JP3197035B2 - Formulation for oral mucosa - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for oral mucosa using a vinylpyrrolidone (co) polymer and a water-swellable (meth) acrylic acid-containing water-absorbing polymer.
An oral mucosa that can be easily adhered to the oral mucosa for a long time, release the active ingredient into the oral mucosa and saliva for a long time, or is suitable for protecting damaged or diseased parts of the oral cavity It relates to the applied formulation.

[0002]

2. Description of the Related Art Conventionally, preparations for oral mucosa which adhere to the oral mucosa and administer active ingredients such as drugs to the oral mucosa and saliva, and intraoral bandages for protecting damaged or diseased parts of the oral cavity. Have been proposed. In such a preparation for oral mucosa and an intraoral bandage, various mucosa-adhering bases are used to adhere to the oral mucosa.
In the present specification, the expression “preparation for oral mucosa” is used to include both the preparation for oral mucosa and the bandage in the oral cavity.

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

However, the conventional mucosa-adhesive base comprising the hydrophilic polymer swells due to a large amount of water,
Since it disintegrated or dissolved, there was a problem in terms of water resistance. Therefore, in order to increase the water resistance of the mucosa-adhering 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, the affinity between the hydrophilic polymer and the water-insoluble polymer was not good, and the interaction was small, so that sufficient water resistance could not be developed.

Japanese Patent Application Laid-Open No. 60-248609 discloses that
One or more polymers selected from the group consisting of water-soluble polyvinylpyrrolidone, alginic acid and pharmaceutically acceptable salts thereof, and maleic anhydride-methyl vinyl ether copolymer; and polyacrylic acid and pharmaceutically acceptable salts thereof. Compositions comprising acceptable salts have been proposed. However, in the combination of polyacrylic acid and a pharmaceutically acceptable salt thereof, and water-soluble polyvinylpyrrolidone, although the water resistance is enhanced as compared with the case of using each alone, both components are water-soluble. For this reason, sufficient water resistance could not be realized.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a mucosa-adhesive base which has excellent water resistance and is hardly disintegrated or dissolved by saliva or the like, and adheres to the oral mucosa easily and for a long time. It is an object of the present invention to provide a preparation for oral mucosa which can protect a 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-absorbable (meth) acrylic acid-containing water-absorbing water-soluble vinyl virolidone (co) polymer having a water-soluble base. It is characterized by containing a polymer as a main component. It has been known that vinylpyrrolidone (co) polymer provides a base having excellent sticking properties to the oral mucosa, but as described above, vinylpyrrolidone (co) polymer alone has the problem of insufficient water resistance. Was. The present inventors have conducted intensive studies to solve this problem, and as a result, it is possible to achieve the above object by using a vinylpyrrolidone (co) polymer and a water-swellable (meth) acrylic acid-containing water-absorbing polymer in combination. Thus, the present invention has been accomplished.

The preparation for oral mucosa application of the present invention is characterized by having the above-mentioned mucosa-adhering base.
It includes not only so-called preparations for oral mucosa but also intraoral bandages used to protect damaged or diseased parts in the oral cavity. The mucosa-adhesive base containing both the vinylpyrrolidone (co) polymer and the water-swellable (meth) acrylic acid-containing water-absorbing polymer exhibits the following excellent effects.

[0009] It absorbs saliva or secretion and adheres locally, and maintains excellent local adhesion even when swollen.
Therefore, it is possible to reliably and directly act the drug directly or locally on the oral cavity or a peripheral disease site, or to effectively protect a damaged site or a diseased site in the oral cavity. By absorbing saliva or secretion and gradually releasing the drug, it becomes possible to continue to administer the drug to the applicable disease site or absorption site for a long time, or to protect the affected area.

[0010] Since it has high water resistance even when it absorbs saliva or secretion, it does not dissolve and flow out, and is excellent in shape retention even after swelling. When the drug is contained, at least a part of the drug is dissolved and present in the mucoadhesive base, so that compared with the case where the drug is merely dispersed in the mucoadhesive base. Excellent initial release of drug.

However, in order to exhibit the above-mentioned excellent effects, it is necessary to use a vinylpyrrolidone (co) polymer and a water-swellable polymer.
Compounding ratio of the (meth) acrylic acid-containing water-absorbent polymer, 95: 5 to 70: it is necessary that in the range of 30 wt%. If the mixing ratio of the water-swellable (meth) acrylic acid-containing water-absorbing polymer is less than 5% by weight, the effect of sufficiently increasing the water resistance cannot be obtained. If it exceeds 30% by weight, the weight of vinylpyrrolidone (co) This is because the sticking property to the wet surface, which is an advantage of the coalescence, is impaired. Preferably, the mixing ratio of the water-swellable (meth) acrylic acid-containing water-absorbing polymer is in the range of 10 to 20% by weight.

Vinylpyrrolidone (co) polymer The vinylpyrrolidone (co) polymer used in the present invention includes, for example, vinylpyrrolidone homopolymer, vinylpyrrolidone and (meth) acrylic acid, (meth) acrylic acid methyl ester, Ethyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, maleic anhydride, vinyl alcohol, and copolymers with two or more of vinyl acetate and the like. It is necessary that such a vinylpyrrolidone (co) polymer should 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,
Achieved excellent properties of vinylpyrrolidone, namely, good adhesion to mucous membrane, non-irritant to skin, and increased water resistance by blending water-swellable (meth) acrylic acid-containing water-absorbing polymer Therefore, the vinylpyrrolidone content in the copolymer needs to be 70 mol% or more, and preferably 90 mol% or more.

Water-swellable (meth) acrylic acid-containing water-absorbent
Polymer The water-swellable (meth) acrylic acid-containing water-absorbing polymer used in the present invention rapidly hydrates and swells when it comes into contact with water (pure water), and weighs about 2 to 1000 times its own weight. those
And specifically, (1) a product obtained by graft-polymerizing (meth) acrylate on starch; (2) a product obtained by graft-polymerization of (meth) acrylate on carboxymethyl cellulose; (3) (meth) acrylic acid One or two of
Any of copolymers with vinyl alcohol and / or acrylamide , or a combination thereof as appropriate
Use

The reason why the addition of the water-swellable (meth) acrylic acid-containing water-absorbing polymer significantly enhances the water resistance of the preparation for oral mucosa application of the present invention is not necessarily clear, but it is not clear why. It is considered that the carboxylic acid of (meth) acrylic acid in the hydrophilic polymer and the pyrrolidone ring of the vinylpyrrolidone (co) polymer interact unexpectedly.

Production The production method of the preparation for oral mucosa application of the present invention is not particularly limited, and examples thereof include the following first and second production methods. In the first production method, a vinylpyrrolidone (co) polymer is dissolved in methanol and a suitable organic solvent,
After the water-swellable (meth) acrylic acid-containing water-absorbing polymer is uniformly dispersed in the solution, each step of casting and drying is provided, whereby a thin film-like mucoadhesive base is obtained. In this case, when a drug is desired to act on the oral mucosa, saliva, or the like, a drug for exhibiting a therapeutic effect may be added together when the vinylpyrrolidone (co) polymer is dissolved in an organic solvent. In addition, if necessary,
A drug absorption promoter, a plasticizer, a flavoring / flavoring agent, or the like may be added. According to the first production method, a water-swellable (meth) acrylic acid-containing water-absorbing polymer is uniformly dispersed in a vinylpyrrolidone (co) polymer film to form a mucosa-adhering base.

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

Drug The drug that can be contained in the oral mucosa preparation of the present invention is not particularly limited. Also, the number of types of drugs is not limited, and one or more drugs can be appropriately compounded as needed. Drugs that can be used include, for example, antipyretic anti-inflammatory analgesics, analgesics, steroidal anti-inflammatory drugs, vasodilators, hypertensives, arrhythmias, antihypertensives, antitussives, local anesthetics, hormones, Asthma / nasal allergy treatment, antihistamine, anticoagulant, antispasmodic, cerebral circulation / metabolism improving agent, antidepressant / antianxiety agent, vitamin D preparation, oral hypoglycemic agent, anti-ulcer agent, sleeping pill, antibiotic, antibacterial And bactericides.

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

Examples of steroidal anti-inflammatory drugs include hydrocortisone, prodnisolone, fluorosinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, hetamethasone acetate, diflucortron valerate, propionclohetane Sol, fluocinonide and the like. Examples of the vasodilator include diltiazem, verapamil, pentaerythritol tetranitrate, dipidamole, isosorbide dinitrate, nifedipine, nitroglycerin and the like.

Examples of the hypertensive agent / arrhythmic agent include propanol, atenolol, pindolol, dikinin sulfate, adimarin, alprenolol hydrochloride, metroprolol tartrate, nadolol, timolol maleate, disopyramide and the like. As antihypertensives, clonidine hydrochloride, captopril, prazosin hydrochloride, penbutolol sulfate, guanabenz acetate, guanfacine hydrochloride, pnazosin hydrochloride, enalapril maleate, alotilol hydrochloride,
And bunitrolol hydrochloride.

Examples of the antitussive expectorant include procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pyrbuteirol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimethoquinol hydrochloride, formoterol fumarate and the like. No. Examples of the anti-ulcer agent include 5-fluorouracil, 1- (2-tetrahydrofuryl) -5-fluorouracil, green tomato C and the like. Examples of the local anesthetic include benzocaine, procaine, lidocaine, tetracaine and the like.

Hormonal agents include estrogen, estradiol, testosterone, progesterone, prostaglandin, insulin and the like. Examples of the therapeutic agent for asthma and nasal allergy include ketotifen fumarate, azelastine hydrochloride, and sodium cromoglycate. Examples of the antihistamine include cyclopeptazine hydrochloride, diphenhydrazine hydrochloride, fenbenzamin, mequitazine and the like. Examples of anticoagulants include heparin, and examples of antispasmodics include scopolamine and clofluperol.

Examples of the cerebral circulation metabolism improver include pinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, brovincamine fumarate, dihydroergotoxin mesylate, ifenprozirne tartrate, isoxpurine hydrochloride and the like. Anti-depressant / anxiolytic drugs include maprotiline hydrochloride,
Etizolam, diazepam, broazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like. Vitamin D agents include alfacalcidol, ergocasiferol and the like, and oral hypoglycemic agents include glibenclamide, gliclazide and the like.

Examples of the anti-ulcer agent include grepobride malate, famotidine, glycopyrronium bromide and the like. Hypnotics include phenobarbital and amobarbital, and antibiotics include tetracycline and chloramphenicol. The amount of these drugs varies depending on the type of the drug, the intended use of the patch, and the like, but is usually contained in the preparation for oral mucosa at a ratio of 0.1 to 40% by weight.

Form of preparation for oral mucosa application The preparation for oral mucosa application of the present invention can be used alone as a mucosa-adhering base. In this case, the thin-film mucosa-adhering 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. Further, the shape, area, thickness, etc. of the mucosa-adhering base obtained by the second production method are appropriately selected.

The preparation for oral mucosa application according to the present invention may be in a form in which a support layer is laminated on one surface of a mucosa-adhering base. As the support layer, a water-insoluble or similar mucosa non-sticking substrate layer can be used. Examples of the material constituting the support layer as described above include a natural polymer, a semi-synthetic polymer, a synthetic polymer, a metal foil, and a composite thereof. By laminating the support layer on one side of the oral mucosa-applied preparation, when applied to the oral mucosa, the amount of permeation of saliva per unit time from the surface opposite to the oral mucosa can be reduced, and the oral cavity Disintegration of the mucoadhesive base due to physical stimuli in the inside is also suppressed. Therefore, as compared with the case where the mucosa-adhering base is used alone, the water resistance and the durability can be further improved, and the oral cavity can be adhered for a longer time.

It is not necessary to use a support layer having a water-insoluble or sparingly soluble property, and a support layer made of a material which does not exhibit tackiness even when it absorbs water may be used. Even when such a water-absorbing support layer is laminated, the phenomenon that the oral mucosa-applied preparation adheres to a finger or the like when applied in the oral cavity as long as the adhesive does not exhibit adhesiveness when absorbing moisture is applied. Can be prevented,
Therefore, the attaching operation 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 of laminating the support layer on the mucosa-adhesive base, heating,
Pressurization or other suitable mechanical method; method of bonding with an adhesive; dissolving the polymer of the support layer component in a suitable volatile solvent, applying the solution to a mucoadhesive base, and drying the 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 the function of absorbing saliva or secretion fluid and causing it to adhere locally to the oral cavity. Therefore, the drug can be directly and locally applied to the oral cavity or the surrounding diseased part, or the affected part can be protected.

After the application, saliva or secretion fluid is removed.
Absorbs vinylpyrrolidone (co) polymerWater swellable
Interaction with the (meth) acrylic acid-containing water-absorbing polymer
It swells in a gel state and releases the drug gradually. Follow
Apply the drug for a long period of time
And keep the affected area protected
Become. Further, the gel-like body was excellent in water resistance.
Melts and does not flow out and is soft in the swollen state.
It has flexibility and excellent shape retention. Therefore,
When the gel is present in the oral mucosa for a long time
However, no foreign body sensation is given to the patient.

[0031]

EXAMPLES Hereinafter, the present invention will be described in detail 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
The mixture was uniformly dissolved in 00 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 (trade name; manufactured by Sanyo Chemical Co., Ltd .; Sunwet IM-10)
(00MPS) 5 parts by weight were uniformly dispersed with stirring by a dissolver. The above-mentioned pressure-sensitive adhesive solution in which the starch-acrylate graft polymer is dispersed is coated on a polyethylene terephthalate (hereinafter, PET) release paper whose surface is treated with silicone so as to have a thickness of 75 μm, and at a temperature of 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 a 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 (trade name: Kollidon 90, manufactured by BASF) and vinylpyrrolidone homopolymer (trade name: Koll, manufactured by BASF)
(idon 30) 15 parts by weight was uniformly dissolved in 300 parts by weight of ethanol to obtain a colorless and transparent adhesive solution. After uniformly dissolving 10 parts by weight of indomethacin in the pressure-sensitive adhesive solution, 15 parts by weight of an acrylic acid-vinyl alcohol copolymer (manufactured by Sumitomo Chemical Co., Ltd., trade name: Sumikagel SP-510) are uniformly stirred with a dissolver. Dispersed. A pressure-sensitive adhesive solution in which the acrylic acid-vinyl alcohol copolymer is uniformly dispersed as described above is coated on a PET release paper whose surface is treated with silicone so as to have a thickness of 50 μm.
The film was dried at a temperature of 0 ° C. for 1 hour to obtain a film-form preparation for oral mucosa.

Comparative Example 2 72 parts by weight of vinylpyrrolidone homopolymer (trade name: Kollidon 90, manufactured by BASF) and vinylpyrrolidone homopolymer (trade name: Koll, manufactured by BASF)
idon 30), and a film-form preparation for oral mucosa was obtained in the same manner as in Example 2 except that 18 parts by weight and the acrylic acid-vinyl alcohol copolymer were not dispersed.

Comparative Example 3 95 parts by weight of vinylpyrrolidone and 5 parts by weight of 2-ethylhexyl acrylate were prepared by using ethanol 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.times.10@5 and a solid content of 35% by weight was obtained. The above vinylpyrrolidone-acrylic acid-2-
Estradiol (10 parts by weight) was uniformly dissolved in ethylhexyl copolymer solution (257.1 parts by weight). After a while
This pressure-sensitive adhesive solution is applied on a PET release paper whose surface is treated with silicone so as to have a thickness of 70 μm.
After drying at 1 ° C. for 1 hour, a film-form preparation for oral mucosa was obtained.

Comparative Example 4 74.1 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90) and vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Ko)
llidon 30) 15.9 parts by weight of ethanol 300
It was uniformly dissolved in parts by weight to obtain a colorless and transparent pressure-sensitive adhesive solution.
5 parts by weight of nifedipine was uniformly dissolved in the adhesive solution. The pressure-sensitive adhesive solution in which the polyacrylate is dispersed is coated on a PET release paper whose surface is treated with silicone so as to have a thickness of 100 μm.
After drying for a time, a film-form preparation for oral mucosa was obtained.

Example 3 Vinylpyrrolidone homopolymer BASF, trade name;
(Kollidon 90) 85 parts by weight of ethanol 200
It was uniformly dissolved in parts by weight to obtain a colorless and transparent pressure-sensitive adhesive solution. A starch-acrylate graft polymer (manufactured by Sanyo Chemical Co., trade name; Sunwet IM-
5 parts by weight (1000 MPS) were uniformly dispersed while stirring with a dissolver. The pressure-sensitive adhesive solution in which the starch-acrylate graft polymer is uniformly dispersed is coated with a thickness of 5%.
PE whose surface is treated with silicone so as to be 0 μm
Coated on a T release paper, dried at a temperature of 60 ° C. for 1 hour,
A film-like preparation for oral mucosa was obtained.

Comparative Example 5 Vinylpyrrolidone homopolymer, manufactured by BASF, trade name;
A film-form preparation for oral mucosa was obtained in the same manner as in Example 3 except that 100 parts by weight of Kollidon 90) was used, and no starch-acrylic acid graft polymer was used.

Example 4 Methacrylic acid-methyl methacrylate copolymer (Ro
hm Pharma, trade name; Eudragit
L) 50 parts by weight and 25 parts by weight of polyethylene glycol 600 (manufactured by NOF CORPORATION) were uniformly dissolved in 300 parts by weight of ethanol. The resulting solution is dried to a thickness of 20
PET whose surface has been treated with silicone to a thickness of μm
The composition was coated on a release paper and dried at a temperature of 60 ° C. for 2 hours to obtain a film-like non-mucosafable substrate. The above-mentioned mucosa non-sticking base material and the preparation for oral mucosa application of Example 3 were thermocompressed to obtain a film-like preparation for oral mucosa application.

Comparative Example 6 50 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90F), 10 parts by weight of lactose, 0.2 parts by weight of magnesium stearate and 6 parts by weight of isosorbide dinitrate were weighed and mixed uniformly. Then, after compression, the tablet is weighed 90 mg, thickness 0.9 mm, diameter 1
A 0.0 mm tablet-type preparation for oral mucosa was obtained.

Comparative Example 7 45 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90F), 5 parts by weight of polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd., trade name: Junlon 110), 10 parts by weight of lactose, stearin Magnesium acid 0.
2 parts by weight of isosorbide dinitrate and 6 parts by weight of isosorbide dinitrate were weighed, uniformly mixed, and then tableted to obtain a tablet-type preparation for oral mucosa having a weight of 90 mg, a thickness of 0.9 mm and a diameter of 10.0 mm.

Example 5 Vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90F) 47.5 parts by weight, starch-acrylate graft copolymer (manufactured by Sanyo Chemical Co., trade name: Sunwet IM-1000MPS) 2.5 parts by weight, lactose 10 parts by weight, magnesium stearate 0.5
Parts by weight and 5 parts by weight of indomethacin were weighed out, mixed uniformly, and then tableted to give a weight of 100 mg and a thickness of 1.0 m.
m, a tablet formulation having a diameter of 10.0 mm for oral mucosa was obtained.

Comparative Example 8 The oral cavity of the tablet was prepared in the same manner as in Example 5 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. A preparation for mucosal application was obtained.

Example 6 Vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90F) 50 parts by weight, acrylic acid-vinyl alcohol copolymer (manufactured by Sumitomo Chemical Co., trade name;
Sumikagel SP-510) 10 parts by weight, 0.5 parts by weight of magnesium stearate and 5 parts by weight of estradiol were weighed, uniformly mixed, and then tableted to give a weight of 100 m.
g, a tablet for oral mucosa having a thickness of 1.0 mm and a diameter of 10.0 mm was obtained.

Comparative Example 9 The oral mucosa of the tablet was prepared in the same manner as in Example 6 , except that the blending amount of the vinylpyrrolidone homopolymer was 60 parts by weight and that the acrylic acid-vinyl alcohol copolymer was not blended. The applied formulation was obtained.

Example 7 The vinylpyrrolidone--2-ethylhexyl acrylate copolymer solution obtained in Comparative Example 3 was diluted with water to a 1% by weight solution, and then a fine powder was obtained by a spray drying method. 47.5 parts by weight of the above-mentioned vinylpyrrolidone-acrylic acid-2-ethylhexyl copolymer fine powder, 2.5 parts by weight of a starch-acrylate graft copolymer (manufactured by Sanyo Chemical Industries, 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, uniformly mixed, and then tableted to give a weight of 105 mg, a thickness of 1.05 mm and a diameter of 10.0 mm.
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 7 , a tablet preparation for oral mucosa was obtained.

Comparative Example 11 50 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90F), 10 parts by weight of lactose and 0.2 part by weight of magnesium stearate were weighed, uniformly mixed, and tableted. A tablet for oral mucosa having a weight of 90 mg, a thickness of 0.9 mm and a diameter of 10.0 mm was obtained.

Comparative Example 12 47.5 parts by weight of vinylpyrrolidone homopolymer (manufactured by BASF, trade name: Kollidon 90F), polyacrylic acid (manufactured by Nippon Pure Chemical Co., trade name: Junron 110)
2.5 parts by weight, lactose 10 parts by weight and magnesium stearate 0.2 parts by weight are weighed, uniformly mixed, and then tableted, weighing 90 mg, thickness 0.9 mm and diameter 10.0 m.
m of the tablet for oral mucosa was obtained.

Evaluation Each of the oral mucosa preparations obtained in Examples 1 and 2 and Examples 5 to 7 and Comparative Examples 1 to 4 and Comparative Examples 6 to 10 was applied to wet pig skin by the method shown in Experiment 1 below. An adhesion test was performed. Experiment 1 Lyophilized pig skin (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 of the adherend. This wet pig skin was punched out 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 steel jig 1 having a weight of 10 g and a diameter of 12 mm and a stainless steel table 2 having a size of 100 × 100 mm with a cyanoacrylate adhesive. The film-form oral mucosa-applied preparation 4 was punched out into a circular shape having a diameter of 10 mm on a wet pig skin on a stainless steel stand 2, and the tablet oral mucosa-applied preparation 4 was stuck as it was. The stainless jig 1 was gently brought into contact therefrom and allowed to stand for 10 minutes.
The stainless jig 1 and the stainless steel table 2 were pulled vertically away from each other at a speed of mm / min, the load generated at that time was measured, and the average of four repetitions was defined as the sticking force. Table 1 shows the sticking force of each oral mucosal preparation to wet pig skin.

[0051]

[Table 1]

As is clear from Table 1, Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, Example 5 and Comparative Example 8, Example 6 and Comparative Example 9, Example 7 and Comparative Example 10 It can be seen from the comparison of the respective adhesive strengths that the preparation for oral mucosa application of the example substantially retains the high adherence to the wet surface of the vinylpyrrolidone (co) polymer itself of the comparative example. Next, a water resistance test was performed on each oral mucosa-applied preparation obtained in Examples 1 and 2 and Examples 5 to 7 and Comparative Examples 1 to 4 and Comparative Examples 6 to 10 according to the method shown in Experiment 2 below. Was.

Experiment 2 A 12-mm-diameter circular punched wet pig skin prepared in the same manner as in Experiment 1 was bonded to a stainless steel plate 5 shown in a plan view in FIG. 2 with a cyanoacrylate adhesive. On the wet pig skin, a film-shaped preparation for oral mucosa application was punched out into a circular shape having a diameter of 10 mm, and a tablet-applied preparation for oral mucosa application was directly applied. 10g /
It was applied under a load of 0.785 cm ² for 10 minutes.
Note that the dimensions a to d in FIG.
m, b = 80 mm, c = 60 mm, d = 10 mm, the thickness of the stainless steel plate 5 is 3 mm, and SIS30
4 was used. According to the dissolution test method 2 of the Japanese Pharmacopoeia General Test Method, this stainless steel plate 5 was immersed in a container containing 600 ml of physiological saline as a test solution so that the preparation was on the bottom, and tested at 100 revolutions per minute. Do
After 1, 6, 24 hours, the properties of the preparation were observed. Table 2 shows the properties of each oral mucosal preparation 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 5 and Comparative Example 8, Example 6 and Comparative Example 9, Example 7 and Comparative Example 10 From the comparison of the water resistance of each, the oral mucosa applied formulation of the example is very high in water resistance, has excellent durability because it adheres to the pump under the rotation of the battle, sticking to the wet surface for a long time It can be seen that is possible.

For each of the oral mucosa preparations obtained in Examples 1 and 2 and Examples 5 to 7 and Comparative Examples 1 to 4 and Comparative Examples 6 to 10, hairless mice were excised according to the method shown in Experiment 3 below. A permeation test of the drug into the skin was performed. Experiment 3 First, a diffusion cell 6 shown in FIG. 3 was prepared. Diffusion cell 6
Consists of an upper donor tank 7 and a lower cylindrical receptor tank 8 with a bottom. An opening 9 is provided at 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 to an upper flange 10 and a lower flange 11, respectively, so as to 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 a side of the receptor tank 8, and a magnetic stirrer 1 is provided inside the receptor tank 8.
3 has been thrown.

After a hairless mouse (8-week-old, male) was killed by cervical spine prolapse, the skin was immediately peeled off to remove subcutaneous fat, and a skin piece of about 5 cm × 5 cm was obtained. The skin piece 14 is mounted between the upper flange 10 and the lower flange 11 of the diffusion cell 6 so that the opening 9 of the donor tank 7 is
At 4 it was completely closed. The film-shaped preparation for oral mucosa application was punched out to a diameter of 10 mm on the skin piece 14, and the tablet for oral mucosa application preparation was affixed as a test piece 15 as it was. The receptor tank 8 was filled with a receptor solution prepared by the following method.

Next, the diffusion cell 6 was placed in a thermostat maintained at a temperature of 37 ° C., and the receptor liquid was stirred by a magnetic stirrer. After the test starts, the sampling port 12
1 ml of the receptor solution was collected from Table 1 and the measured permeation amount of each patch is shown in Table 3. Preparation 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 10 mg of gentamicin are dissolved in 500 ml of distilled water, and the pH of the resulting solution is 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, Examples 1 and Comparative Examples 1, Example 2 and Comparative Example 2, Examples 5 and Comparative Example 8, Examples 6 and Comparative Example 9, Examples 7 and Comparative Example 10 From the comparison of the amount of permeation through the skin, the preparations for oral mucosa application of the examples show better drug release than the vinylpyrrolidone (co) polymer alone. This is because, in the preparation for oral mucosa applied in the example, the degree of swelling when absorbing moisture is high, and the drug is easily diffused in the mucosa-adhesive base, as compared with the case of the vinylpyrrolidone (co) polymer alone. It is thought to be.

Examples 3 and 4 and Comparative Examples 5 and 1
Each of the oral mucosa-applied preparations obtained in 1 and 12 was subjected to a sticking test for humans according to the method shown in Experiment 4 below. Experiment 4 About the film-form oral mucosal preparation, the diameter was 10 mm.
Then, the tablet was applied to the oral mucosa of the five subjects while the preparation for oral mucosa application was left as it was, the peeling time was measured, and the foreign body sensation was also evaluated. Table 4 shows the average time required for each oral mucosal preparation to be exfoliated.

[0062]

[Table 4]

As is clear from Table 4, the oral mucosa preparations of Examples 3 and 4 adhered for a longer time than the oral mucosa preparations of Comparative Examples 5, 11 and 12, and therefore had good adhesion. It can be seen that they have water resistance, water resistance and durability.
In addition, the preparation for oral mucosa applied in Example 4 adhered to the preparation for oral mucosa applied in Example 3 for a long time, and therefore, a support layer comprising a water-insoluble or poorly soluble polymer in the mucosa-adhesive base. It can be seen that the water resistance and durability are improved by laminating.

In the preparations for oral mucosa of each Example,
Although a little foreign body sensation was recognized in the early stage of application, the patient did not give a special foreign body sensation, probably because it absorbed water and swelled immediately.

[0065]

As described above, according to the present invention, since the vinylpyrrolidone (co) polymer is blended in the adhesive base, it absorbs saliva or secretion fluid to form a localized portion of the oral mucosa. It can be securely attached. Therefore, it becomes possible to make the drug directly and locally act on the oral cavity or the surrounding diseased part, or to effectively protect the affected part. In the present invention, a water-wettable (meth) acrylic acid-containing water-absorbing polymer is blended in addition to the vinylpyrrolidone (co) polymer. When
The water-wettable (meth) acrylic acid-containing water-absorbing polymer becomes gel-like and swells due to the interaction. As a result, since the drug is gradually released, the drug can be continuously administered to the applied disease site or the absorption site for a long time, or the affected area can be protected.

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

[Brief description of the drawings]

FIG. 1 is a perspective view showing a test apparatus used in Experiment 1 (sticking test on wet pig skin).

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

FIG. 3 is a perspective view showing a test apparatus used in Experiment 3 (a test for permeation of a drug into the excised skin of a hairless mouse).

[Explanation of symbols]

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

Claims (1)

(57) [Claims] An oral mucosal preparation comprising a material comprising a water-soluble vinylpyrrolidone (co) polymer and a water-swellable (meth) acrylic acid-containing water-absorbing polymer. there are, it is said vinylpyrrolidone (co) polymers of (co) vinylpyrrolidone content in the polymer is 70 mol% or more, the vinyl pyrrolidone (co) and the polymer, the water-swellable (meth) acrylate The compounding ratio of the acid-containing water-absorbing polymer is 95: 5 to 7
0:30 wt% der is, of the water swellable (meth) acrylic acid-containing water-absorbent polymers
But grafted (meth) acrylate on starch
(Meth) acrylic to carboxymethylcellulose
Graft polymerized oxalate; of (meth) acrylic acid
One or two kinds of vinyl alcohol and / or
Selected from the group consisting of copolymers with rilamide
A preparation for oral mucosa, characterized in that it is one kind .