JP2959833B2 - Sustained-release oral disease therapeutic agent and method for producing the same - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to a therapeutic agent for a sustained-release oral disease for use in the treatment of periodontal disease, pulpitis, etc., which is used by inserting it into periodontal pockets, periodontal sites, pulp, etc. And its manufacturing method.

BACKGROUND ART With the development of basic research centering on bacteriology, it is said that bacteria in subgingival plaque is one of the causes of periodontal disease. On the other hand, it has also been reported in clinical terms that a significant therapeutic effect can be recognized if deposits on the root surface such as subgingival plaque and subgingival mycelia are thoroughly removed.

However, no method has been established for controlling subgingival plaque that is important in the treatment of gingival disease. In recent years, the following methods have been reported as methods for controlling subgingival plaque.

A method of perfusing or injecting a bacterial solution into a pocket [JH Hardy, NH Newman, JDStrahan; J. Clinical Peri
odontology: 9, 57-65, (1982)].

Injection of antibiotic gel [Yuka Naora et al., Periodontal Journal 29,2,484 (1987), Osamu Isojima et al., Periodontal Journal 29,2,472
(1987), Yoji Murayama et al., Japanese Journal of Periodontology 30,1,206 (1988)].

A method of containing a bactericide in a strip made of a water-insoluble polymer substance, placing the strip in a periodontal pocket, and sterilizing anaerobic bacteria in the pocket [M. Addy, Periodontal Novembe
r, 693 (1982)].

Method of inserting a film or sheet containing a water-soluble film containing a drug for treating periodontal disease into a periodontal pocket (Japanese Patent Laid-Open Nos. 59-222406, 62-223112, 62-223112)
-223113, 62-223114).

However, in the above methods, the medicine cannot reach the bottom of the periodontal pocket.

In the method of the above, since the polymer substance is insoluble in water,
There is a problem of irritating the affected area.

In the method of (1), the base water-soluble polymer easily swells and dissolves due to exudate in the pocket, saliva, etc., so that the base falls off from the pocket or the drug release from the base is high. There were problems such as too much.

On the other hand, there is a similar problem in the treatment of pulpitis, and it has been desired to develop a preparation that can reliably administer a drug to the pulp and that can release the drug slowly.

Problems to be Solved by the Invention The present invention solves the above-mentioned problems (1) to (4), in which the base material reaches the bottom of the pocket and the pulp, and suppresses swelling and dissolution, so that the base material remains in the pocket and pulp for a long time It is an object of the present invention to provide a sustained-release therapeutic agent for oral diseases in which the drug is retained and the release of a drug from a base is controlled, and a method for producing the same.

The therapeutic agent for sustained release oral disease of the present invention contains a water-soluble polymer other than the anionic water-soluble polymer and a metal salt capable of forming a cross-linkable or poorly water-soluble salt with the anionic water-soluble polymer. A layer-structure base obtained by laminating the layer A and the layer B containing a nonionic water-soluble polymer and an anionic water-soluble polymer is made to contain a substance effective for treating oral diseases. The crosslink is formed by the metal salt of the layer and the anionic water-soluble polymer of the layer B, or a poorly water-soluble salt is formed.

This sustained-release therapeutic agent for oral diseases is formed by casting a solution for forming an A layer containing the component of the A layer and a solution for forming a B layer containing the component of the B layer, and removing the solvent. It is obtained by forming the layered film and the layered B film into a laminate of two or three or more layers and then curing.
Substances effective for treating oral diseases include layer A and / or B
It is blended in the layer forming solution. The film laminate can be manufactured, for example, by the following method.

On the film surface of the layer A, the solution for forming the layer B is cast and the solvent is removed, or the solution for forming the layer A is further cast and the solvent is removed, and the A: B2 layer laminated film or A: B: A3 layer laminated Form a film.

On one side of the layer B film, the solution for forming the layer A is cast,
After removing the solvent, or further, the solution for forming the A layer is cast on the remaining one surface of the B layer film, and the solvent is removed to form an A: B 2 layer laminated film or an A: B: A 3 layer laminated film.

The solution for forming the A layer and the solution for forming the B layer are separately cast, the solvent is removed, and the A layer film and the B layer film are separately formed. A film or an A: B: A three-layer laminated film is formed.

B: A: B 3 layer laminated film and 4 or more layer laminated film
It can be manufactured by applying the above method.

Since the therapeutic agent of the present invention is based on a water-soluble polymer, it can be formed into a flexible film and can be inserted into periodontal pockets and pulp without discomfort. Further, after insertion, the metal salt of the layer A dissolved by the exudate in the pocket, saliva and the like and the anionic water-soluble polymer of the layer B form a cross-link, or form a poorly water-soluble salt, thereby forming a base having a multilayer structure. Swellability and solubility are suppressed. As a result, the retention of the base material in the pocket or the pulp is improved, and the sustained release of the drug and local sustainability are realized.

 Hereinafter, the present invention will be described in more detail.

The therapeutic agent for sustained release oral disease of the present invention has a laminated structure of A layer and B layer. The number of layers in this multi-layer structure may be two or more, and the upper limit is not particularly limited. However, in terms of easiness of the manufacturing method and manufacturing cost, a two-layer (A: B) or three-layer structure Is preferred. In the case of three or more layers, the outermost layer on both sides is preferably an A layer, and in the case of a three-layer structure,
The laminated structure of A: B: A is preferable. This type is excellent in the effect of suppressing swelling and solubility after insertion into a pocket or the like, has good retention of a base, and has good sustained release properties and local sustainability of a drug.

The thickness of each of the layer A and the layer B is preferably 10 to 1000 μm. Further, the thickness of the entire multilayer structure is desirably 1200 μm or less, and more preferably 200 to 500 μm.

When the film thickness of the layer A is less than 10 μm, the content of the metal salt is small, and it is difficult to control the swelling and solubility of the base material sufficiently. When the thickness of the B layer is less than 10 μm,
The amount of the anionic water-soluble polymer that is crosslinked or forms a poorly water-soluble salt is reduced, and sufficient sustained release of the drug cannot be obtained.

If the total thickness of the multi-layered structure base exceeds 1200 μm, it is difficult to insert it into the periodontal pocket, and even if it can be inserted, it does not reach the bottom of the pocket or gives painful stimuli and discomfort to the affected area It has the difficulty of being easy.

The B layer contains both a nonionic water-soluble polymer and an anionic water-soluble polymer as a base. The mixing ratio of (a) the nonionic water-soluble polymer to (b) the anionic water-soluble polymer is preferably in a range of (a) / (b) = 30/70 to 95/5 by weight, more preferably. Is 40/60 to 85/15. When the compounding ratio is less than 30/70, the compatibility of the nonionic water-soluble polymer and the anionic water-soluble polymer in the dried film is reduced, a flexible film is hardly formed, and the metal salt is hardly formed. Even when a cross-linking reaction occurs, it is difficult to sufficiently suppress the swelling and solubility of the base because the number of dissociable groups of the anionic polymer is large.

On the other hand, if the compounding weight ratio exceeds 95/5, the number of dissociated groups is too small, the cross-linking density does not increase, and the swelling and solubility of the entire multilayer structure base cannot be sufficiently suppressed. Poor sustained release.

Specific examples of the nonionic water-soluble polymer used for the layer B include the following, which may be used alone or in combination of two or more.

・ Methylcellulose, hydroxypropylcellulose,
Cellulose lower alkyl ether compounds such as hydroxypropylmethylcellulose ・ Vinyl compounds such as polyvinylpyrrolidone and polyvinyl alcohol ・ Polysaccharides such as pullulan and starch and derivatives thereof ・ Polyacrylamide ・ Polyethylene oxide ・ Polyoxyalkylenes such as high molecular weight polyethylene glycol Specific examples of the anionic water-soluble polymer used for the layer B include the following, which may be used alone or as a mixture of two or more.

・ Carboxyvinyl polymer ・ Salts such as carboxymethylcellulose and carboxymethylcellulose calcium ・ Salts such as polyacrylic acid and sodium polyacrylate ・ Salts such as alginic acid, sodium alginate, ammonium alginate, and triethanolamine alginate ・ Tragant ・ Methacrylic acid, Copolymers of styrene or vinyl-type ether monomers and the like copolymerized with acrylic acid and salts thereof In addition, a water-soluble polymer other than those described above can be blended in the B layer. For example, one or more of the following are added: .

-Polypeptides such as gelatin-Guar gum-Gum arabic-Chitin, chitosan On the other hand, the layer A contains a water-soluble polymer and a water-soluble metal salt as bases.

As the water-soluble polymer of the A layer, a water-soluble polymer other than the anionic water-soluble polymer that can be used for the B layer is suitably used alone or in combination of two or more. Does not produce metal salts and insolubles,
If the layer A film does not become uneven after removing the solvent, a small amount of an anionic water-soluble polymer may be used.

The amount of the water-soluble polymer in the layer A or B is not particularly limited as long as the layer or film can be formed.

As the metal salt of the layer A, any type of metal salt can be used as long as it forms a crosslink with the anionic water-soluble polymer added to the layer B or forms a poorly water-soluble salt. Magnesium, calcium,
Divalent or higher valent inorganic or organic metal salts such as barium, zinc, copper, iron, aluminum and tin are preferred. In particular, the following are described in official documents such as the local government and have excellent safety.

Magnesium salt: magnesium chloride, magnesium sulfate, magnesium acetate, magnesium oxide, magnesium carbonate Calcium salt: calcium chloride, calcium sulfate, calcium citrate, calcium hydroxide, calcium pantothenate, calcium propionate, calcium gluconate, calcium acetate, shu Calcium acid, calcium phosphate, calcium carbonate, calcium oxide, calcium acid pyrophosphate Barium salt: barium chloride, barium oxide Zinc: zinc chloride, zinc sulfate, zinc gluconate, zinc acetate Copper: copper gluconate, copper citrate, cupric acetate , Copper chlorophyllin sodium iron: ferrous chloride, ferric chloride, sodium ferrous citrate, sodium iron citrate, ammonium ammonium citrate, ferrous gluconate, iron gluconate, iron chloride Villingen sodium, iron pyrophosphate, aluminum: aluminum chloride, aluminum alum, potassium alum tin: stannous other chloride, antacids that contain metal, e.g. alk Mack also Gurishinaru like.

The above-mentioned metal salts can be used as one kind or a mixture of two or more kinds. The amount of the metal salt used is appropriately determined depending on the kind and the amount of the anionic water-soluble polymer blended in the B layer.
Usually, it is preferable to add 0.5 to 20% by weight in the A layer.

In the therapeutic agent for sustained release oral disease of the present invention, a substance effective for the treatment (including prevention) of oral diseases such as periodontal disease, pulp disease and the like is blended in both or one of the layers A and B. Is done. These active substances are most preferably incorporated in both the A and B layers, and when incorporated in only one of the layers, it is desirable to be incorporated in the B layer. By being blended in both A and B layers, the active substance in the outermost layer A exhibits a rapid effect, and the active substance in the layer B exhibits a sustained release effect.
When compounded only in the B layer, it has a small immediate effect, but exhibits a sustained release effect. When compounded only in the layer A, the quick-acting effect is exhibited, but the sustained-release property is reduced.

These substances are used alone or in combination of two or more. The amount of the substances is appropriately determined depending on the strength of the pharmacological action of the drug, the symptoms of the target disease, and the like. Among the active substances, a drug having a bactericidal action, a drug having an antibacterial action, a drug having a plaque dissolving action, a drug having a local anesthetic action, a drug having an anti-inflammatory action, and a drug having an antihistamine action are particularly preferable. The specific examples are as follows.

(1) Drug having bactericidal action Chlorhexidine or hydrochloride, methylosal, silver protein, chloramine, iodoglycerin, iodoform, boric acid, paraformaldehyde, phenol, hexylresorcin, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, bromide Phenododecium, decalinium chloride, cetylpyridinium chloride, ofloxacin, pompidone iodine and the like.

(2) Drugs having antibacterial activity Tetracycline, tetracycline hydrochloride, benzylpenicillin, ampicillin, carpenicillin, acetylkitasamycin, amoxicillin, pacitracin, cefarotin sodium, cefarolidin, cefalexin, erythromycin, chloramphenicol, oxytetracycline hydrochloride, Doxycycline hydrochloride, polymyxin B sulfate, fradiomycin sulfate, gentamicin sulfate, minocycline hydrochloride and the like.

(3) Drug having plaque dissolving action Lysozyme chloride, amylase, dextranase, protease and the like.

(4) Drugs acting as local anesthetics Procaine hydrochloride, oxyprocaine hydrochloride, tetracaine hydrochloride, chloroprocaine hydrochloride, ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, cocaine hydrochloride, thecaine and the like.

(5) Drugs having anti-inflammatory activity Sulfirin, antipyrine, aspirin, phenylbutazone, mepyrizole, oxyfenbutazone, fenbufen, mefenamic acid, flurbibrofen, diclofenac sodium, ketoprofen, nabroxen, tiaramid hydrochloride, pendidamine hydrochloride, alclofe Nac, Ibufenac, Perisosasar Citrate, Ibuprofen, Indomethacin, Aluminum Flufenamic Acid, Tinolidine Hydrochloride, Clofezone Protidic Acid,
Dexamethasone, triamcinolone acetonide, prostaglandin, isotipendyl hydrochloride, mefenamic acid, bufexamac, hydrocortisone, prednisolone, fluonosinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone acetate, betamethasone valerate
Flumethasone and the like.

(6) Antihistamines diphenhydramine hydrochloride, chlorpheniramine maleate, clemastine and the like.

Further, in the therapeutic agent of the present invention, various additives can be blended in the A layer or the B layer as needed. Examples of these are as follows.

1) Plasticizer: polyethylene glycol (200 to 600
0), glycerin, propylene glycol, 1,3-butylene glycol, sorbit, ethylene oxide / propylene oxide copolymer, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, ethylene glycol, dipropylene glycol, triacetin, spun type Fatty acid lauric acid and the like.

2) Colorant: tar dye and the like.

3) Flavoring agents: natural or synthetic flavors, saccharin,
Citric acid, fumaric acid, menthol, peppermint oil, tartaric acid, aspartame, etc.

4) Dissolution modifiers: higher fatty acids such as shellac, stearic acid and palmitic acid, water-insoluble polymers such as ethyl cellulose, pH-sensitive polymers such as Eudragit E, L, S, higher alcohols such as cetanol, and HLB1-8 Inorganic powders such as lipophilic surfactants and titanium oxide.

5) Stabilizers: vitamin C, vitamin E, sodium sulfite, sodium pyrosulfite, sodium bisulfite, butylhydroxytoluene, propylpyrrole, butylhydroxyanisole and the like.

The shape of the therapeutic agent of the present invention is appropriately determined depending on the application site. For example, when inserted into a periodontal pocket or a periodontal portion, the shape is preferably a film shape, a sheet shape or a rod shape, and when inserted into a dental pulp, a rod shape is preferable. In addition, the size of the therapeutic agent is determined by the size and condition of the affected part, but usually, for pocket insertion, a width of 0.5 to 2.0 mm and a length of 3 to
It is generally 15 mm and 0.02 to 1.2 mm thick. on the other hand,
For pulp insertion, width 0.1-1.5mm, length 0.5-5mm, thickness 0.
02 to 1.0 mm.

Next, the method for producing the sustained-release oral therapeutic agent of the present invention will be described.

The multilayer structure base of the present invention comprises the following solution for forming layer A and B
Layer forming solutions can be individually prepared, cast and dried by a wet method. The substance effective for the treatment of oral diseases is mixed in one or both of the following solutions.

A layer forming solution: a solution containing a metal salt, a water-soluble polymer, and an additive compounded as required.

B-layer forming solution: a solution containing a nonionic water-soluble polymer, an anionic water-soluble polymer, and additives to be added as required.

Hereinafter, a case of producing a preparation having a three-layer structure of A: B: A layer will be described as an example. In the case of two layers, one layer can be omitted, and in the case of four or more layers, the same operation can be repeated. In the following three production methods, Production Method I is suitable, and these can be selected or combined as needed.

(1) Production Method I The solution for forming the A layer, the solution for forming the B layer, and the solution for forming the A layer are sequentially cast and solvent-separated in this order to form a three-layer film. By curing this film, a therapeutic agent having a three-layer structure of A: B: A is obtained.

(2) Production method II A solution for forming the B layer is cast and the solvent is removed to form a B layer film. The solution for forming the layer A is cast on one side of the layer B film, the solvent is removed, and the solution for forming the layer A is cast on the remaining side of the film, and the solvent is removed to form a three-layer film. Ring.

(3) Production method III The solution for forming the A layer and the solution for forming the B layer are separately cast, and the solvent is removed.
It is manufactured by stacking and laminating in order of layer and layer A, and then curing.

Among the above, the production method I requires a little production time because the film is continuously laminated, but the operation method is easy and the production method is excellent.

In the manufacturing method II, after laminating two layers of A: B, A
When the layer forming solution is cast and dried, the three-layer laminated film having a uniform thickness cannot be obtained unless the two-layer laminated film of A: B is firmly fixed to the horizontal plate by vacuum suction or the like. With difficulty.

The production method III has a feature that the multilayer film can be manufactured in a short time because the layer A film and the layer B film can be dried at the same time. However, it is not technically easy to bond them so that air is not mixed. The bonding can be performed by applying a constant pressure, and in some cases, the bonding can be increased by heating. Specifically, pressure bonding is performed using a press plate, a roller, or the like. In order to improve the adhesive strength, a solvent such as water or ethanol may be applied between the films, or an adhesive may be applied to integrate the films.

It is also possible to produce by a combination of production methods I and III. After making two A: B two-layer films by the manufacturing method I,
By bonding the B layer surfaces together, a three-layer film of A: B: A can be prepared (Strictly speaking, this is a four-layer film of A: B: B: A, but since the B-layer film has the same composition, Interpreted as a three-layer film). This manufacturing method
It has the advantage that a uniform three-layer film can be prepared in a shorter time than the production method II.

Solvents that can be used for preparing the solution for forming the layer A or the layer B include water, methanol, ethanol, isopropanol, acetone, methylene chloride, cellosolve, and the like, and these are used alone or as a mixed solvent. From the viewpoints of solubility and safety of the water-soluble polymer and drug used, water, ethanol or a mixed solvent thereof is preferred.

Further, in the case of the production methods I and II, when the solution for forming the A layer is cast on the film surface of the B layer, the anionic water-soluble polymer in the B layer film dissolves and the metal in the solution for forming the A layer is dissolved. It is desirable to suppress the reaction with the salt. If this reaction proceeds too much, the interface will undergo phase separation and become non-uniform. For this reason, it is desirable that the poor solvent of the anionic water-soluble polymer is used as the solvent of the solution for forming the A layer. For example, when a water-ethanol mixed solvent is used, the blending amount of ethanol is 30% by weight or more. .

As the casting method, a method of uniformly casting on a metal plate, a glass plate, a plastic plate, a Teflon plate or the like is adopted.

The drying method is appropriately selected depending on the stability of the drug used. For example, room temperature drying, air drying, heat drying, low temperature drying, reduced pressure drying (middle to reduced pressure of 50 mmHg or more), and reduced pressure heating drying (middle to 50 mmHg or more) Low pressure reduction), low pressure low temperature drying (50mmHg)
Medium to reduced pressure).

The final curing of the multi-layer structure base material is drying at room temperature using a desiccant and drying under reduced pressure at room temperature (high vacuum degree less than 50 mmHg)
Alternatively, drying can be performed by heating under reduced pressure (high degree of reduced pressure of less than 50 mmHg) to thoroughly remove water and stabilize the active ingredient.

The therapeutic agent of the present invention comprising a multi-layered structure base can be produced by a production method other than the above-mentioned casting-drying method, for example, adopting a calendering method, a melt extrusion method, a wet extrusion method, a graft printing method and the like. it can.

Effects of the Invention According to the therapeutic agent for sustained release oral disease of the present invention, the base can reliably reach the bottom of the periodontal pocket with less discomfort, and the swelling property of the base after insertion, Since the solubility can be suppressed, the base can be retained in the periodontal pocket for a long time, the release of the drug from the base can be controlled, and the drug effect can be expressed locally for a long time. It is possible to realize a fundamental remedy for periodontal disease.

Similarly, for other oral diseases such as acute and chronic pulpitis, the drug can be reliably administered to the site of inflammation and the like, and the release of the drug can be controlled, which is useful for treatment of pulpitis and the like.

Examples / Experimental Examples Comparative Example 1 100 parts by weight of a 2% aqueous solution of hydroxypropylcellulose having a viscosity of 2,000 centipoise at 20 ° C. and 1 part by weight of chlorhexidine gluconate were slowly added to 1250 ml of ethanol and dissolved by stirring. The mixture was allowed to stand overnight to defoam, then cast on a clean glass plate to have a uniform thickness using a doctor knife, air-dried, and then forcibly dried at 40 ° C to obtain a film-form preparation having a thickness of 300 µm. The chlorhexidine gluconate concentration of this preparation was 1.0% by weight. In the following, unless otherwise specified, it is based on weight.

Example 1 (1) Preparation of solution A layer forming solution: The following components were dissolved and dissolved in 140 g of ethanol.

Hydroxypropylcellulose 8.4 g Glycerin 1.0 g Zinc chloride 0.5 g Chlorhexidine gluconate 0.1 g B layer forming solution: Prepared by dissolving the following components in 140 g of water.

Hydroxypropylcellulose 6.9 g Sodium alginate 1.0 g Alginate 1.0 g Glycerin 1.0 g Chlorhexidine gluconate 0.1 g (2) Preparation of multilayer film (therapeutic agent of the present invention) The solution for forming layer A was poured on a polyethylene terephthalate sheet placed horizontally. About 100mmHg at room temperature
The film is dried under reduced pressure at a reduced pressure to prepare a layer A film. The solution for forming the layer B is cast on the film surface of the layer A, and the temperature is 20 to
It was air-dried in an atmosphere at room temperature of 70%. The resulting two-layer laminated film was dried under reduced pressure at 60 ° C. for 1 hour (about 5 mmH
g) to obtain a therapeutic agent of the present invention comprising a multilayer structure film.
The thickness of each of the A and B layers was 150 μm, and a transparent and flexible one having a total thickness of 300 μm could be produced. The chlorhexidine gluconate concentration of this formulation was 0.98%.

Example 2 After forming a two-layer laminated film in the same manner as in Example 1,
Further, the solution for forming the layer A was cast on the film surface of the layer B, dried, and dried under reduced pressure at 60 ° C. for 1 hour to prepare a multilayer structure film (therapeutic agent) comprising a three-layer laminated film of A: B: A. . The thickness of each of the A and B layers was 100 μm, and a transparent and flexible layer having a total thickness of 300 μm was obtained. The chlorhexyl gluconate concentration of this formulation was 0.99%.

Experimental Example 1 The preparations obtained in Comparative Example 1 and Examples 1 and 2 were cut into a width of 1 mm and a length of 10 mm, and inserted into periodontal pockets of 10 patients with alveolar pyorrhea. The leachate in the pocket was collected, and the remaining chlorhexidine gluconate was quantified by high performance liquid chromatography. The results are as shown in Table 1.

In a multi-layered preparation having two or more layers consisting of a layer A containing a metal salt and a water-soluble polymer and a layer B containing an anionic water-soluble polymer, a sustained release / local sustained effect of the drug was observed.

Also, using the solution for forming the A layer and the B layer used in Examples 1 and 2, and preparing the same two-layer or three-layer type multi-layered preparation as in Examples 1 and 2 according to the above-mentioned production method II or III. As a result, similarly, sustained release and local persistence of the contained chlorhexidine gluconate were confirmed.

Comparative Examples 2 and 3, Examples 4 to 7 and Experimental Example 2 As shown in Table 2 below, the composition of both A and B layers was changed.
According to the same procedure as in Example 2, a therapeutic agent for oral diseases comprising a three-layered laminated film of A: B: A was prepared.

Next, the same evaluation as in Experimental Example 1 was performed, and tetracycline hydrochloride remaining in the exudate in the periodontal pocket was quantified by bioassay, and the results are shown in Table 3 below (Experimental Example 2).

Comparative Example 2 in which the metal salt was not added to the A layer and Comparative Example 3 in which the metal salt was added to the A layer but the anionic water-soluble polymer was not added to the B layer had low local persistence of the drug.

The combination of a water-soluble polymer containing a metal salt (layer A) and a layer B blended with an anionic polymer showed sustained release and local persistence of the drug (Examples 4 to 7).

Comparative Example 4, Examples 8 to 11 and Experimental Example 3 A therapeutic agent for oral diseases comprising a three-layered film of A: B: A having the composition shown in Table 4 below was prepared.

For these, the same evaluation as in Experimental Example 1 was performed, and minocycline hydrochloride remaining in the exudate in the periodontal pocket was quantified by bioassay (Experimental Example 3).
It was shown to.

When the mixing weight ratio of the nonionic polymer / anionic water-soluble polymer in the B layer was in the range of 30/70 to 95/5, remarkable sustained release and local persistence were observed.

If it is less than 30/70, the swellability and solubility of the anionic water-soluble polymer cannot be sufficiently suppressed by metal ions. On the other hand, if it exceeds 95/5, the amount of the anionic water-soluble polymer to be cross-linked is small, so that the solubility of the base material cannot be sufficiently suppressed and the sustained release of the drug becomes low.

Comparative Example 5, Examples 12 to 14, Experimental Example 4 A therapeutic agent for oral diseases comprising an A: B: A three-layer structure film having the composition shown in Table 6 below was prepared.

These were evaluated in the same manner as in Experimental Example 1, and the amount of tetracycline hydrochloride remaining in the exudate in the periodontal pocket was quantified by a bioassay (Experimental Example 4).
It was shown to.

As the amount of the anionic water-soluble polymer in the layer B increased, the residual amount of tetracycline hydrochloride in the exudate in the periodontal pocket increased.

Comparative Examples 6 and 7, Examples 15 and 16, and Experimental Example 5 A therapeutic agent for oral diseases comprising an A: B: A three-layer structure film having the composition shown in Table 8 below was prepared.

The formulations of Examples 15 and 16 were evaluated in the same manner as in Experimental Example 1, and ofloxacin remaining in the exudate in the periodontal pocket was quantified by bioassay. The results are shown in Table 9 (Experimental Example 5).

When the metal salt is mixed with the anionic polymer of the layer B, a metal salt of an anionic water-soluble polymer which is hardly soluble in water is formed, and the phase is separated from the polyvinylpyrrolidone of the water-soluble polymer. Becomes non-uniform (Comparative Examples 6 and 7).

On the other hand, if a metal salt is blended into the A layer and separated and blended with the anionic polymer in the B layer, a uniform B layer film and three layer film can be prepared (Examples 13 and 14).

Further, when the preparations of Examples 15 and 16 were inserted into the human periodontal pocket, the metal salt of layer A dissolved by the exudate in the pocket and the anionic water-soluble polymer of layer B formed a crosslinked or poorly soluble salt. Suppress the swelling and solubility of the three-layer base,
Thereby, the retention property of the base material in the pocket was improved, and the local persistence of the drug became possible.

The blending amount of the metal salt is not particularly limited, but the greater the blending amount of the metal salt, the higher the local persistence (Table-9).

Comparative Example 8, Examples 17 to 20 and Experimental Example 6 A therapeutic agent for oral diseases comprising an A: B: A three-layer structure film having the composition shown in Table 10 below was prepared.

These were evaluated in the same manner as in Experimental Example 1, and tetracycline hydrochloride remaining in the exudate in the periodontal pocket was quantified by bioassay, and the results are shown in Table 11 (Experimental Example 6).

All of the three-layered preparations of Examples 17 to 20 have a film thickness of 400 μm.
The concentration of tetracycline hydrochloride is 3%,
The persistence of the drug in the periodontal pocket can be controlled by changing the compounding ratio of the drugs in the A layer and the B layer or changing the thickness of each film. For example,
When it is desired to release a large amount of a drug immediately after administration, the drug concentration in the A layer may be increased. Conversely, when it is desired to obtain a long-term drug release, the drug concentration in the layer B may be increased.

Comparative Example 9, Examples 21 and 22, and Experimental Example 7 A therapeutic agent for oral diseases comprising a three-layer film of A: B: A or B: A: B having the composition shown in Table 12 below was prepared.

For these, the same evaluation as in Experimental Example 1 was performed, and clindamycin hydrochloride remaining in the exudate in the periodontal pocket was quantified by a bioassay (Experimental Example 7).
13

In the case of a three-layered preparation, as in the three-layered preparation of A: B: A, the local persistence of the drug is higher when the layer A containing the metal salt is disposed on the outer layer and the layer B is disposed on the inner layer. This is because when inserted into the periodontal pocket, A
This is because the metal salt of the layer forms a crosslink with the anionic water-soluble polymer in the layer B before dissolution and effluent, and most of the base is likely to remain in the pocket.

On the other hand, in the case of a three-layer structure preparation composed of B: A: B, the anionic water-soluble polymer in the outer layer dissolves and flows out by the leaching solution before cross-linking with the metal salt in the inner layer. Is slightly inferior, and the local persistence of the drug is slightly lower.

Therefore, the local sustained effect is higher in the three-layered preparation composed of A: B: A than in B: A: B.

Comparative Example 10, Examples 23 to 25, and Experimental Example 8 A therapeutic agent for oral diseases comprising a three-layered film of A: B: A having the composition shown in Table 14 below was prepared.

These were evaluated in the same manner as in Experimental Example 1, and the amount of minocycline hydrochloride remaining in the exudate in the periodontal pocket was quantified by bioassay. The results are shown in Table 15 (Experimental Example 8).

All three-layer formulations of Examples 23-25 have a membrane thickness of 200
μm.

When the film thickness of the layer A and the layer B was 10 μm or more, sustained release and local persistence were recognized.

When the thickness of the layer A is less than 10 μm, the content of the metal salt is small, so that it is difficult to sufficiently control the swelling and solubility with respect to the base. The amount of the conductive polymer is small, and sufficient sustained release of the drug cannot be obtained.

Comparative Example 11, Example 26 A three-layer film of A: B: A having the composition shown in Table 16 below was prepared and cut into a width of 0.2 mm and a length of 2 mm to obtain a therapeutic agent for oral diseases.

As Comparative Example 12, the liquid preparations shown in Table 17 were prepared.

For these, the degree of injury is comprehensively evaluated in Experimental Example 9 described later.

Experimental Example 9 An 8-week-old male wistar rat was anesthetized with a dental diamond disc at the collapsed portion of one maxillary incisor, that is, almost at the level of the gingival crest, under anesthesia with Nembutal (0.1 ml / 100 g intraperitoneally). . Further, under a stereoscopic microscope, a hole having a diameter of 0.7 mm and a depth of about 1 mm was made in the pulp of the cut tooth with a dental drill, and the pulp was pierced about 1 mm with a hand reamer, thereby causing inflammation.

Next, the preparation of Comparative Example 11 or Example 26 was inserted into the dental pulp.

The solution of Comparative Example 12 was administered such that the drug solution reached the hole in the dental pulp.

Twenty-four hours after the induction of inflammation, dissections and incisors were removed, and specimens were prepared according to the following procedure.

1. Dissection, incisor removal 2. Bouin fixation (24-72 hours) 3. Decalcification (Plank-Rychoro solution, 24 hours) 4. Neutralization (5% sodium sulfate, 10-12 hours) 5. Rinse with running water ( Day and night) 6. Embedding (histomatic, 40-45 hours) 7. Slicing 8. Hematoxylin-eosin staining (HB staining) 9. Specimen completion The specimen is necrotic by HB staining. The range, the degree of cell infiltration, edema and bleeding of polymorphonuclear leukocytes is determined in five steps according to the criteria shown in Table 18 below,
Furthermore, a comprehensive judgment of the degree of injury was made for all items.

 Table 19 shows the overall judgment results.

[Overall Judgment] The scores of the four items were totaled and judged as follows.

Comprehensive judgment Total score of 4 items +++ 10 points or more ++ 8-9 points + 6-7 points ± 4-5 points −3 points or less As shown in the results of Example 26, when this drug was inserted into the pulp, the exudate from the pulp dissolved the A layer first,
Since the metal salt in the layer and the anionic water-soluble polymer in the layer B form a crosslinked or poorly soluble salt, the retention of the drug in the dental pulp has been improved, and local sustained release of the drug has become possible. A medicinal effect was observed.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 9/70

Claims (2)

(57) [Claims] 1. A layer containing a water-soluble polymer other than the anionic water-soluble polymer and a metal salt capable of forming a cross-linkable or poorly water-soluble salt with the anionic water-soluble polymer, and a nonionic water-soluble polymer And B containing anionic water-soluble polymer
In a layer structure base obtained by laminating layers, a substance effective for treating oral diseases is contained, and a crosslink is formed by the metal salt of layer A and the anionic water-soluble polymer of layer B during oral administration,
Alternatively, a sustained-release therapeutic agent for oral diseases characterized by forming a poorly water-soluble salt. 2. A layer-forming solution containing a water-soluble polymer other than an anionic water-soluble polymer and a metal salt capable of forming a cross-linkable or poorly water-soluble salt with an anionic water-soluble polymer; A solution for forming a B layer containing a conductive polymer and an anionic water-soluble polymer, in the order of a solution for forming an A layer and a solution for forming a B layer, or an order of a solution for forming a B layer and a solution for forming an A layer. Or, in order of the solution for forming the layer A, the solution for forming the layer B, and the solution for forming the layer A, successively casting and removing the solvent to form a multilayer structure film, and then curing, and At least one of the forming solution and the B layer forming solution contains a substance effective for treating an oral disease, and is administered by intraoral administration using the metal salt of the A layer and the anionic water-soluble polymer of the B layer. To form crosslinks, or A method for producing a sustained-release therapeutic agent for oral diseases, which comprises producing a layer-structured agent capable of forming a poorly water-soluble salt.