JPH07267868A - Biofilm-removing agent - Google Patents

Abstract

PURPOSE:To obtain a biofilm-removing agent containing a macrolide antibiotic at a low concentration, capable of removing biofilm formed by periodontal pathogens, making a drug effectively penetrate to and act on an affected part and also suppressing the formation of the biofilm and useful for self-care. CONSTITUTION:This is a removing agent of biofilm of periodontal pathogens containing a macrolide antibiotic having a 14-membered ring, preferably belonging to an erythromycin, a clarithromycin, a triacetyloleandomycin or a roxithromycin. For administration, the antibiotic may be contained in e.g. a slow-releasing ointment or film or in a solvent such as a mouth-washing preparation. The dose of the macrolide antibiotic is preferably 0.5-10mg/day, especially preferably 1-5mg/day.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the chemical removal of periodontal disease-causing bacteria. More specifically, it relates to a biofilm removing agent that removes biofilms formed by periodontal pathogens and promotes penetration of a medicinal agent.

[0002]

2. Description of the Related Art Periodontal disease is regarded as an infectious disease caused by bacteria and occupies a large position as one of the general reasons for tooth loss.
This is considered to be a disease in which destruction of the periodontal ligament, which is a connective tissue, and alveolar bone resorption progress in the interaction with the enzymes emitted from pathogenic bacteria, the toxic substances, and the inflammatory reaction that occurs in the host side accordingly. Initially, gingival inflammation is observed and the periodontal pocket is formed. After that, the resorption of the alveolar bone progresses and the teeth fall off. In periodontal disease, plaque formation and accompanying colonization of periodontopathic bacteria are problems. Plaques are formed and accumulated on the gingival margin by Gram-positive bacteria mainly of Streptococcus. In the process of its accumulation, oxygen is consumed in the lower part of the plaque, becoming anoxic, forming a convenient environment for the growth of gram-negative anaerobic rods, which are positioned as periodontopathic bacteria. Go. In addition, secretion of gingival crevicular fluid increases due to inflammation of the gingiva, and a sufficient nutritional environment is formed. Then, under the gingival margin, periodontopathic bacteria form a colony, causing tissue destruction and exacerbation of the disease state. Thus, under the gingival margin, a complex flora is formed mainly of gram-negative bacteria and gram-positive bacteria on the gingival margin and gram-negative bacteria. Examples of these connections are Streptococcus olaris, Streptococcus mititis and Fusobacterium nucleatum or Actinobacillus actinomycetemcomitans and Fusobacterium nucleatum or Porphyromonas gingivalis, Prevotella intermedius and Fusobacterium nucleatene or Treatocorta nuraceum. There is a bond between them. Furthermore, among Gram-negative anaerobes, some bacteria are believed to secrete viscous substances such as Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, and Aikenella colodens. It is considered that the biofilm villages that have become

It is well known that biofilms formed in lesions are difficult to remove, and respiratory diseases such as diffuse bronchiolitis are well known, and there are cases in which therapeutic effects cannot be obtained. Many have been reported. This is because the biofilm formed mainly by Pseudomonas bacteria does not affect the bacteria existing inside it by antibiotics, etc., and the effect can be obtained even when administered in an amount that is several thousand times the minimum inhibitory concentration. It is confirmed that it cannot be done. These things are considered to be the same in the biofilm formed in the periodontal pocket, and it is desired to administer the drug with the biofilm removed. Up to now, it has been possible to deal with plaque on the gingival margin by using an anti-plaque agent or physically removing it by brushing, and many products are sold in the market. However, no measures have been taken for the biofilm found under the gingiva, and the present situation is that it depends on the physical removal at the dental clinic. Therefore, an object of the present invention is to provide a method by chemical treatment using a drug, as opposed to a therapeutic method which has hitherto been able to perform only physical treatment.

[0004]

[Means for Solving the Problems] As a result of intensive studies to achieve the above object, the present inventors have found that macrolide antibiotics are extremely effective in removing or preventing oral bacterial biofilms. The present invention has been completed by discovering a certain thing. The macrolide antibiotics used in the present invention include acetylspiramycins, erythromycins, triacetyloleandomycins, acetylquitasamycins, clarithromycins, midecamycin acetates, midecamycins, josamycins, Examples include spiramycins, roxithromycins, and rokitamycins. Of these, the 14-membered ring macrolide antibiotics are particularly effective and useful. As an administration method, for example, it may be contained in an ointment or film having a sustained release property, or may be contained in a liquid preparation such as a mouthwash. The dosage of these macrolide antibiotics varies depending on the dosage form and the degree of disease, but is preferably about 0.5 to 10 mg / day,
1 to 5 mg / day is more preferable. These doses are lower than those for general sterilization, and there is no problem in terms of safety such as side effects.

[0005]

[Effects and Effects of the Invention] The method of the present invention chemically eliminates the biofilm and effectively permeates the drug into the affected area.
Since it can act and the formation can be suppressed, it can be used as an effective means of self-care. The macrolide antibiotics used in the present application have a biofilm-removing action, and are used at a concentration lower than the conventionally known concentration exhibiting antibacterial properties.

[0006]

EXAMPLES The effects of the present invention will be specifically described with reference to the following examples. The present invention is not limited to these examples. Test Example 1: The bacteria shown in the table are cultured on a filter for 10 days to form a biofilm. The medium is replaced on the 5th day. After culturing, the filter is sandwiched between the glass containers shown in FIG. A biofilm is formed from the drug solution opening opened in this container. Inner diameter 43m
The filter is sandwiched between glass containers having a height of m and a height of 30 mm. Separately, the following antibiotics and minocycline hydrochloride solution are injected into one side (the surface on which bacteria are grown) and distilled water is injected into the other side from the drug solution port opened in this container. As a control, a solution containing only minocycline hydrochloride solution is used. The results are shown in Table 1. The criteria of judgment in Table 1 are that the permeation amount of minocycline hydrochloride is remarkably improved (permeation amount is 5 times or more) ++, improvement (permeation amount is 2 times or more and less than 5 times) is +, and there is no effect compared with the control. It is shown by-.

From these results, it was found that macrolide antibiotics have a superior effect on the formed biofilm in eliminating the biofilm, as compared with other drugs.

[0008]

[Table 1]

Test Example 2: The following bacteria were used to observe the effect of inhibiting biofilm formation. After culturing for 5 days, the following antibiotics are exchanged with a medium containing 1/10 amount of MIC, and after culturing for 5 days, the same medium is exchanged again and culturing for 5 days. As a control, culture is performed in the same manner with a medium containing no antibiotics. After culturing, the outer membrane polysaccharide component is washed with bacteria and then extracted with a 1N NaOH aqueous solution. The amount of sugar is quantified by the sulfuric acid-phenol method. The results are shown in Table 2. The criteria for judgment in Table 2 are ++ when the amount of outer membrane polysaccharide produced is 50% or more lower than that of the control, + when 20% or more and less than 50%, and when only less than this effect is observed. And From these results, it became clear that the production of macrolide antibiotics can be suppressed during the biofilm formation process by bacteria. This also indicates that the remover of the present invention is effective not only as a therapeutic agent but also as a preventive agent.

[0010]

[Table 2]

Example 1: Ingredients Mixing ratio (weight) Erythromycin 5 parts Ethanol 65 parts Purified water 30 parts Fragrance A small amount of erythromycin is dissolved in ethanol and purified water is added to form a mouthwash. Separately, a small amount of fragrance was added to obtain a desired liquid pharmaceutical preparation. This product is diluted before use.

Example 2: Ingredients Mixing ratio (weight) Clarithromycin 2 parts Hydroxyethyl cellulose 3 parts Aminoalkylmethacrylate copolymer RS 2 parts Triacetin 10 parts Concentrated glycerin 83 parts Glycerin and hydroxyethyl cellulose are kneaded to form a non-aqueous gel. create. Clarithromycin, Eudragit RS, and triacetin were added thereto to obtain a pharmaceutical preparation having a desired sustained release property. This drug is filled in a syringe modified so that it can be administered into the periodontal pocket, and is injected into the affected area pocket for use.

Example 3: Ingredients Mixing ratio (weight) (Drug layer) Erythromycin 2 parts Carboxyvinyl polymer 20 parts Polyvinyl acetic acid 50 parts Hydroxypropylmethyl cellulose 30 parts Sodium citrate 1.5 parts (Support layer) Polyvinyl acetic acid 100 parts

Carboxyvinyl polymer as a drug layer,
Hydroxypropyl methylcellulose and polyvinyl acetic acid are swollen in water to obtain a stock gel. Take an appropriate amount of these, add erythromycin dissolved in ethanol, and mix well. After the resulting gel is spread and dried (75 ° C,
10 minutes), cut. Separately, a methanol solution of polyvinyl acetic acid was spread on a release paper as a support layer, dried (75 ° C., 8 minutes), and then cut. The drug layer and the support layer were thermocompression-bonded with an iron (110 ° C., 30 seconds) and cut into an appropriate size to obtain a desired film-form pharmaceutical preparation. This film is attached to the gums or inserted into a pocket for use.

Example 3 Beagle dogs were used to induce plaque accumulation in experiments. On the other hand, solutions of erythromycin, clarithromycin and cetylpyridinium chloride (CPC) were used to observe plaque elimination and inflammation relieving, respectively. The results are shown in Table 3, and the numerical values are shown by the plaque index and gingivitis index. From these results, it was shown that the system using erythromycin and clarithromycin has a prominent improving effect and is effective for improving various symptoms related to periodontal disease.

[0016]

[Table 3]

Plaque Index 0: No plaque is found on any tooth surface in the block. 1: 2 mm from the gingival margin on any tooth surface in the block
Above that there is a small amount of plaque. 2: There are plaques on the tooth surface in the block that do not exceed one-half of the crown. 3: Plaques are present on more than half of the crown. Gingivitis index 0: clinically normal gingiva 1: mild inflammation. Almost no slight change in color tone or change in texture is observed. No bleeding due to abrasion of the edges. 2: Moderate inflammation. Bleeding due to gloss, redness, edema, hypertrophy, and abrasion. 3: Severe inflammation. Marked redness, hypertrophy, and spontaneous bleeding tend to occur. A. Usually, the evaluations of 1 and 2 are carried out by rubbing the gingival margin with a pocket probe to check for bleeding. B. If the degree of evaluation is confusing, the higher value is used.

[0018]

EFFECTS OF THE INVENTION According to the present invention, the effect of removing biofilms produced by periodontal disease bacteria is high, and therefore various medicinal agents can be directly permeated and acted on the affected area.

[0019]

[Brief description of drawings]

FIG. 1 Device of Test Example 1

Claims (5)

[Claims] 1. A biofilm remover for periodontopathic bacteria, which comprises a macrolide antibiotic. 2. The remover according to claim 1, wherein the macrolide antibiotic is a macrolide having a 14-membered ring. 3. The macrolide antibiotics are erythromycins, clarithromycins, triacetyloleandomycins and roxithromycins.
Remover as described. 4. The remover according to claim 1, wherein the remover is directly administered into the periodontal pocket of periodontal disease. 5. An aggregation inhibitor of periodontal pathogens, which comprises a macrolide antibiotic.