched into a circular shape having a diameter of 10 mm on the moist pig skin on the stainless steel table 2, and the tablet oral mucosa-applied preparation 4 was applied as it was. The stainless steel jig 1 is gently contacted from above and left for 10 minutes, and then 200
The stainless steel jig 1 and the stainless steel table 2 were pulled at a speed of mm / min so as to be separated from each other in the vertical direction, the load generated at that time was measured, and the average of four times of repetition was taken as the sticking force. Table 1 shows the sticking force of each preparation for oral mucosa application to moist pig skin.

[0051]

[Table 1]

As is clear from Table 1, Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, Example 3 and Comparative Example 3, Example 4 and Comparative Example 4, Example 8 and Comparative Example 6 And 7, Example 9
From the comparison of the adhesive strengths of Comparative Example 8, Example 10 and Comparative Example 9, and Example 11 and Comparative Example 10, the oral mucosal preparation of Example has the vinylpyrrolidone (co) polymer itself of Comparative Example. It can be seen that almost all the high adhesiveness to the wet surface is maintained. Next, a water resistance test is performed on each oral mucosa-applied preparation obtained in Examples 1 to 5 and Examples 8 to 13 and Comparative Examples 1 to 4 and Comparative Examples 6 to 10 according to the method shown in the following Experiment 2. It was

Experiment 2 Wet pig skin punched into a circle having a diameter of 12 mm prepared in the same manner as in Experiment 1 was adhered to a stainless plate 5 shown in a plan view in FIG. 2 with a cyanoacrylate adhesive. A film-shaped preparation for oral mucosa application was punched into a circle having a diameter of 10 mm, and a tablet-shaped preparation for oral mucosa application was applied on the wet pig skin as it was. 10g / from above
It was applied with a load of 0.785 cm ² for 10 minutes.
The dimensions a to d in FIG. 2 are a = 100 m, respectively.
m, b = 80 mm, c = 60 mm, d = 10 mm, the thickness of the stainless steel plate 5 is 3 mm, and SIS30
The one consisting of 4 was used. According to the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2, this stainless plate 5 is submerged in the bottom of a container containing 600 ml of physiological saline as a test solution so that the formulation is on top, and tested at 100 rpm. And then
The properties of the preparation were observed after 1, 6 and 24 hours. Table 2 shows the properties of each preparation for oral mucosa application at each time.

[0054]

[Table 2]

As is clear from Table 2, Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, Example 3 and Comparative Example 3, Example 4 and Comparative Example 4, Example 8 and Comparative Example 6 And 7, Example 9
From the comparison of the water resistance of each of Comparative Example 8, Example 10 and Comparative Example 9, and Example 11 and Comparative Example 10, the oral mucosa-applied formulation of Example has a very high water resistance and is pumped under the rotation of a battle. It can be seen that it has excellent durability and can be attached to a wet surface for a long period of time. Further, by comparing Example 4 and Example 5 and Example 12 and Example 13, by laminating a support layer made of a water-insoluble or sparingly soluble polymer on the mucoadhesive base,
It can be seen that the water resistance and durability are further enhanced.

Hairless mice were isolated from each of the preparations for oral mucosa obtained in Examples 1 to 4 and Examples 8 to 11 and Comparative Examples 1 to 4 and Comparative Examples 6 to 10 according to the procedure shown in the following Experiment 3. A skin permeation test of the drug was performed. Experiment 3 First, the diffusion cell 6 shown in FIG. 3 was prepared. Diffusion cell 6
Is composed of an upper donor tank 7 and a lower bottomed cylindrical receptor tank 8. An opening 9 is provided in the center of the bottom wall of the donor tank 7, and the lower end of the donor tank 7 and the upper end of the receptor tank 8 are connected so that an upper flange 10 and a lower flange 11 face each other. By overlapping, the donor tank 7 and the receptor tank 8 are airtightly and concentrically stacked. A sampling port 12 projecting laterally is attached to the side of the receptor tank 8. Inside the receptor tank 8, the magnetic stirrer 1 is installed.
3 has been thrown in.

Hairless mice (8-week-old, male) were sacrificed by cervical decapitation, and the skin was immediately peeled off to remove subcutaneous fat to obtain a skin piece of about 5 cm × 5 cm. The skin piece 14 is mounted between the upper flange 10 and the lower flange 11 of the diffusion cell 6, and the opening 9 of the donor tank 7 is inserted into the skin piece 1.
I tried to close it completely at 4. The film-shaped preparation for oral mucosa application was punched out on the skin piece 14 to have a diameter of 10 mm, and the tablet-shaped preparation for oral mucosa application was applied as it was as a test piece 15. The receptor tank 8 was filled with the receptor liquid prepared by the following method.

Next, the diffusion cell 6 was placed in a constant temperature bath kept at a temperature of 37 ° C., and the receptor liquid was stirred by a magnetic stirrer. After starting the test, sampling port 12
1 ml of the receptor liquid was collected from Table 1 and the measured permeation amount of each patch is shown in Table 3. Preparation method of receptor solution NaH ₂ PO ₄ (5 × 10 ⁻⁴ mol), Na ₂ HPO
₄ (2 × 10 ^-4 mol), NaCl (1.5 × 10 ^-4 mol) and gentamicin 10 mg were dissolved in 500 ml of distilled water, and the pH of the resulting solution was adjusted to 7.2 with 0.1N NaOH aqueous solution. After that, the volume is adjusted to 1000 with distilled water.
ml.

[0059]

[Table 3]

As is clear from Table 3, Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, Example 3 and Comparative Example 3, Example 4 and Comparative Example 4, Example 8 and Comparative Example 6 And 7, Example 9
From the comparison of the skin permeation amount of Comparative Example 8, Example 10 and Comparative Example 9, and Example 11 and Comparative Example 10, the oral mucosa-applied formulation of Example was compared with the case of vinylpyrrolidone (co) polymer alone. Good drug release is observed. This is because the preparations for application to the oral mucous membrane of the Example have a higher degree of swelling when absorbing water than in the case of vinylpyrrolidone (co) polymer alone, and the drug easily diffuses in the mucoadhesive base. It is thought to be because.

With respect to each oral mucosa-applied preparation obtained in Examples 6 and 7 and Examples 12 to 14 and Comparative Examples 5 and 11 and 12, a patching test for humans was conducted according to the method shown in the following Experiment 4. It was Experiment 4 10 mm in diameter for the film-form preparation for oral mucosa
The preparation for oral mucosa application of the tablet was punched out, and the tablet was applied to the oral mucosa of 5 subjects, the peeling time was measured, and the foreign body sensation was also evaluated. Table 4 shows the average time until peeling of each preparation for oral mucosa application.

[0062]

[Table 4]

As is clear from Table 4, the oral mucosa-applied formulations of Examples 6 and 7 adhered for a longer period of time than the oral mucosa-applied formulations of Comparative Examples 5, 11 and 12, and therefore, good patching was achieved. It can be seen that the material has water resistance, water resistance and durability.
In addition, the preparations for oral mucosa application of Examples 7 and 13 were
Each of the preparations applied to the oral mucosa of Examples 6 and 12 adheres for a long time. Therefore, by laminating a support layer made of a water-insoluble or sparingly soluble polymer on a mucoadhesive base, water resistance and durability can be obtained. It can be seen that the quality is enhanced.

Further, as compared with the twelfth embodiment, the fourteenth embodiment
As a result, no sticking phenomenon was observed on the finger when it was stuck in the oral cavity, and the sticking work could be performed easily. In addition,
In the preparations for oral mucosa application of each example, a little foreign body sensation was observed at the early stage of application, but the patient did not have a special foreign body sensation, probably because it swelled by absorbing water immediately.

[0065]

As described above, according to the present invention, since the vinylpyrrolidone (co) polymer is incorporated into the adhesive base, it is possible to absorb saliva or secretory fluid to the oral mucosa locally. Can be reliably attached. Therefore, it becomes possible to reliably and locally act the drug on the diseased part in the oral cavity or the surrounding area, or to effectively protect the affected part. Further, in the present invention, since the (meth) acrylic acid-containing water-absorbing polymer is blended in addition to the vinylpyrrolidone (co) polymer, when saliva or secretory fluid is absorbed, the vinylpyrrolidone (co) polymer and (meth) Due to the interaction with the acrylic acid-containing water-absorbing polymer, it becomes a gel and swells. As a result, since the drug is gradually released, the drug can be continuously administered to the applied disease site or absorption site or the affected site can be protected for a long time.

Further, since the gel-like material has excellent water resistance and durability, it does not dissolve and flow out. Therefore, under swelling, since it has sufficient flexibility and is excellent in shape retention, it gives a feeling of foreign matter even when the preparation for oral mucosa application of the present invention is adhered to the oral cavity for a long time. Not even.

[Brief description of drawings]

FIG. 1 is a perspective view showing a test device used in Experiment 1 (pasting test for wet pig skin).

FIG. 2 is a plan view showing a stainless plate used in Experiment 2 (water resistance test).

FIG. 3 is a perspective view showing a test device used in Experiment 3 (drug permeation test into the extracted skin of hairless mice).

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 ... Stainless jig 2 ... Stainless material 3 ... Wet pig skin 4 ... Oral mucosa application formulation 5 ... Stainless plate 6 ... Diffusion cell 7 ... Donor tank 8 ... Receptor tank 9 ... Opening part 10 ... Upper flange 11 ... Lower flange 12 ... Sampling port 13 ... Stirrer 14 ... Skin piece 15 ... Test piece

Claims (1)

[Claims] 1. A preparation for application to the oral mucosa, wherein the mucoadhesive base comprises a material containing a water-soluble vinylpyrrolidone (co) polymer and a water-swellable (meth) acrylic acid-containing water-absorbing polymer. And the content of vinylpyrrolidone in the (co) polymer of the vinylpyrrolidone (co) polymer is 70 mol%
The above is the compounding ratio of the vinylpyrrolidone (co) polymer and the (meth) acrylic acid-containing water-absorbing polymer to 9
A preparation for application to the oral mucosa, which is 5: 5 to 70: 30% by weight.