JPH05155760A - Preparation for applying to oral cavity mucosa - Google Patents

Abstract

PURPOSE:To provide a preparation which is used for applying to oral cavity mucosa and contains, a mucosa-adhesive base agent having excellent water resistance, thereby substantially not causing the collapse or dissolution of the preparation with salivas, etc., and which can readily adhere to the oral cavity mucosa over a long period. CONSTITUTION:A preparation for applying to oral cavity mucosa has a mucosa- adhering base agent containing a water-soluble vinyl pyrrolidone (co)polymer and a water-swellable (meth)acrylic acid-containing water-absorbing polymer in a weight ratio of 95:5 to 70:30 as main components, the content of the vinyl pyrrolidone in the vinylpyrrolidone (compolymer being >=70mol.%.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a preparation for oral mucosa using a carboxylic acid-containing water-soluble polymer and cross-linked polyvinylpyrrolidone. Also, the present invention relates to a preparation for oral mucosa which can be sustained in saliva for a long period of time or is suitable for protecting a damaged part or a diseased part in the oral cavity.

[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]

In the preparation for oral mucosa application according to the present invention, the mucoadhesive base is poly (meth) acrylic acid and a pharmaceutically acceptable salt thereof, alginic acid and a pharmaceutically acceptable salt thereof. Salt, and one or more polymers selected from the group consisting of maleic anhydride-methyl vinyl ether copolymer and crosslinked polyvinylpyrrolidone, and the crosslinked polyvinylpyrrolidone is water-swellable and water-insoluble, Furthermore, the ratio of cross-linked polyvinylpyrrolidone used as the polymer component is in the range of 5 to 50% by weight, which is a preparation for oral mucosa application.

That is, one selected from the group consisting of poly (meth) acrylic acid and pharmaceutically acceptable salts thereof, alginic acid and pharmaceutically acceptable salts thereof, and maleic anhydride-methyl vinyl ether copolymer, or It has been known that a base having excellent adhesiveness to the mucosal surface can be obtained by using two or more carboxylic acid-containing water-soluble polymers, but as described above, when these water-soluble polymers are used alone Had a problem of insufficient water resistance. The present inventors have conducted extensive studies to solve this problem, and found that the above-mentioned problems can be achieved by using the carboxylic acid-containing water-soluble polymer in combination with a cross-linked polyvinylpyrrolidone to form the present invention. I arrived.

The oral mucosa-applied preparation of the present invention is characterized by having the above-described 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. A group consisting of poly (meth) acrylic acid and a pharmaceutically acceptable salt thereof, alginic acid and a pharmaceutically acceptable salt thereof, and a maleic anhydride-methyl vinyl ether copolymer as a main component of a mucoadhesive base. One or more polymers selected from
When a material containing crosslinked polyvinylpyrrolidone is used, the following excellent effects are obtained.

It absorbs saliva or secretory fluid and locally adheres to it, and maintains an excellent local adhesive action even when it swells.
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. It has high water resistance even if it absorbs saliva or secretions,
It does not dissolve and flow out, and it has excellent shape retention even after swelling.

However, in order to exert the above-mentioned excellent effects, it is necessary that the blending ratio of the crosslinked polyvinylpyrrolidone in the polymer component is in the range of 5 to 50% by weight. This is because if the blending ratio of the crosslinked polyvinylpyrrolidone is less than 5% by weight, the effect of sufficiently enhancing water resistance cannot be obtained, and if it exceeds 50% by weight, poly (meth) acrylic acid and a pharmaceutically acceptable salt thereof, This is because the adhesiveness to the wet surface, which is a characteristic of alginic acid and its pharmaceutically acceptable salts, and maleic anhydride-methyl vinyl ether copolymer, is reduced. Preferably, the compounding ratio of crosslinked polyvinylpyrrolidone in the polymer component is in the range of 10 to 30% by weight.

Poly (meth) acrylic acid and its pharmaceutically
Acceptable Salts Poly (meth) acrylic acid includes homopolymers of (meth) acrylic acid, copolymers with one or more other monomers, and pharmaceutically acceptable salts thereof include Examples thereof include those obtained by neutralizing poly (meth) acrylic acid with an alkali metal salt such as Na or K. The above-mentioned poly (meth) acrylic acid and its pharmaceutically acceptable salt need to exhibit tackiness when a small amount of water such as saliva is applied, and therefore need to be soluble in water as a property. .. As for the copolymer, as in the case of the homopolymer, in order to develop the mucoadhesiveness when water such as saliva is applied, and to increase the water resistance by blending the crosslinked polyvinylpyrrolidone, the whole polymer is used. The total amount of the other monomers is not more than 20% by weight, preferably not more than 5% by weight. Preferable examples of poly (meth) acrylic acid and pharmaceutically acceptable salts thereof include commercially available products such as Jurimer, Junron and Aronbis manufactured by Nippon Pure Chemical.

Alginic acid and its pharmaceutically acceptable salt Alginic acid is a copolymer of D-mannuronic acid and L-glucuronic acid extracted from seaweeds such as kelp,
Examples of the pharmaceutically acceptable salt include those neutralized with alkali metal salts such as Na and K. Maleic anhydride-methyl vinyl ether copolymer Maleic anhydride-methyl vinyl ether copolymer is a copolymer consisting of maleic anhydride and methyl vinyl ether, based on the cosmetic raw material "methoxyethylene maleic anhydride copolymer" It is listed under the chemical name, and a suitable example is GANTREZ AN-11 manufactured by GAF.
9, GANTREZ AN-139, GANTREZ
Commercial products such as AN-149 and GANTREZ AN-169 can be used.

Crosslinked polyvinylpyrrolidone Crosslinked polyvinylpyrrolidone has an appropriate swelling property in water, but it must be water-insoluble in order to exhibit the water resistance improving effect by addition, and therefore it has mucoadhesiveness. I don't. The crosslinked polyvinylpyrrolidone is prepared by copolymerizing N-vinyl-2-pyrrolidone and a polyfunctional monomer, and is contained in the base in the form of fine particles.

As the polyfunctional monomer used for the copolymerization, hexamethylene glycol di (meth) acrylate, ethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, tetraethylene glycol di (meth) acrylate. Or di (meth) acrylate such as polyethylene glycol di (meth) acrylate; tri (meth) acrylate such as trimethylolpropane triacrylate; tetra (meth) acrylate such as tetramethylolmethane tetraacrylate; diethylene glycol bisallyl carbonate, triallyl glycerin , Polyallyl compounds such as triallyl cyanurate; and polymaleimide compounds such as ethylene bismaleimide. Alternatively, N, N '
-Divinylimidazolidone, N, N'-divinylhexahydropyrimidinone, N-vinyl-3-ethylidene-
Cyclic acid amide compounds such as pyrrolidone, divinylbenben,
N, N'-methylenebisacrylamide, ethylidenebisvinylpyrrolidone, divinylketone, butadiene, isoprene and the like are also used.

The amount of the polyfunctional monomer to be copolymerized is 0.1 to 20% by weight based on the vinylpyrrolidone monomer.
Is preferable, and a ratio of 0.5 to 10% by weight is particularly preferable. The amount of polyfunctional monomer is 0.1
When the content is less than wt%, the resulting crosslinked polyvinylpyrrolidone becomes water-soluble or extremely swells in an aqueous solution to make it difficult to maintain the particle structure, and the water resistance improving effect is lowered. When the amount of the polyfunctional monomer exceeds 20% by weight, the interaction between the obtained crosslinked polyvinylpyrrolidone and the carboxylic acid-containing water-soluble polymer is low and the water resistance is lowered.

As another method for preparing crosslinked polyvinylpyrrolidone, it can be obtained by heating soluble non-crosslinked polyvinylpyrrolidone with thionyl chloride, phosphorous trichloride, phosphorous pentachloride or the like in an organic solvent. A suitable example is Kollidon CL
^R (manufactured by BASF), Polyplasdone XL ^R (manufactured by GAF) and the like. These compounds are described in US Pat.
880, No. 3933766, No. 3689439,
No. 4,139,688 and No. 4,180,633.

The reason why the addition of the crosslinked vinylpyrrolidone significantly enhances the water resistance of the preparation for oral mucosa of the present invention is not understood in detail, but the pyrrolidone ring of the crosslinked polyvinylpyrrolidone and the carboxylic acid of the carboxylic acid-containing water-soluble polymer are It is considered that the carboxylic acid-containing water-soluble polymer binds to the crosslinked vinylpyrrolidone that is insoluble in water and has an appropriate swelling property due to the interaction with water in the presence of water.

Production The production method of the preparation for oral mucosa application of the present invention is not particularly limited, but the following first and second production methods can be exemplified. The first production method was selected from the group consisting of poly (meth) acrylic acid and pharmaceutically acceptable salts thereof, alginic acid and pharmaceutically acceptable salts thereof, and maleic anhydride-methyl vinyl ether copolymer. 1
One or two or more polymers and a polymer component consisting of cross-linked polyvinylpyrrolidone are sufficiently mixed, and an appropriate amount of the mixture is directly pressure-molded using a punch, a die and a press, whereby a desired shape is obtained. A mucoadhesive base is obtained. In this case, when it is desired to act the drug on the oral mucosa, saliva, etc., the drug for exerting the therapeutic effect may be added together at the time of mixing the polymer components or after the mixing. 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 first production method described above, a mucoadhesive base comprising a blend polymer of the carboxylic acid-containing water-soluble polymer and crosslinked polyvinylpyrrolidone as a main component is obtained.

The second production method is a group consisting of poly (meth) acrylic acid and a pharmaceutically acceptable salt thereof, alginic acid and a pharmaceutically acceptable salt thereof, and a maleic anhydride-methyl vinyl ether copolymer. One or more polymers selected from the above are dissolved in a suitable organic solvent such as ethanol to form a solution, and cross-linked polyvinylpyrrolidone is uniformly dispersed in the solution, followed by casting and drying. As a result, a thin film mucoadhesive base can be obtained. Also in the second production method, when it is desired to act a drug on the oral mucosa, saliva, etc., a drug for exerting a therapeutic effect is also added when the carboxylic acid-containing water-soluble polymer is dissolved in an organic solvent. If necessary, one or more kinds of absorption promoters, plasticizers, and flavoring agents for drugs may be added.

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.

Antipyretic anti-inflammatory analgesics include 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 local anesthetics include benzocaine, procaine, lidocaine and tetracaine. Hormonal agents include estrogen, estradiol,
Testosterone, progesterone, prostaglandin, insulin and the like can be mentioned. As asthma / nasal allergy treatment agents, ketotifen fumarate, azelastine hydrochloride, Na cromoglycate, etc., and antihistamines, cyclopeptazine hydrochloride, diphenhydrazine hydrochloride,
Examples include fenbenzamine and mequitazine. Heparin, etc. as anticoagulant, scopolamine, antispasmodic,
Examples include 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 the antiulcer 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 shape of the mucosal adhesive base obtained by the first production method is , Area, thickness, etc. are appropriately selected. The thickness of the thin film mucoadhesive base obtained by the second production method is preferably 10 μm or more and 5000 μm or less, more preferably 30 μm or more 50
It is 0 μm or less. 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 constituting the support layer as described above,
Examples include natural polymers, semi-synthetic polymers, synthetic polymers, metal foils, and composites thereof.

By laminating the above support layer on one side of the preparation for oral mucosa, when applied to the oral mucosa, the permeation amount of saliva per unit time from the surface opposite to the oral mucosa can be reduced. Also, the disintegration of the mucoadhesive base due to physical irritation in the oral cavity is 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.

[0032]

[Function] In the preparation for oral mucosa application of the present invention, poly (meth)
Acrylic acid and pharmaceutically acceptable salts thereof, alginic acid and pharmaceutically acceptable salts thereof, and one or more polymers selected from the group consisting of maleic anhydride-methyl vinyl ether copolymer are saliva or It has the function of absorbing the secretory fluid and attaching it locally in the oral cavity. Therefore, it is possible to directly and locally act the drug on the diseased area in the oral cavity or the surrounding area, or to protect the affected area.

After the application, poly (meth) acrylic acid and its pharmaceutically acceptable salts, alginic acid and its pharmaceutically acceptable salts, which absorb saliva or secretory fluid,
In addition, one or more polymers selected from the group consisting of maleic anhydride-methyl vinyl ether copolymer interacts with the cross-linked polyvinylpyrrolidone to swell in the form of gel and gradually release the drug. Therefore, it becomes possible to continue to administer the drug to the diseased site or the absorption site for a long time and protect the affected area. 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.

[0034]

EXAMPLES The present invention will be described in detail below by giving Examples and Comparative Examples of the present invention. Example 1 Polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd., trade name; Junron 1)
10) 25 parts by weight, cross-linked polyvinylpyrrolidone (BAS
Company F, trade name; Kollidon CL ^R ) 5 parts by weight, lactose 5 parts by weight, magnesium stearate 0.2 parts by weight and isosorbide dinitrate 5 parts by weight are weighed and uniformly mixed and then tableted to give a weight of 100 mg. , Thickness 1.0 mm, diameter 10.0
A preparation for oral mucosa of mm tablets was obtained.

Comparative Example 1 A tablet preparation for oral mucosa was prepared in the same manner as in Example 1 except that the blending ratio of polyacrylic acid was 30 parts by weight and no cross-linked polyvinylpyrrolidone was blended. Obtained. Comparative Example 2 In the same manner as in Example 1, except that 5 parts by weight of polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon 90F) was used in place of the crosslinked polyvinylpyrrolidone, a preparation for oral mucosa application of tablets was prepared. Obtained.

Example 2 45 parts by weight of sodium alginate (manufactured by Kimitsu Chemical Co., Ltd .; trade name; Kimitsu algin M-1), 5 parts by weight of crosslinked polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon CL ^R ), 20 parts by weight of lactose, Magnesium stearate 0.5
Weight and 10 parts by weight of indomethacin were weighed out, uniformly mixed, and then tableted to give a weight of 120 mg and a thickness of 1.2 mm,
A tablet preparation having a diameter of 10.0 mm for oral mucosa was obtained.

Comparative Example 3 A tablet-prepared preparation for oral mucosa was obtained in the same manner as in Example 2 except that the blending ratio of sodium alginate was 50 parts by weight and no crosslinked polyvinylpyrrolidone was blended. It was

Example 3 Maleic anhydride-methyl vinyl ether copolymer (GA
Company F, trade name; GANTREZ AN-149) 45
By weight, 5 parts by weight of crosslinked polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon CL ^R ), 0.5 parts by weight of magnesium stearate and 5 parts by weight of estradiol are weighed and uniformly mixed, and then tableted, Weight 105 mg,
A tablet having a thickness of 1.1 mm and a diameter of 10.0 mm, which was applied to the oral mucosa, was obtained. Comparative Example 4 The tablet was applied to the oral mucosa in the same manner as in Example 3 except that the amount of the maleic anhydride-methyl vinyl ether copolymer was set to 50 parts by weight and the cross-linked polyvinylpyrrolidone was not added. A formulation was obtained.

Example 4 Polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd., trade name; Junron 1)
10) 30 parts by weight, sodium polyacrylate (manufactured by Nippon Pure Chemical Co., Ltd., trade name: Aronbis) 10 parts by weight, crosslinked polyvinylpyrrolidone (manufactured by GAF, trade name: Polyplasdone XL ^R ) 10 parts by weight, lactose 5 parts by weight Parts, 0.3 parts by weight of magnesium stearate and 10 parts by weight of nifedipine were weighed and uniformly mixed, and then tableted to give a weight of 110 mg,
A tablet having a thickness of 1.1 mm and a diameter of 10.0 mm, which was applied to the oral mucosa, was obtained. Comparative Example 5 The compounding amount of polyacrylic acid was 37.5 parts by weight,
A tablet-prepared preparation for oral mucosa was obtained in the same manner as in Example 4, except that the amount of sodium polyacrylate added was 12.5 parts by weight and the cross-linked polyvinylpyrrolidone was not added.

Example 5 Polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd., trade name; Junron 1)
10) 27 parts by weight, cross-linked polyvinylpyrrolidone (BAS
Company F, trade name; Kollidon CL ^R ) 3 parts by weight, lactose 5 parts by weight and magnesium stearate 0.2 parts by weight were weighed out and uniformly mixed, and then tableted to give a weight of 100 mg and a thickness of 1. A preparation for buccal mucosa application with a tablet of 0 mm and a diameter of 10.0 mm was obtained.

Example 6 Methacrylic acid-methyl methacrylate copolymer (Rohm
Made by Pharma, trade name; Eudragit
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 5 and then dried at 60 ° C. for 30 minutes 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.

Example 7 Each component was blended in the same manner as in Example 5 and then tableted to give a weight of 90 mg, a thickness of 0.9 mm and a diameter of 10.0 m.
A tablet I of m was obtained. 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 tablet I and compressed to give a weight of 100 m.
Thus, a preparation for application to the oral mucosa of tablets having a thickness of 1.0 mm and a diameter of 10.0 mm was obtained.

Comparative Example 6 Polypyrrolic acid was used in an amount of 25 parts by weight, and 3 parts by weight of crosslinked polyvinylpyrrolidone was replaced with polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon 90).
F) A tablet-prepared preparation for oral mucosa was obtained in the same manner as in Example 5, except that 5 parts by weight was blended. Comparative Example 7 A tablet oral preparation for oral mucosa was obtained in the same manner as in Example 5, except that the amount of polyacrylic acid was 30 parts by weight and that the crosslinked polyvinylpyrrolidone was not added.

Example 8 Polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd., trade name; Junron 1)
10) 70 parts by weight were 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 isosorbide dinitrate in the adhesive solution,
20 parts by weight of crosslinked polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon CL ^R ) was uniformly dispersed while stirring with a dissolver. The ethanol solution in which the cross-linked polyvinylpyrrolidone is dispersed is applied onto polyethylene terephthalate (hereinafter abbreviated as PET) release paper whose surface is treated with silicone so that the thickness is 50 μm, and the temperature is 60 ° C. for 1 hour. After drying, a film-form preparation for oral mucosa was obtained. Comparative Example 8 A film-form preparation for oral mucosa was obtained in the same manner as in Example 8 except that the amount of polyacrylic acid used was 90 parts by weight and no crosslinked polyvinylpyrrolidone was used.

Example 9 Maleic anhydride-methyl vinyl ether copolymer (GA
Company F, trade name; GANTREZ AN-149) 80
Part by weight was uniformly dissolved in 300 parts by weight of ethyl acetate to obtain a colorless and transparent adhesive solution. After uniformly dissolving 10 parts by weight of indomethacin in the adhesive solution, crosslinked polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon CL ^R )
10 parts by weight were uniformly dispersed while stirring with a dissolver. The ethyl acetate solution in which the crosslinked polyvinylpyrrolidone was dispersed was applied onto a PET release paper whose surface was treated with silicone so that the thickness was 70 μm, and the temperature was 60 ° C.
It was dried at the temperature of 1 hour for 1 hour to obtain a film-form preparation for oral mucosa. Comparative Example 9 A film-form oral mucous membrane was prepared in the same manner as in Example 9 except that the amount of the maleic anhydride-methyl vinyl ether copolymer used was 90 parts by weight and no cross-linked polyvinylpyrrolidone was used. An applied formulation was obtained.

Example 10 Polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd., trade name; Junron 1)
10) 45 parts by weight and polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd.,
20 parts by weight of product name: Julimer AC-10HP) was uniformly dissolved in 300 parts by weight of ethanol to obtain a colorless and transparent adhesive solution. Estradiol 1 was added to the adhesive solution.
After uniformly dissolving 0 part by weight, 25 parts by weight of crosslinked polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon CL ^R ) was uniformly dispersed while stirring with a dissolver. The ethanol solution in which the crosslinked polyvinylpyrrolidone is dispersed is applied onto a PET release paper whose surface is treated with silicone so that the thickness becomes 60 μm, and dried at a temperature of 60 ° C. for 1 hour to obtain a film-shaped oral mucosa. An applied formulation was obtained.

Comparative Example 10 Polyacrylic acid (trade name; Junron 1 manufactured by Nippon Pure Chemical Co., Ltd.)
10) 63 parts by weight and polyacrylic acid (manufactured by Nippon Pure Chemical Co., Ltd.,
Twenty-seven parts by weight of the product name: Julimer AC-10HP) was uniformly dissolved in 300 parts by weight of ethanol to obtain a colorless and transparent adhesive solution. 10 parts by weight of estradiol was uniformly dissolved in the adhesive solution. The ethanol solution in which the estradiol is dissolved has a thickness of 60 μm after drying.
So that the surface thereof was coated on PET release paper treated with silicone, and dried at a temperature of 60 ° C. for 1 hour to obtain a film-form preparation for oral mucosa application.

Example 11 Maleic anhydride-methyl vinyl ether copolymer (GA
Company F, trade name; GANTREZ AN-119) 20
Parts by weight, and maleic anhydride-methyl vinyl ether copolymer (manufactured by GAF, trade name; GANTREZ AN-
169) 65 parts by weight were uniformly dissolved in 300 parts by weight of ethyl acetate to obtain a colorless and transparent adhesive solution. After uniformly dissolving 10 parts by weight of nifedipine in the adhesive solution, 25 parts by weight of crosslinked polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon CL ^R ) was stirred with a dissolver,
Dispersed evenly. The ethyl acetate solution in which the crosslinked polyvinylpyrrolidone is dispersed is coated on a PET release paper whose surface is treated with silicone so that the thickness after drying is 70 μm, and dried at a temperature of 60 ° C. for 1 hour to form a film. A preparation for oral mucosa application was obtained.

Comparative Example 11 Maleic anhydride-methyl vinyl ether copolymer (GA
F company, trade name; GANTREZ AN-169) was changed from 65 parts by weight to 50 parts by weight, and the same manner as in Example 11 except that the crosslinked polyvinylpyrrolidone was not used. A film-form preparation for oral mucosa was obtained.

Example 12 Methacrylic Acid-Methyl Methacrylate Copolymer (Ro
hm Pharma Co., trade name; Euidragit
L) 50 parts by weight and polyethylene glycol 600
25 parts by weight (manufactured by Nippon Oil & Fats Co., Ltd.) was uniformly dissolved in 300 parts by weight of ethanol. The resulting solution was applied onto a PET release paper whose surface was treated with silicone so that the thickness after drying would be 20 μm, and dried at a temperature of 60 ° C. for 2 hours to give a film-like mucous membrane non-sticking group. I got the wood. The non-mucoadhesive base material obtained as described above and the preparation for oral mucosa application of Example 11 were thermocompression bonded to obtain a film-form preparation for oral mucosa application.

Example 13 Maleic anhydride-methyl vinyl ether copolymer (GA
Company F, trade name; GANTREZ AN-119) 20
Parts by weight, and maleic anhydride-methyl vinyl ether copolymer (manufactured by GAF, trade name; GANTREZ AN-
169) 50 parts by weight was uniformly dissolved in 300 parts by weight of ethyl acetate to obtain a colorless and transparent adhesive solution. In the obtained pressure-sensitive adhesive solution, 25 parts by weight of cross-linked polyvinylpyrrolidone (manufactured by BASF, trade name; Kollidon CL ^R ) was uniformly dispersed while stirring with a dissolver. The ethyl acetate solution in which the crosslinked polyvinylpyrrolidone was dispersed had a thickness of 7 after drying.
The surface of the P is treated with silicone so that it becomes 0 μm.
Apply on ET release paper and dry at 60 ° C for 1 hour,
A film-form preparation for oral mucosa was obtained.

Comparative Example 12 A film-form preparation for oral mucosa was obtained in the same manner as in Example 13 except that the crosslinked polyvinylpyrrolidone was not added. Example 14 A mucous membrane non-sticking substrate obtained in Example 12, and Example 13
The preparation for oral mucosa application was heat-pressed to obtain a film-form preparation for oral mucosa application.

Evaluation Each of the oral mucosa-applied preparations obtained in Examples 1 to 4 and Examples 8 to 11 and Comparative Examples 1 to 5 and Comparative Examples 8 to 11 was subjected to wet pig skin 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. On the moist pigskin on the stainless steel table 2, the tablet-oral mucosa-applied preparation 4 was stuck as it was, and the film-shaped oral mucosa-applied preparation was punched into a circle having a diameter of 10 mm and attached. Gently touch the stainless steel jig 1 from above 1
After leaving for 0 minutes, 200mm using a tensile tester
The stainless steel jig 1 and the stainless steel table 2 were pulled at a speed of / 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 repetitions was taken as the sticking force. Table 1 shows the sticking force of each preparation for oral mucosa application to moist pig skin.

[0054]

[Table 1]

As is clear from Table 1, Example 1 and Comparative Examples 1 and 2, Example 2 and Comparative Example 3, Example 3 and Comparative Example 4, Example 4 and Comparative Example 5, and Example 8 were compared. From the comparison of the adhesive strengths of Example 8, Example 9 and Comparative Example 9, Example 10 and Comparative Example 10, and Example 11 and Comparative Example 11, the oral cavity mucosa-applied formulation of Example shows that the carboxylic acid-containing aqueous solution of Comparative Example is used. It can be seen that the high adhesiveness of the hydrophilic polymer itself to the wet surface is almost maintained.

Next, with respect to each oral mucosa-applied preparation obtained in Examples 1 to 6 and Examples 8 to 12 and Comparative Examples 1 to 4 and Comparative Examples 8 to 11, according to the procedure shown in the following Experiment 2, water resistance was obtained. The test was conducted. 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 steel plate 5 shown in a plan view in FIG. 2 with a cyanoacrylate adhesive. On this moist pork skin, the tablet for oral mucosa application is as it is, and the film for oral mucosa application is 10 mm in diameter.
It was punched out in a circle of mm and attached. 10g / from above
It was applied with a load of 0.785 cm ² for 10 minutes.

The dimensions a to d in FIG.
a = 100 mm, b = 80 mm, c = 60 mm, d = 1
0 mm, the thickness of the stainless plate 5 is 3 mm,
The one made of SIS304 was used. According to the second dissolution method of the Japanese Pharmacopoeia General Test Method, this stainless steel plate 5
Was submerged on the bottom of a container containing 600 ml of physiological saline as a test solution so that the preparation was on the top, and the test was performed at 100 rpm, and the properties of the preparation after 1,6 and 24 hours were observed.
Table 2 shows the properties of each preparation for oral mucosa application at each time.

[0058]

[Table 2]

As is clear from Table 2, Example 1 and Comparative Examples 1 and 2, Example 2 and Comparative Example 3, Example 3 and Comparative Example 4, Example 4 and Comparative Example 5, and Example 8 were compared. From the comparison of the water resistance of each of Example 8, Example 9 and Comparative Example 9, Example 10 and Comparative Example 10, and Example 11 and Comparative Example 11, the oral mucosa-applied formulation of Example had extremely high water resistance, It has excellent durability because it is attached to the pump under the rotation of the battle,
It can be seen that it can be applied to a wet surface for a long time.
Also, a comparison between Example 5 and Example 6 and Example 11
It is understood from a comparison between Example 12 and Example 12 that the water resistance and durability can be further enhanced by laminating a support layer made of a water-insoluble or sparingly soluble polymer on the mucoadhesive base.

Hairless mice were isolated from the preparations for oral mucosa preparations obtained in Examples 1 to 6 and Examples 8 to 11 and Comparative Examples 1 to 4 and Comparative Examples 8 to 11 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 vertebrae excision, and immediately the skin was 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. On the skin piece 14, the tablet-made preparation for oral mucosal application was punched out as it was, and the film-shaped preparation for oral mucosal application was punched out to a diameter of 10 mm and attached as a test piece 15. In the receptor tank 8,
The receptor solution prepared by the following method was filled.

Then, 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.

[0063]

[Table 3]

As is clear from Table 3, Example 1 and Comparative Examples 1 and 2, Example 2 and Comparative Example 3, Example 3 and Comparative Example 4, Example 4 and Comparative Example 5, and Example 8 were compared. From the comparison of the skin permeation amount of Example 8, Example 9 and Comparative Example 9, Example 10 and Comparative Example 10, and Example 11 and Comparative Example 11, the carboxylic acid-containing water-soluble polymer alone was prepared in the oral mucosa preparation of Example. Good drug release is recognized as compared with the case of. This is because, compared with the case of using the carboxylic acid-containing water-soluble polymer alone, in the preparation for oral mucosa application of the example, the degree of swelling when absorbing water is high, and the drug easily diffuses in the mucoadhesive base. It is considered that the crosslinked polyvinylpyrrolidone itself also absorbs water and swells, and the drug dissolved in the crosslinked polyvinylpyrrolidone is easily released.

The preparations for application to the oral mucosa obtained in Examples 5 to 7 and Examples 13 and 14 and Comparative Examples 5 and 6 and Comparative Example 12 were subjected to a human patching test according to the method shown in the following Experiment 4. It was Experiment 4 Oral mucosa-applied preparations of tablets were left as they were, and film-shaped oral mucosa-applied preparations were punched out to a diameter of 10 mm, attached to the oral mucosa of 5 subjects, and the peeling time was measured. evaluated. Table 4 shows the average time until peeling of each preparation for oral mucosa application.

[0066]

[Table 4]

As is clear from Table 4, the oral mucosa-applied formulations of the examples adhered for a longer period of time than the oral mucosa-applied formulations of the comparative examples, and therefore had good stickability, water resistance and durability. You can see that Moreover, the oral mucosa-applied formulations of Examples 6 and 14 adhered to the oral mucosa-applied formulations of Examples 5 and 13 for a long time, respectively, and therefore were insoluble or sparingly soluble in the mucoadhesive base. It is understood that the water resistance and the durability can be enhanced by laminating the support layer made of the polymer.

Further, as compared with Example 5, in Example 7, no sticking phenomenon was observed on the finger when it was stuck in the oral cavity, and the sticking operation could be performed easily. 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 particular foreign body sensation, probably because it absorbs water immediately and swells.

[0069]

As described above, according to the present invention, poly (meth) acrylic acid and its pharmaceutically acceptable salt, alginic acid and its pharmaceutically acceptable salt, and maleic anhydride-methyl vinyl ether. Since one or more polymers selected from the group consisting of copolymers are blended as one of the main components of the adhesive base, the saliva or secretory fluid can be absorbed to ensure local administration to the oral mucosa. Can be attached to. Therefore, it becomes possible to cause the drug to act directly or locally on the oral cavity or the peripheral disease, or to effectively protect the affected area.
Further, in the present invention, in addition to the carboxylic acid-containing water-soluble polymer, since cross-linked polyvinylpyrrolidone is blended, saliva or secretory fluid is absorbed, and the interaction between the cross-linked polyvinylpyrrolidone and the carboxylic acid-containing water-soluble polymer. The resulting gel becomes swollen. 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 area 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 mucoadhesive base comprising poly (meth) acrylic acid and a pharmaceutically acceptable salt thereof, alginic acid and a pharmaceutically acceptable salt thereof, and a maleic anhydride-methyl vinyl ether copolymer. A material containing one or more polymers selected from the group consisting of and a crosslinked polyvinylpyrrolidone, wherein the crosslinked polyvinylpyrrolidone is water-swellable and water-insoluble, and the proportion of the crosslinked polyvinylpyrrolidone used as the polymer component is 5 A preparation for application to the oral mucosa, characterized in that it is from 50% by weight.