JPH04266819A - Preparation for application to mucosa of oral cavity - Google Patents

Abstract

PURPOSE:To obtain a preparation for application to mucosa of oral cavity having a tacky base slightly collapsible with spittle, being in contact with mucosa of oral cavity, readily for many hours, making a medicinal compound through mucosa of oral cavity, effectively developing systematic and/or local action or protecting damaged part and disease part in oral cavity. CONSTITUTION:A preparation for application to mucosa of oral cavity comprising (A) a vinylpyrrolidone (co)polymer soluble in water and/or an alcohol, (B) a (meth)acrylic acid copolymer in the ratio of component A:B=99:1-50:50 and preferably further (C) a weakly basic organic carboxylic acid salt in a ratio of 100 pts.wt. components A+B and 0.1-20 pts.wt. component C. Being blended with the component A, the preparation absorbs spittle, etc., can be bonded to mucosa of oral cavity. Further being mixed with the component B, the preparation is made into a gelatinous material having excellent water resistance, flexibility and shape retention, a medicine can gradually be released for many hours, is not dissolved, does not flow and does not provided a feeling of physical disorder.

Description

[Detailed description of the invention]

0001

[Field of Industrial Application] The present invention relates to a preparation for oral mucosa that uses a vinylpyrrolidone (co)polymer and a (meth)acrylic acid copolymer, and in particular, it adheres easily and for a long time to the oral mucosa. The present invention relates to oral mucosal preparations that allow medicinal ingredients to be transdermally absorbed via the oral mucosa to exert systemic and local effects, or to protect damaged or diseased areas in the oral cavity.

0002

BACKGROUND OF THE INVENTION Various oral patch preparations and oral bandages have been proposed. For example, a composition consisting of hydroxypropyl cellulose and an acrylic acid (co)polymer or its salt (Japanese Patent Publication No. 58-7605): a composition consisting of gelatin or agar, gluten, carboxyvinyl polymer, and vinyl acetate resin or gums. Composition (JP-A No. 59-186913): polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol,
Compositions consisting of alginic acid or its salts, maleic anhydride/methyl vinyl ether copolymers, etc., and acrylic acid polymers or their salts (JP-A-60-215622): polycarboxylic acids, polycarboxylic anhydrides, and vinyl acetate Composition consisting of copolymer (JP-A-61-24947
No. 3). In the conventional oral preparations as described above, a hydrophilic polymer is used as an intraoral patch base. However, the hydrophilic polymers used as the base for intraoral patching exhibit adhesive properties when exposed to small amounts of water such as saliva, but they swell and disintegrate when exposed to large amounts of saliva, resulting in poor water resistance. . Therefore, in order to impart water resistance to the base material, a composition in which a water-insoluble polymer such as vinyl acetate or rubber is blended has been proposed. However, with this method, the affinity between the hydrophilic polymer and the water-insoluble polymer is not good, and there is little interaction, so sufficient water resistance cannot be obtained.

0003

SUMMARY OF THE INVENTION An object of the present invention is to have an adhesive base that is unlikely to be disintegrated by saliva, etc., and that can be easily adhered to the oral mucosa for a long period of time.
Therefore, we provide an oral mucosal preparation that allows medicinal ingredients to be absorbed through the oral mucosa, effectively exerting systemic and local effects, and protecting damaged and diseased areas in the oral cavity. It's about doing.

0004

[Means for Solving the Problems] In the oral mucosal preparation of the present invention, the mucosal adhesive base is mainly composed of a blend polymer of vinylpyrrolidone (co)polymer and (meth)acrylic acid copolymer. In other words, it was known that by using vinylpyrrolidone (co)polymer, a base with excellent adhesion to wet mucosal surfaces could be obtained, but as mentioned above, there was a problem of insufficient water resistance. . As a result of studies to solve this problem, the present inventors developed a formulation for oral mucosa by mixing a (meth)acrylic acid copolymer that is compatible with vinylpyrrolidone (co)polymer and has a high affinity. It has been discovered that the above-mentioned problems can be achieved by preparing the following, and the present invention has been completed. When a blend polymer of a vinyl pyrrolidone (co)polymer and a (meth)acrylic acid copolymer is used, the following excellent effects can be obtained. (1) It absorbs saliva or secretions and adheres locally, and has excellent local adhesion even when swollen. Therefore, it is possible to reliably cause the drug to directly and locally act on the oral cavity or surrounding diseased areas, or to effectively protect damaged or diseased areas within the oral cavity. (2) By absorbing saliva or secretions and gradually releasing the drug, it becomes possible to continue administering the drug to the target disease site or absorption site over a long period of time, or to protect the affected area. . (3) Even if it absorbs saliva or secretions, it is water resistant, so it does not dissolve and flow out, and even when it swells, it has excellent shape retention. However, in order to exhibit the above-mentioned excellent properties, in the present invention, the vinyl pyrrolidone (co)polymer and the (meth)acrylic acid copolymer are mixed in a weight ratio of 99:1 to 50:50. It is necessary that the content be within the following range. This is because if the blending ratio of the (meth)acrylic acid copolymer is less than 1% by weight, the effect of increasing moisture resistance cannot be obtained. This is because the adhesion performance to surfaces is lost. Preferably, the (meth)acrylic acid copolymer is blended in an amount of 5 to 40% by weight. In addition, the present inventors have discovered that moisture resistance can be further enhanced by adding a weakly basic organic carboxylic acid salt in addition to the above-mentioned vinylpyrrolidone (co)polymer and (meth)acrylic acid copolymer. The inventors have found that the second invention of the present application has been achieved.

Vinylpyrrolidone (co)polymer Examples of the vinylpyrrolidone (co)polymer include vinylpyrrolidone homopolymer, vinylpyrrolidone and (meth)acrylic acid, (meth)acrylic acid methyl ester,
(meth)acrylic acid ethyl ester, maleic anhydride,
Examples include copolymers with one or more of vinyl alcohol, vinyl acetate, and the like. Such vinyl pyrrolidone (co)polymers need to exhibit tackiness when a small amount of moisture, such as saliva, is applied. Therefore, water and/or
Or it needs to be soluble in alcohol. The content of vinyl pyrrolidone in the copolymer is determined in order to maintain the excellent properties of vinyl pyrrolidone, that is, good adhesion to mucous membranes and non-irritation to the skin, and to maintain the content of (meth)acrylic acid copolymer. In order to improve water resistance by blending, the content should be 70 mol% or more, preferably 90 mol% or more.

(Meth)acrylic acid copolymer (meth)
Examples of acrylic acid copolymers include one or more types of (meth)acrylic acids such as acrylic acid and methacrylic acid, and vinyl alcohol, vinyl acetate, vinyl pyrrolidone, maleic anhydride, and (meth)acrylic acid. Methyl, (
meth)ethyl acrylate, butyl (meth)acrylate,
One or more monomers that do not have a free carboxylic acid in the molecule, such as 2-ethylhexyl (meth)acrylate, dimethylaminoethyl (meth)acrylate, or trimethylammoniumethyl (meth)acrylate chloride. Examples include copolymers of The above (meth)acrylic acid copolymer is a copolymer containing 5 mol% to 90 mol% of (meth)acrylic acid. If the content of (meth)acrylic acid is less than 5 mol%, the effect of increasing moisture resistance will not be obtained, and if it exceeds 90 mol%, water resistance will increase, but on the contrary, it will be difficult to improve moisture resistance. Since the compatibility decreases and it becomes difficult to obtain a uniform preparation when producing a preparation for application to the oral mucosa, the preferred range is 5 mol% to 90 mol%, and more preferably 20 mol% to 80 mol%. It is. The reason why the water resistance of the oral mucosal formulation of the present invention is significantly enhanced by the addition of the (meth)acrylic acid copolymer is not known in detail, but the combination of the carboxylic acid of the copolymer and the vinylpyrrolidone (co)polymer is unknown. This is thought to be due to an unexpected interaction with the pyrrolidone ring. Therefore, in order to obtain the desired effect by adding a (meth)acrylic acid copolymer, it is not necessary for the (meth)acrylic acid copolymer to develop tackiness due to the addition of a small amount of water such as saliva. , it is necessary to interact with the vinylpyrrolidone (co)polymer when water is added, and the properties include water and/or water with a pH of 4 or more.
Alternatively, it is preferably soluble in alcohol. Furthermore, it is also possible to use a copolymer salt obtained by adding a monovalent or divalent metal salt to the copolymer to neutralize the copolymer, if necessary.

Weakly basic organic carboxylic acid salts Examples of the organic carboxylic acid salts used in the second invention of the present application include sodium salts of acetic acid, stearic acid, fumaric acid, maleic acid, citric acid, phthalic acid, and polyacrylic acid. , potassium salt,
Examples include calcium salts. As these properties, 1
% aqueous solution is preferably in the range of 7 to 9. The amount added to 100 parts by weight of the blend polymer is 0.1 parts by weight to 20 parts by weight, preferably 1 part by weight to 10 parts by weight.
If the amount exceeds 0 parts by weight, the moisture resistance will decrease due to the water solubility of the organic carboxylic acid itself.

[0008] Production The oral mucosal preparation provided by the present invention is produced by adding polymer components such as a (meth)acrylic acid copolymer and a vinylpyrrolidone (co)polymer, a drug that exhibits a therapeutic effect, and, if necessary, This can be easily carried out by preparing a solution of additives such as drug absorption enhancers and plasticizers in a suitable solvent, casting the solution, and forming it into a thin film through a drying process. In addition, as other manufacturing methods, we also use polymer components such as (meth)acrylic acid copolymer and vinylpyrrolidone (co)polymer, drugs that exhibit therapeutic effects, and, if necessary, drug absorption enhancers and lubricants. , a binder, an excipient, a flavoring agent, and one or more of them are thoroughly mixed to form a homogeneous mixture, and an appropriate amount of these is directly pressure-molded using a punch, die, or press. It can also be manufactured by

Drugs The drugs of the present invention are not particularly limited as long as they are transdermally absorbable, and one or more drugs may be used in combination as needed. These drugs include, for example, antipyretic and antiinflammatory analgesics, analgesics, steroidal anti-inflammatory agents, vasodilators, antihypertensive and arrhythmic agents, antihypertensive agents, antitussive expectorants, local anesthetics, hormonal agents, asthma and nasal Allergy treatment agents, antihistamines, anticoagulants,
Examples include antispasmodics, cerebral circulation/metabolism improving agents, antidepressants/anxiolytics, vitamin D preparations, oral hypoglycemic agents, antiulcer agents, sleeping pills, antibiotics, antibacterial agents, and bactericidal agents. Antipyretic and antiinflammatory analgesics include indomethacin, salicylic acid, aspirin, acetaminophen, diclofenac sodium,
Examples include ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibufenac, fenbufen, alclofenac, phenylbutazone, mefenamic acid, piroxicam, flurbiprofen, bendazac, and the like. Examples of analgesics include pentazocine, buprenorphine hydrochloride, eptazocine hydrobromide, butorphanol tartrate, and the like. Steroid anti-inflammatory drugs include hydrocortisone, prednisolone,
Examples include fluocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, hetamethasone acetate, diflucortolone valerate, propion clohetasol, fluocinonide, and the like. Examples of vasodilators include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide nitrate, nifedipine, nitroglycerin, and the like. Agents for hypertension and arrhythmia include propanolol, atenolol, pindolol, quinidine sulfate, ajmaline, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, disopyramide, and the like. Antihypertensive agents include clonidine hydrochloride, captryl, prazosin hydrochloride, benbutrol sulfate, guanabenz acetate, guanfacine hydrochloride, guanabenz acetate, punazosin hydrochloride, elanapril maleate, arotinolol hydrochloride,
Examples include bunitrol hydrochloride.

[0010] Antitussive expectorants include procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pyrobuterol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride,
Trimethoquinol hydrochloride, formoterol fumarate, and the like. Examples of antiulcer agents include 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, mitomycin C, and the like. Local anesthetics include benzocaine, procaine, lidocaine, tetracaine, and the like. Examples of hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone, and prostaglandin; peptide hormones such as insulin; and the like. Asthma/nasal allergy therapeutic agents include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate, and the like. Examples of antihistamines include cycloheptadine hydrochloride, diphenhydramine hydrochloride, fenbenzamine, mequitazine, and the like. Anticoagulants include heparin and the like. Examples of antispasmodics include scopolamine and clofluperol. Examples of cerebral circulation and metabolism improving agents include pinpocetine, flunagiline hydrochloride, nicardipine hydrochloride, brobincamine fumarate, dihydroergotoxine mesylate, ifenprodil tartrate, isoxsuprine hydrochloride, and the like. Examples of antidepressant/anxiolytics include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, mianserin hydrochloride, and the like. Examples of vitamin D agents include α-calcidol and ergocasiferol. As an oral hypoglycemic agent,
Examples include glibenclamide and gliclazide. Anti-ulcer agents include grepobride malate, famotidine,
Examples include glycopyrronium bromide. Examples of sleeping pills include phenobarbital, amobarbital, and the like. Antibiotics include tetracycline, chloramphenicol, and the like. 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 patch at a ratio of 0.1 to 40% by weight.

Form Example The preparation for oral mucosa application of the present invention has a form in which a water-insoluble or poorly soluble polymer layer or a similar non-mucosal base material is laminated as a support layer on one side of a mucosal adhesive base material. It is also possible to do this. This support layer can be formed from a layer consisting of a natural polymer, a semi-synthetic polymer, a synthetic polymer, a metal foil, or a composite thereof. Methods for laminating this support layer and the mucosal adhesive base include heating, pressure, or other suitable mechanical methods; adhesive bonding; and dissolving the polymer component of the support layer in an appropriate volatile solvent. A method of dissolving the components of the mucosal adhesive base in an appropriate volatile solvent, applying the mixture to the supporting layer, and laminating the mixture can be adopted. . As mentioned above, by using a water-insoluble or sparingly soluble and saliva-impermeable support layer, the amount of permeation from the opposite side of the mucous membrane per unit time is reduced, and the mucosal adhesion due to physical stimulation in the oral cavity is reduced. Disintegration of the base material is suppressed. Therefore, compared to the case of a mucosal adhesive base alone, water resistance and durability can be further improved, and it becomes possible to adhere the adhesive in the oral cavity for a longer period of time.

0012

[Action] In the preparation for oral mucosa application of the present invention, the vinylpyrrolidone (co)polymer in the preparation acts to absorb saliva or secretions and deposit them locally in the oral cavity, thereby causing diseases in the oral cavity or surrounding areas. It is said that it is possible to apply drugs directly and locally to the affected area, or to protect the affected area. In addition, it absorbs saliva or secretions, and the vinyl pyrrolidone (co)polymer and (meth)acrylic acid copolymer interact to form a gel-like swell that gradually releases the drug over a long period of time. It becomes possible to continue administering the drug to the applied disease site or absorption site over a long period of time, and to protect the affected area. Furthermore, this gel-like body has excellent water resistance, so it does not dissolve and flow out, and in a swollen state, it is flexible and has excellent shape retention. Therefore, even if the gel-like material remains in the oral cavity for a long time, it can be used without giving a foreign body sensation.

[0013]

[Explanation of Examples] The present invention will be specifically explained below using Examples. Example 1 Vinylpyrrolidone homopolymer (manufactured by BASF, Kol
Solution I was obtained by uniformly dissolving 75 parts by weight of Lidon 30) in 200 parts by weight of ethanol. Methacrylic acid-methyl methacrylate copolymer [Rohm Pharma
A solution II was obtained by dissolving 25 parts by weight of Euidragit L (methacrylic acid content: 38-52%) manufactured by Eudragit Co., Ltd. in 50 parts by weight of ethanol. The above solutions I and II were mixed uniformly to obtain a colorless and transparent adhesive solution. A 5% ethanol solution of isosorbide nitrate was added to this adhesive solution so that the concentration of isosorbide nitrate in the adhesive was 10%, and the mixture was uniformly mixed with a dissolver to obtain an ethanol solution with a non-volatile content of approximately 30%. . This ethanol solution was coated onto a silicone-treated polyethylene terephthalate (PET) release paper so that the thickness after drying was 40 μm, and dried at 60° C. for 1 hour to form a preparation for oral mucosa application. Comparative Example 1 Vinylpyrrolidone homopolymer (manufactured by BASF, Kol
100 parts by weight of lidon 30) was uniformly dissolved in 200 parts by weight of ethanol to obtain a colorless and transparent adhesive solution. A 5% ethanol solution of isosorbide nitrate was added to this adhesive solution so that the concentration of isosorbide nitrate in the adhesive was 10%, and the mixture was uniformly mixed with a dissolver to reduce the non-volatile content to approximately 30%.
% ethanol solution. This ethanol solution was coated onto a silicone-treated polyethylene terephthalate (PET) release paper so that the thickness after drying was 40 μm, and dried at 60° C. for 1 hour to form a film-like preparation for oral mucosa application.

Example 2 Vinylpyrrolidone homopolymer (manufactured by BASF, Kol)
Solution I was obtained by uniformly dissolving 75 parts by weight of Lidon 30) in 200 parts by weight of ethanol. Methacrylic acid-methyl methacrylate copolymer [Rohm Pharma
A solution II was obtained by dissolving 25 parts by weight of Euidragit L (methacrylic acid content: 38-52%) manufactured by Eudragit Co., Ltd. in 50 parts by weight of ethanol. Solution III was obtained by dissolving 5 parts by weight of 3Na citric acid in 50 parts by weight of distilled water. The above solutions I, II, and III were uniformly mixed to obtain a colorless and transparent adhesive solution. A 10% ethanol solution of isosorbide nitrate was added to this adhesive solution so that the concentration of isosorbide nitrate in the adhesive was 10%, and the mixture was uniformly mixed with a dissolver to obtain an ethanol solution with a non-volatile content of approximately 30%. . The thickness of this ethanol solution after drying is 40 μm.
It was coated on a polyethylene terephthalate (PET) release paper whose surface was treated with silicone so as to have the following properties, and dried at 60° C. for 1 hour to form a preparation for application to oral mucosa.

Example 3 Vinylpyrrolidone homopolymer (manufactured by BASF, Kol
lidon 30) 67.5 parts by weight, methacrylic acid-
Methyl methacrylate copolymer [Rohm Pharm
22.5 parts by weight of Euidragit L (methacrylic acid content 38-52%), 0.5 parts by weight of magnesium stearate, and 10 parts by weight of isosorbide nitrate, manufactured by Company A, were uniformly mixed and tableted. 1.0mm, diameter 7
．． A preparation for application to the oral mucosa was prepared in the form of a tablet having a diameter of 0 mm and a weight of 100 mg. Comparative Example 2 Vinylpyrrolidone homopolymer (manufactured by BASF, Kol
Lidon 30) 90 parts by weight, 0.5 parts by weight of magnesium stearate, and 10 parts by weight of isosorbide nitrate were uniformly mixed and compressed into tablets with a thickness of 1.0 mm and a diameter of 10.0 m.
A preparation for application to the oral mucosa was prepared in the form of a tablet having a weight of 120 mg.

Example 4 Vinylpyrrolidone homopolymer (manufactured by BASF, Kol
22.5 parts by weight of Kollidon 30) and vinylpyrrolidone homopolymer (manufactured by BASF, Kollidon 9)
Solution I was obtained by uniformly dissolving 67.5 parts by weight of 0) in 200 parts by weight of ethanol. Methacrylic acid-methyl methacrylate copolymer [manufactured by Rohm Pharma, E
uidragit S (methacrylic acid content 25.
0-34.5%)] and methacrylic acid-ethyl acrylate copolymer (Euidragit L100-55
) 5 parts by weight of each were dissolved in 20 parts by weight of ethanol to form solution I.
I got I. The above solutions I and II were mixed uniformly to obtain a colorless and transparent adhesive solution. A 10% ethanol solution of indomethacin was added to this adhesive solution so that the indomethacin content in the adhesive was 10%, and the mixture was mixed uniformly with a dissolver to prepare an ethanol solution with a non-volatile content of approximately 30%. This ethanol solution was coated onto a silicone-treated polyethylene terephthalate (PET) release paper so that the thickness after drying was 40 μm, and dried at 60° C. for 1 hour to form a film-like preparation for oral mucosa application.

Example 5 60 parts by weight of polyvinyl acetate and 30 parts by weight of sorbitan monolaurate were dissolved in ethanol. This solution was cast on a PET film whose surface had been treated with silicone and dried to obtain a film-like non-adhesive base for mucous membranes with a thickness of 60 μm. This mucosal non-adhesive base and the film-like oral mucosa preparation of Example 4 were bonded under heat to obtain a film-like oral mucosa preparation. Comparative Example 3 Vinylpyrrolidone homopolymer (manufactured by BASF, Kol
25 parts by weight of Kollidon 30) and vinylpyrrolidone homopolymer (manufactured by BASF, Kollidon 90)
) was uniformly dissolved in 200 parts by weight of ethanol. A 10% ethanol solution of indomethacin was added to this adhesive solution so that the indomethacin content in the adhesive was 10%, and the mixture was uniformly mixed with a dissolver, and the non-volatile content was approx.
The solution was adjusted to be 0% ethanol solution. The surface of silicone-treated polyethylene terephthalate (PET) was coated with this ethanol solution so that the thickness after drying was 40 μm.
It was coated on release paper and dried at 60° C. for 1 hour to form a mucosal adhesive base. The above-mentioned film-like mucosal adhesive base and the mucosal non-adhesive base obtained in Example 5 were thermocompressed to obtain a film-like oral mucosa-applicable preparation.

Example 6 95 parts by weight of vinylpyrrolidone, 5 parts by weight of methyl methacrylate
parts by weight, using ethanol as a solvent and adding 0.3 parts by weight of lauroyl peroxide as a polymerization catalyst,
Polymerization was carried out at 60°C, and the weight average molecular weight was 7.5 x 105.
A vinylpyrrolidone-methyl methacrylate copolymer solution having a solid content of 35% was obtained (solution I). methacrylic acid 8
0 parts by weight, 20 parts by weight of vinylpyrrolidone, ethanol as a solvent, 0.5 parts by weight of lauroyl peroxide as a polymerization catalyst, and polymerization was carried out at 60°C.
A methacrylic acid-vinylpyrrolidone copolymer solution having a weight average molecular weight of 9.0×10 4 and a solid content of 30% was obtained (Solution II). 257.1 parts by weight of the above solution I, solution II
33.3 parts by weight were uniformly mixed to obtain a colorless and transparent adhesive solution. Add 10% of estradiol to this adhesive solution.
% ethanol suspension solution was added so that the estradiol in the adhesive was 10%, and mixed uniformly with a dissolver to prepare an ethanol solution with a nonvolatile content of about 30%. This ethanol solution was coated onto a silicone-treated polyethylene terephthalate (PET) release paper so that the thickness after drying was 50 μm, and dried at 60° C. for 1 hour to form a film-like preparation for oral mucosa application.

Example 7 90 parts by weight of vinylpyrrolidone and 10 parts by weight of acrylic acid were polymerized at 60°C using ethanol as a solvent and 0.5 parts by weight of lauroyl peroxide as a polymerization catalyst. A vinylpyrrolidone-acrylic acid copolymer solution having an average molecular weight of 4.0×10 5 and a solid content of 35% was obtained (solution I). 50 parts by weight of acrylic acid and 50 parts by weight of dimethylaminoethyl acrylate were polymerized at 60°C using ethanol as a solvent and 0.5 parts by weight of lauroyl peroxide as a polymerization catalyst, resulting in a weight average molecular weight of 1. .5 x 104, 30% solids acrylic acid-
A dimethylaminoethyl acrylate copolymer was obtained (solution II). 228.6 parts by weight of the above solution I, 66.7 parts by weight of solution II, and 200 parts by weight of glycerin (manufactured by NOF Corporation, Japan Standards) were uniformly mixed to obtain a colorless and transparent adhesive solution. . Add 10% of nifedipine to this adhesive solution.
An ethanol solution was added so that the nifedipine content in the adhesive was 10%, and the mixture was mixed uniformly with a dissolver to prepare an ethanol solution with a non-volatile content of about 30%. The surface of this ethanol solution was siliconized polyethylene terephthalate (P) so that the thickness after drying was 100 μm.
ET) It was coated on release paper and dried at 60° C. for 1 hour to form a film-like preparation for oral mucosa application.

Example 8 95 parts by weight of vinylpyrrolidone and 5 parts by weight of 2-ethylhexyl acrylate were polymerized at 60°C using ethanol as a solvent and 0.3 parts by weight of lauroyl peroxide as a polymerization catalyst. was carried out, and the weight average molecular weight was 5.5.
×105, a vinylpyrrolidone-2-ethylhexyl acrylate copolymer solution with a solid content of 35% was obtained (solution I
). Methacrylic acid-methyl methacrylate copolymer (
Eudragit-L manufactured by Rohm Pharma
) was dissolved in 100 parts by weight of ethanol to obtain solution II. 228.6 parts by weight of the above solution I and solution I
All of I was mixed uniformly to obtain a colorless and transparent adhesive solution. A 10% ethanol solution of isosorbide nitrate was added to this adhesive solution so that the concentration of isosorbide nitrate in the adhesive was 10%, and the mixture was uniformly mixed with a dissolver to obtain an ethanol solution with a non-volatile content of approximately 30%. . The surface of this ethanol solution was silicone-treated polyethylene terephthalate (PE) so that the thickness after drying was 50 μm.
T) It was coated on release paper and dried at 60°C for 1 hour to form a film-like preparation for oral mucosa application.

[0021] The preparations for oral mucosa obtained in Examples 1 to 8 and Comparative Examples 1 to 3 were tested for adhesion to wet pig skin using the method shown in Experiment 1. Experiment 1 Sterilized freeze-dried pork skin (manufactured by Mitsui Pharmaceutical Industries, Ltd., trade name Metaskin) was regenerated with physiological saline, and excess water was removed with gauze to obtain wet pig skin as an adherend. This wet pork skin has a diameter of 12 mm.
It was punched out into a mm circle. As shown in FIG. 1, a punched wet pork skin 3 was adhered to a stainless steel jig 1 weighing 10 g and having a diameter of 12 mm and a stainless steel stand 2 measuring 100×100 mm with a cyanoacrylate adhesive. stainless steel stand 2
A film-like oral mucosa application preparation (Example 5,
4 (other than Comparative Example 3) were punched out into a circle with a diameter of 10 mm, and the oral mucosa application preparation 4 in the form of a tablet was pasted as is. Gently touch the stainless steel jig 1 on top of it, leave it for 10 minutes, and then test it using a tensile tester.
The stainless steel jig 1 and the stainless steel stand 2 were pulled in the vertical direction at a speed of 0.00 mm/min, the load generated at that time was measured, and the average of 4 repetitions was taken as the sticking force. Example 5,
For Comparative Example 3, a circle with a diameter of 10 mm was punched out, the non-mucosal adhesive base side was directly adhered to the stainless steel stand 2 with cyanoacrylate adhesive, and wet pork skin was adhered on top of it in the same manner as above. After gently contacting the stainless steel jig 1 and leaving it for 10 minutes, the adhesion force was measured in the same manner as above. Table 1 shows the adhesion strength of each preparation for oral mucosa to wet pig skin.
Shown below.

[0022]

[Table 1]

As is clear from Table 1, from the comparison of the adhesion strength between Example 1 and Comparative Example 1, Example 3 and Comparative Example 2, and Example 5 and Comparative Example 3, it was found that the preparation for oral mucosa of the present invention It is recognized that the vinyl pyrrolidone polymer of the comparative example maintains its own high adhesion to wet surfaces. Moreover, from the results of Examples 2, 4, 6, 7, and 8, it is recognized that the preparation for application to oral mucosa of the present invention has high stickability to wet surfaces. A water resistance test was conducted on the oral mucosa preparations obtained in Examples 1 to 8 and Comparative Examples 1 to 3 by the method shown in Experiment 2. Experiment 2 The wet pork skin prepared in Experiment 1 and punched out into a circular shape with a diameter of 12 mm was adhered to the stainless steel plate 5 shown in FIG. 2 with a cyanoacrylate adhesive. The film-like preparation for oral mucosa was punched out into a circle with a diameter of 10 mm on the wet pigskin, and the tablet-like preparation for oral mucosa was applied as it was by applying a load of 10 g/3.14 cm 2 for 10 minutes. In addition, dimensions a to d in FIG. 2 are a
=100mm, b=80mm, c=60mm, d=10
mm, the thickness of the stainless steel plate is 3 mm, and SU
A material made of S304 was used. According to the dissolution test method 2 of the Japanese Pharmacopoeia General Tests, this stainless steel plate was submerged in the bottom of a container containing 600 ml of physiological saline as the test solution with the formulation facing up, and the test was performed at 100 revolutions per minute. conduct, 1
The properties of the preparation were observed after 6 and 24 hours. Table 2 shows the properties of each preparation for oral mucosa application at each time. In Comparative Example 3, only the non-mucosal adhesive base was peeled off.

[0024]

[Table 2]

As is clear from Table 2, the comparison of the moisture resistance between Example 1 and Comparative Example 1, Example 3 and Comparative Example 2, and Example 5 and Comparative Example 3 shows that the formulation for oral mucosa of the present invention It has very high water resistance, and since it was applied to pig skin under rotating battle conditions, it is recognized that it has excellent durability and can be applied to wet surfaces for long periods of time. In addition, Example 1 and Example 2
From the comparison, it is recognized that the moisture resistance is improved by adding the weakly basic organic carboxylate. Also,
From a comparison between Example 4 and Example 5, it was found that by laminating a water-insoluble or poorly soluble polymer layer on a mucosal adhesive base,
It is recognized that water resistance and durability are improved. From the results of Examples 6, 7, and 8, the water resistance of the preparation for oral mucosa application of the present invention is very high, and since it is applied to pig skin under rotating battle, it has excellent durability and can be used for a long time. It is confirmed that it can be applied to wet surfaces. In addition, in Comparative Example 3, only the mucosal non-sticking base was peeled off and present. For the preparations for oral mucosa application obtained in Examples 1 to 8 and Comparative Examples 1 to 3, a drug permeation test on the excised skin of hairless mice was conducted by the method shown in Experiment 3.

Experiment 3 First, the diffusion cell 6 shown in FIG. 3 was prepared. The 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 in the center of the bottom wall of the donor tank 7, and an upper flange 10 and a lower flange 1 are provided at the lower end of the donor tank 7 and the upper end of the receptor tank 8, respectively.
1 is provided. Then, by overlapping the upper flange 10 and the lower flange 11 so as to face each other, the donor tank 7 and the receptor tank 8 are made airtight.
and are stacked concentrically. A sampling port 12 projecting laterally is attached to the side of the receptor tank 8, and a magnetic stirrer 13 is placed inside the receptor tank 8. Hairless mouse (8 weeks old,
After sacrificing the male (male) by cervical dislocation, the skin was immediately peeled off and subcutaneous fat was removed to obtain a skin piece of approximately 5 cm x 5 cm. This piece of skin 14 is sandwiched 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
was completely closed with a piece of skin 14. On the upper surface of the skin piece 14, for a film-like preparation for oral mucosa application, a diameter of 1
The tablet was punched out to a size of 0 mm, and the tablet formulation for oral mucosa was attached as it was as test piece 15. The receptor tank 8 was filled with a receptor liquid prepared by the method described below. Next, the diffusion cell 6 was placed in a constant temperature bath maintained at a temperature of 37° C., and the receptor liquid was stirred using a magnetic stirring device. After the start of the test, 1 ml of the receptor fluid was collected from the sampling port 12, and the amount of drug permeated into this receptor fluid was measured by high performance liquid chromatography. Table 3 shows the measured values of the amount of permeation for each patch. Preparation method of receptor fluid NaH2 PO4 (5 x 10-4 mol), Na2 H
PO4 (2 x 10-4 mol), NaCl (1.5 x 1
0-4 mol) and 10 mg of gentamicin in 50 ml of distilled water.
0ml, and the pH of the resulting solution was adjusted to 0.1N Na.
After adjusting the volume to 7.2 with an OH aqueous solution, the volume was made up to 1000 ml with distilled water.

[0027]

[Table 3]

As is clear from Table 3, from the comparisons between Example 1 and Comparative Example 1, Example 3 and Comparative Example 2, and Example 5 and Comparative Example 3, in the case of the preparation for oral mucosa of the present invention, vinyl Better drug release properties are observed compared to the case of pyrrolidone polymer alone. This is because, compared to the vinyl pyrrolidone polymer alone, the preparation for oral mucosa application of the present invention has a higher degree of swelling when absorbing water, making it easier for the drug to diffuse through the mucosal adhesive base. it is conceivable that. Also, Example 2
, 4, 6, 7, and 8, it is similarly recognized that the oral mucosal preparation of the present invention has good drug release properties for each drug. For the oral mucosal preparations obtained in Examples 2, 3, and 5, a drug permeation test for humans was conducted using the method shown in Experiment 4. Experiment 4 For the film-like preparation for oral mucosa application, the diameter was 10 mm.
The tablets were punched out, and the oral mucosa preparation of the tablet was applied as it was to the oral mucosa of five subjects to measure the peeling time and also observe the foreign body sensation. Table 4 shows the average time taken for each preparation for oral mucosa to peel off.

[0029]

[Table 4]

[0030] As is clear from Table 4, all of them adhere to mucous membranes for a long time, and it is confirmed that the preparation for oral mucosa of the present invention has good adhesion, water resistance, and durability. . Regarding the foreign body sensation, in the case of the film, there was no foreign body sensation immediately after application, and in the case of the tablet, there was a slight foreign body sensation at the initial stage of application, but there was no foreign body sensation after swelling after absorbing water.

[0031]

As described above, according to the present invention, since the vinylpyrrolidone (co)polymer is blended into a mucosal adhesive base, it can be applied locally to the oral mucosa by absorbing saliva or secretions. can be attached reliably. Therefore, it is possible to reliably apply the drug directly and locally to the oral cavity or surrounding diseased areas, or to effectively protect the affected areas. In addition, in the present invention, since a (meth)acrylic acid copolymer is blended in addition to the vinylpyrrolidone (co)polymer, saliva or secreted fluid is absorbed, and the vinylpyrrolidone (co)polymer and (meth)acrylic acid copolymer are absorbed. It becomes gel-like and swells due to the interaction of the acrylic acid copolymer. As a result, since the drug is gradually released, it is possible to continue administering the drug to the applied disease site or absorption site over a long period of time, and to protect the affected area. Furthermore, since the gel-like body has excellent water resistance and durability, it does not dissolve and flow out. Therefore, it has sufficient flexibility under swelling and also has excellent shape retention, so it can be used without giving a foreign body feeling even when it is attached to the oral cavity for a long time.

[Brief explanation of the drawing]

FIG. 1 is a perspective view showing a stainless steel jig and a stainless steel stand used to test the adhesion of a preparation for oral mucosa to wet pig skin.

FIG. 2 is a plan view showing a stainless steel plate used to test the durability of oral mucosal preparations.

FIG. 3 is a perspective view showing a diffusion cell used to test the skin permeability of a drug contained in an oral mucosal preparation.

[Explanation of symbols]

1... Stainless steel jig, 2... Stainless steel stand, 3... Moist pork skin, 4... Preparation for application to oral mucosa, 5... Stainless steel plate, 6... Diffusion cell, 7... Donor tank, 8... Receptor tank, 9... Opening part,
10...Upper flange, 11...Lower flange, 12...Sampling port, 13...Magnetic stirrer, 14...Skin piece,
15...Test piece.

Claims (2)

[Claims] [Claim 1] The mucosal adhesive base is vinylpyrrolidone (
co)polymer and a (meth)acrylic acid copolymer, and the weight ratio of the vinylpyrrolidone (co)polymer and the (meth)acrylic acid copolymer is 99:1 to 50:50. A preparation for oral mucosa application, characterized in that the vinylpyrrolidone (co)polymer is soluble in water and/or alcohol. [Claim 2] The mucosal adhesive base is vinylpyrrolidone (
co)polymer, a (meth)acrylic acid copolymer, and a weakly basic organic carboxylate, the weight ratio of the vinylpyrrolidone (co)polymer to the (meth)acrylic acid copolymer being 99:1 to 50:50, the vinylpyrrolidone (co)polymer is soluble in water and/or alcohol.