JPH0597708A - Treating agent for improving periodontitis - Google Patents

Abstract

PURPOSE:To provide a treating agent for improving periodontitis, exhibiting an excellent inhibitory effect on alveolar bone absorption caused by endotoxins of periodontitis pathogenic bacteria. CONSTITUTION:The objective treating agent for improving periodontitis, exhibiting the above-mentioned effect is obtained by mixing, as the active components, one or more components selected from an adenosine triphosphatase inhibitor such as acetazolamide, amiloride, ouabain, dibucaine or ethacrylic acid, a cysteine proteinase inhibitor such as E-64, E-64C, P-mercuribenzoic acid or antipain, a serine proteinase inhibitor such as diisopropyl fluorophosphate, tosylphenylalanyl chloromethyl ketone or chymostation and a protein kinase C inhibitor such as staurosporin, sphingosine, H-7, H-8 or H-9 in an amount of 0.000001-5wt.%, preferably 0.005-1wt.% therein. The frequency of dose of the above-mentioned agent to a patient as an indication of the dosage can be 1 to several times a day.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for periodontal disease, and more particularly to a therapeutic agent for periodontal disease which exerts an inhibitory effect on bone resorption by endotoxin of periodontopathic bacteria which is a main cause of alveolar bone resorption.

[0002]

BACKGROUND OF THE INVENTION Periodontal disease is caused by plaques formed by periodontopathic bacteria.
It is a disease in which the periodontal tissues such as gingiva and periodontal ligament are inflamed and eventually lead to absorption of alveolar bone, resulting in tooth loss.

Conventionally, prevention of inflammation of connective tissue of periodontal tissue,
For the treatment, plaque suppression by anti-plaque agents and anti-inflammatory agents are used.

On the other hand, as another method for treating periodontal disease, a method for actively suppressing the absorption of alveolar bone that supports teeth has been studied. For example, use of indomethacin, which is a prostaglandin synthesis inhibitor inhibitor, etc. Has been studied (J.
of Periodont. Res. 1983 (18)
110-117), the effect is not sufficient, and the development of a more effective alveolar bone resorption inhibitor is desired.

[0005]

Means for Solving the Problems and Actions The present inventor has conducted extensive studies on a therapeutic agent for periodontal disease having an alveolar bone resorption inhibitory effect in order to meet the above-mentioned demand, and as a result, adenosine triphosphatase inhibitor (hereinafter referred to as ATPase inhibitor) It was found that cysteine proteinase inhibitors, serine proteinase inhibitors, and protein kinase C inhibitors (hereinafter referred to as PKC inhibitors) are excellent in alveolar bone resorption inhibiting effect.

That is, ATPase inhibitors are conventionally known as diuretics, cardiotonics, etc., cysteine proteinase inhibitors and serine proteinase inhibitors are known as metabolism improving agents, and PKC inhibitors are used as intracellular signal transduction inhibitors. But A
TPase inhibitor, cysteine proteinase inhibitor, serine proteinase inhibitor, PK
The present inventors have found that the C inhibitor strongly suppresses bone resorption caused by endotoxin of periodontopathic bacteria, which is the main cause of alveolar bone resorption, unlike these applications, and has completed the present invention.

Therefore, the present invention provides a therapeutic agent for periodontal disease containing at least one selected from ATPase inhibitors, cysteine proteinase inhibitors, serine proteinase inhibitors and PKC inhibitors.

The present invention will be described in more detail below. The therapeutic agent for periodontal disease of the present invention comprises an ATPase inhibitor, a cysteine proteinase inhibitor, a serine proteinase inhibitor, P as an active ingredient for inhibiting alveolar bone resorption.
It comprises one or more KC inhibitors.

Here, as the ATPase inhibitor, acetazolamide, amiloride, ouabain, dibucaine, ethacrynic acid, digitoxin, digoxin, diphenidol, mesulfen, N-ethylmaleimide,
Examples thereof include myricetin, clofebrate, cinchonidine, quinoline and its derivatives, copiamycin A, bafilomycin Al and the like.

Examples of cysteine proteinase inhibitors include E-64, E-64C, p-mercuribenzoic acid, antipain and the like.

Examples of serine proteinase inhibitors include diisopropylfluorophosphate, tosylphenylalanyl chloromethyl ketone, chymostatin and the like.

Examples of PKC inhibitors include staurosporine, sphingosine, H-7, H-8, H-9, calfostin C, K-252a, K-252b and KT5.
720, KT5823, KT5926, R59022,
Examples include genistin, halomethyl ketone, tyrphostin, herbimycin and the like.

The therapeutic agent for periodontal disease of the present invention is prepared by adding to the one or more of the above-mentioned active ingredients a excipient or an adjuvant which is commonly used as a preparation for the oral cavity. Peripheral pocket insert, oral gel formulation, oral mucoadhesive ointment,
It can be prepared and applied in a dosage form such as a gingival adhesive tape preparation and an oral pasta preparation.

In this case, the content of the above-mentioned active ingredient in the therapeutic agent for periodontal disease is preferably 0.000001 to 5% (weight%, the same shall apply hereinafter), particularly 0.005 to 1%. , The dose is 1 per day as the number of times of administration to the affected area.
It can be several times to several times.

In the therapeutic agent for periodontal disease of the present invention, those which are preferably used as the above-mentioned excipients or auxiliary agents include cellulose such as methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, lower alkyl ether compounds, polyvinyl. Vinyl compounds such as pyrrolidone and polyvinyl alcohol, polysaccharides and derivatives thereof such as pullulan and starch, polyoxyalkylenes such as polyacrylamide, polyoxyethylene oxide, and high molecular weight polyethylene glycol, carboxyvinyl polymer, carboxymethyl cellulose, carboxymethyl cellulose calcium, etc. , Salts of alginic acid, sodium alginate, ammonium alginate, triethanolamine alginate, tragacanth gum, methacrylic acid, suture Copolymerized copolymers and salts thereof, such as alkylene or vinyl-type ether monomers, polypeptides such as gelatin, guar gum, gum arabic, chitin,
Higher fatty acids such as chitosan, shellac, stearic acid, palmitic acid, water-insoluble polymers such as ethyl cellulose,
PH-sensitive polymers such as Eudragit E, L, S, higher alcohols such as cetanol, surfactants such as lipophilic surfactants such as HLB1-8, inorganic powders such as titanium oxide, liquid paraffin, white petrolatum, collagen , And atelocollagen are preferably used.

These substances may be used alone or in combination of two or more, and the type may be appropriately selected according to the dosage form.

[0017]

EFFECTS OF THE INVENTION The therapeutic agent for periodontal disease of the present invention provides an excellent inhibitory effect on alveolar bone resorption by endotoxin of periodontopathic bacteria.

[0018]

EXAMPLES The present invention will be specifically described below by showing experimental examples and examples, but the present invention is not limited to the following examples.

[Experimental Example 1] A skull of a newborn (5 to 7 days old) BALB / c mouse was excised, divided into two, and each was divided into 2 ml of α-MEM medium for 24 hours in a CO ₂ incubator. Was pre-cultured in. Then, one of the divided skulls is Porphyromonas gingivalis (P
orphyromonas gingivalis) 3
81 strains, Actinobacillus actinomycetemcomitans (Actinobacillus actinomyc
Add endotoxin (LPS, 1 μg / ml each) separated and prepared from etemcomitans) Y4, and add the same amount of endotoxin and the test drug to the other skull at the predetermined concentrations, and then in a CO ₂ incubator for 48 hours. It was cultured in. The Ca ⁺⁺ released in each medium was measured by Corning 940.

The results are shown in Table 1. The results show that the amount of Ca released when the mouse skull was stimulated with LPS was 10%.
It is expressed as a 50% inhibition rate (ED50) when 0 is set.

[0021]

[Table 1] *: The amount of Ca released into the medium when the skull was cultured with LPS for 2 days (μg)

As shown in the results of Table 1, ATPase inhibitor, cysteine proteinase inhibitor, serine proteinase inhibitor, which were subjected to the test,
The PCK inhibitor strongly suppressed the LPS-stimulated bone resorption activity of periodontopathic bacteria at a very low concentration.

Next, examples of the therapeutic agent for periodontal disease of the present invention will be shown.

Example 1 Periodontal pocket insertion agent

Example 2 Periodontal pocket insertion agent

Example 3 Periodontal pocket insertion agent

Example 4 Periodontal pocket insertion agent

[Example 5] Pasta for oral use H-7 1.0% Cetanol 10.0 Squalane 20.0 Precipitable silica 5.0 Polyoxyethylene (40 mol) hydrogenated castor oil 0.1 Sorbitan monooleate 1.0 Sodium lauryl sulfate 0.2 Glycyrrhetinic acid 0.1 Sodium saccharin 0.6 Eugenol 0.1 Perfume 0.6 Water Residual 100%

[Experimental Example 6] troche

[Example 7] Oral massage cream

[Procedure amendment]

[Submission date] November 29, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction content]

On the other hand, as another method for treating periodontal disease, a method of actively suppressing the absorption of alveolar bone supporting teeth has been studied, and for example, the use of indomethacin , which is a prostaglandin synthesis inhibitor , etc. Has been studied (J. of
Periodont. Res. 1983 (18) 11
0-117), the effect is not sufficient, and development of a more effective alveolar bone resorption inhibitor is desired.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0009

[Correction method] Change

[Correction content]

Here, as the ATPase inhibitor, acetazolamide, amiloride, ouabain, dibucaine, ethacrynic acid, digitoxin, digoxin, diphenidol, mesulfen, N-ethylmaleimide,
Myricetin, Kurofibureto, cinchonidine, quinoline and its derivatives, copier mycin A, bafilomycin A1, and the like.

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] 0019

[Correction method] Change

[Correction content]

[Experimental Example 1] The skulls of newborn BALB / c mice (5 to 7 days old) were excised, divided into two, and each was divided into 2 ml of α-MEM medium for 24 hours in a CO ₂ incubator. Was pre-cultured in. After that, Porphyromonas gingivalis (P
orphyromonas gingivalis) 3
81 strains, Actinobacillus actinomycetemcomitans (Actinobacillus actinomyc
Add endotoxin (LPS, 1 μg / ml each) separated and prepared from etemcomitans) Y4, and add the same amount of endotoxin and the test drug to the other skull at the predetermined concentrations, and then in a CO ₂ incubator for 48 hours. It was cultured in. The Ca ⁺⁺ released into each medium was measured by Corning 940.

[Procedure correction 4]

[Document name to be amended] Statement

[Name of item to be corrected] 0022

[Correction method] Change

[Correction content]

As shown in the results of Table 1, ATPase inhibitor, cysteine proteinase inhibitor, serine proteinase inhibitor, which were subjected to the test,
The PKC inhibitor strongly suppressed the LPS-stimulated bone resorption activity of periodontopathic bacteria at a very low concentration.

[Procedure amendment 5]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

[Experimental Example 6] troche

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Claims (1)

[Claims] 1. A therapeutic agent for periodontal disease comprising at least one selected from adenosine triphosphatase inhibitor, cysteine proteinase inhibitor, serine proteinase inhibitor and protein kinase C inhibitor.