JPH04217626A - Composition for oral cavity - Google Patents

Abstract

PURPOSE:To obtain a composition for oral cavity effective for preventing and treating periodontosis, containing nordihydroguaiaretic acid. CONSTITUTION:A composition for oral cavity containing nordihydroguaiaretic acid, a resin component of creosote bush. The compound suppresses activity of human derived collagenase and has inhibitory activity against multiplication of bacteria belonging to the genus Bacteroides, Actinobacillus and Fusobacterium considered to be much concerned with crisis and progress of periodontosis.

Description

[Detailed description of the invention]

0001

[Field of Industrial Application] The present invention relates to an oral composition containing nordihydroguaiaretic acid useful for the prevention and treatment of periodontal disease. The present invention relates to an oral composition having antibacterial activity against bacteria.

0002

[Prior Art] Periodontal disease is a general term for inflammatory diseases that include various pathological conditions in the periodontal tissue.Generally, periodontal disease is gingivitis, in which inflammation is limited to the gingival region, and periodontal disease, in which inflammation reaches the alveolar bone and becomes chronic. It is broadly classified into periitis. Periodontitis used to be called alveolar pyorrhea, but as it becomes chronic, it causes destruction of the gingiva and alveolar bone, leading to tooth loss. Periodontal disease accounts for 50% of tooth loss, and approximately 80% of middle-aged and elderly people are affected.

[0003] As the cause of periodontal disease, a specific bacterial group in the plaque of periodontal pockets, especially the black pigment-producing Bacteroides group, is considered to be the most likely cause (for example, Journal of Cli
nical Periodontology, Volume 13,
912, 1986). It is thought that direct acting factors derived from bacteria (enzymes, endotoxins, etc.) and indirect acting factors (those mediated by the host's immune response) are involved in its periodontal tissue destructive action, but in any case, What is common is that the collagen in the gums and alveolar bone is degraded and resorbed over time (American Journal
of Pathology, Volume 92, Page 509, 1
978).

[0004] Collagenase derived from Bacteroides and gingival fibroblasts are attracting attention as collagenases associated with periodontal disease. The former is a rare enzyme that has recently been partially purified and requires metals and thiols at the same time, but there are still many unknowns (Journal
of Periodontal Research
, vol. 23, p. 258, 1988). On the other hand, fibroblast-derived interstitial collagenase (hereinafter referred to as collagenase unless otherwise specified) has been elucidated in detail and its primary structure has been clarified (The Journal of Bi
(See Logical Chemistry, Vol. 261, p. 6600, 1986).

[0005] Collagenase is a rate-limiting enzyme in degrading interstitial collagen (type I, type II, and type III collagen) in connective tissue, and plays an important role in collagen metabolism. Collagenase activity increases in inflamed gingiva (Journal of P
Eriodontal Research, Volume 16, 4
17, 1981), and that collagen decreases from the early stages of gingivitis (Archieve et al.
s of Oral Biology, vol. 18, 899
1973), it is thought that gingival collagenase is deeply involved in the progression of periodontal disease.

[0006] Conventionally, methods such as removing plaque and tartar in periodontal pockets by scaling and root planing, and removing periodontal pockets (gingivectomy) have been used to prevent and treat periodontal disease.

[0007] Recently, a therapeutic agent containing the antibacterial agent minocycline has been developed as a drug therapy. It has been reported that minocycline has not only antibacterial activity but also the activity of inhibiting collagenase derived from Bacteroides and neutrophils in vitro (Journal of th
e Japanese Association of
Periodontology, Volume 30, 182
p. 1988).

[0008]

The above-mentioned known methods are based on physical, surgical, or drug treatment as directed by a physician. However, considering that periodontal disease is a common disease with a high incidence rate, and that the condition tends to worsen before it is treated by a doctor, it is important to consider For oral compositions such as mouthwashes, it is desirable to use highly safe substances that eliminate the above-mentioned causes and are useful for the prevention and treatment of periodontal disease.

[0009] Accordingly, an object of the present invention is to provide an oral composition that can be expected to have preventive and therapeutic effects on periodontal disease and is highly safe.

0010

[Means for Solving the Problems] The present inventors have discovered that among the above-mentioned causes of periodontal disease, inhibiting the activity of collagenase, which plays an important role in controlling the decomposition and absorption of gingival and alveolar bone collagen, is effective for periodontal disease. Focusing on its effectiveness in preventing and improving peripheral diseases,
We conducted extensive research in search of collagenase inhibitors from a wide range of plant-derived materials.

As a result, it was discovered that nordihydroguaiaretic acid, a resin component of creosote bush, has strong collagenase inhibitory activity, and more surprisingly, it has been found to be deeply involved in the onset and progression of periodontal disease. Bacteroides actinobacillus and Fusobacterium bacteria (Journal of t
he Japanese Association of
Periodontology, volume 29, page 463,
(1987)), and have completed the present invention.

Nordihydroguaiaretic acid is a well-known compound that is present as a resinous component of many other plants, including the creosote bush. It is permitted to be used as an antioxidant only in butter and fats and oils, but is not used in other foods or toothpastes.

The method for producing nordihydroguaiaretic acid used in the present invention is not particularly limited, and any commonly used method may be used.

[0014] The oral composition of the present invention may optionally contain commonly used known ingredients depending on the type thereof.

[0015] The oral composition of the present invention can be used in liquid form, solid form,
Any semi-solid formulation may be used, and preferred compositions include foods such as chewing gum, candy, and drinks, as well as dentifrices, mouthwashes, troches, and liquid coatings.

[0016] The excipients or adjuvants used to produce these oral compositions may be appropriately selected from those commonly used for the same purpose depending on the dosage form, and are not particularly limited. However, for example, lactose, magnesium stearate, sorbitol, mannitol, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, saccharin, sodium lauryl sulfate, sodium lauroyl sarcosine, glycerin, polyethylene glycol, polyvinyl alcohol, carrageenan, gum arabic, Ethanol, menthol, fatty acids, citric acid, silicic anhydride, dicalcium phosphate, hydroxyapatite, calcium carbonate, titanium dioxide, etc. are used.

Sweeteners, coloring agents, flavoring agents, preservatives, etc. commonly used in foods can be added to the above composition as appropriate, and a bactericidal agent such as chlorhexidine or an antibiotic such as ampicillin can be added to the composition. It can also enhance the effect of preventing and improving peripheral diseases.

The amount of nordihydroguaiaretic acid in the oral composition useful for the prevention and treatment of periodontal disease produced in this way varies depending on the dosage form, but is usually 0.0
005-2. O weight %, preferably 0.005-1.0
Preferably, it is % by weight.

[0019]

Effects of the Invention The oral composition of the present invention contains nordihydroguaiaretic acid, so it has excellent inhibitory activity against collagenase, which is the cause of collagen absorption in the gingiva and alveolar bone in periodontal disease. It is useful for the prevention and treatment of periodontal disease, as it not only has the In addition, it is extremely safe in use regardless of the amount blended.

[0020]

【Example】

(Test Example-1) Collagenase inhibitory effect of nordihydroguaiaretic acid

1. Test drug nordihydroguaiaretic acid (N-426 manufactured by Sigma)
8) was used.

2. Collagenase Collagenase is human procollagenase produced in anchorage-independent cells derived from human fibrosarcoma cells in a serum-free protein-free medium, and CM Sepharose (manufactured by Pharmacia) and zinc chelating Sepharose (manufactured by Pharmacia). Trypsin (Sigma, Type 12) was added as an activator, incubated at 35°C for 5 minutes, and soybean trypsin inhibitor (Merck) was added. Trypsin was inactivated using
(See Publication No. 238941).

3. Measurement of Collagenase Inhibitory Activity The inhibitory activity of nordihydroguaiaretic acid against collagenase is measured as follows. First, nordihydroguaiaretic acid was dissolved in dimethyl sulfoxide to obtain an 8% by weight solution, and then a measurement buffer {0.2M salt, 5mM calcium chloride, 0.05% by volume Brij-
35 (polyoxyethylene (23) lauryl ether manufactured by ICI), and 50 mM Tris-HCl buffer containing 0.02% by volume sodium azide, pH 7.5}
Dilute 200 to 6600 times.

[0024] Mix equal amounts of this diluted solution and the above standard collagenase solution in a known amount (0.7 units; 1 unit indicates the amount of enzyme that decomposes 1 μg of type I collagen in 1 minute at 35°C). Using type I collagen labeled with fluorescein isothiocyanate (Cosmo Bio) as a substrate, the method of Nagai et al.
al of Inflammation, Volume 4, 123
% inhibitory activity is determined by measuring the collagenase activity according to the method (see J. P., 1984).

4. Test results Table 1 shows the results. Nordihydroguaiaretic acid exhibited dose-dependent collagenase inhibitory activity, with an IC50 value of approximately 8 μg/ml (approximately 26 μM). Table 1 ──────────────────── Final concentration of reagent
Collagenase inhibition rate (μg/ml)
(%) ────────
──────────── 100
91.430.0
79.510.0 53.93.
0 32.4──────────
──────────

(Test Example-2) Antibacterial activity of nordihydroguaiaretic acid

1. The same nordihydroguaiaretic acid as in Test Drug Test Example-1 was used.

2. Antibacterial activity test method Nordihydroguaiaretic acid was prepared at 0.63 to 20 mg/ml by 2-fold serial dilution with dimethyl sulfoxide (DMSO) and diluted 10-fold with a modified GAM agar medium (manufactured by Nissui Pharmaceutical Co., Ltd.). , 0.063 to 2 mg of nordihydroguaiaretic acid-containing medium was prepared.

[0029] One platinum loopful of the test bacteria that had been previously cultured anaerobically at 37°C for 24 hours in GAM broth medium (manufactured by Nissui Seiyaku) was taken, and after anaerobic culture at 37°C for 5 days, the growth of the bacteria was determined. The presence or absence was determined visually.

The lowest concentration of the sample contained in the medium at which growth was completely inhibited was defined as the minimum growth inhibiting concentration (MIC, mg/ml).

3. The test bacterium Bacteroides gingivalis
s gingivalis ATCC33277),
Bacteroides intermedius (B.inter
B. medius ATCC15032), B. melaninogeni
cus ATCC25845), Fusobacterium nucleatum
atum ATCC10953), and Actinobacillus actinomycetemcomitans (Actino
bacillus actinomycetemcom
Five anaerobic strains of S. itans ATCC29522) were used.

4. As a result, growth was observed for all strains at 0.125 mg/ml, but as shown in Table 2, growth was observed at 0.25 mg/ml.
The growth of all strains was completely inhibited.

[0033] In the control modified GAM agar medium (sample concentration, 0 mg/ml) to which only DMSO was added, the growth of none of the bacterial strains was inhibited.

Table 2 ────────────────────── Strains
Minimum inhibitory concentration#
──────────────────────B.
gingivalis
0.25B. intermedius
0.25B. melaninog
enicus 0.25F. n
ucleatum
0.25A. actinomycetem commit
ans 0.25──────────────
─────────#; MIC, mg/ml

[0035] Examples of the oral compositions of the present invention are listed below.

Example 1 (chewing gum) composition
Weight%────
────────────────Chewing gum base 20.0 powdered sugar
50.99 glucose
10.0 Starch syrup (
water 15%) 18.0 nordihydroguaiaretic acid 0.01 fragrance
1.0────
──────────────────

40°C
Put all of the chewing gum base and all of the starch syrup that were kept warm into a kneader and knead for 10 minutes.
3 and the entire amount of glucose was added and kneaded for 5 minutes, then 1/3 amount of powdered sugar was added and kneaded for 5 minutes. Next, a mixture of nordihydroguaiaretic acid and fragrance with the remaining 1/3 amount of powdered sugar was added and kneaded for 5 minutes to obtain a gum mix.

Example 2 (nougat)

[0039] Mix and whisk. ■ Boil down to 130℃. Add ■ little by little to ■ and whisk further. To this, while mixing, it was spread and molded on a cooling plate to obtain a nougat.

Example 3 (Toothpaste) Composition
Weight%──────────────────────
─Dibasic calcium phosphate 42 Glycerin 18
carrageenan
0.9 Sodium lauryl sulfate
1.2 Saccharin
1.0 Butyl paraoxybenzoate
0.005 Chlorhexidine digluconate
0.1 fragrance
0.1 nordihydroguaiaretic acid 0.1 water
Remaining amount──────────
──────────────

[0041] It is produced according to a conventional method. That is, after measuring the prescribed amounts of water, glycerin, carrageenan, saccharin, butyl paraoxybenzoate, chlorhexidine digluconate, fragrance, and nordihydroguaiaretic acid and mixing them to swell the binder, the second Calcium phosphate and sodium lauryl sulfate are added, mixed well, defoamed, and then filled into tubes to obtain a toothpaste.

Example 4 (Toothpaste) Addition amount of nordihydroguaiaretic acid is 0.5% by weight
A toothpaste is obtained in the same manner as in Example 3 except for the following.

Example 5 (lozenge) Composition
Weight%────────────────────
───Polyethylene glycol 6000 2
．． 0 silicic anhydride
1.0 Magnesium Stearate
0.6 talc
0.3 hydroxypropyl cellulose 0.7 nordihydroguaiaretic acid
0.1 mannit
Remaining amount──────────────────
────

[0044] A lozenge having the above formulation is manufactured according to a conventional method.

Example 6 (Mouthwash) Composition Weight %──────────────────── Ethanol 20.0 Sodium saccharin 0.1 Fragrance
1
．． 0 Sucrose fatty acid ester 0.5
nordihydroguaiaretic acid 0.2 water
Remaining amount────────────────────Produce a mouthwash with the above formulation according to a conventional method.

Claims (1)

[Claims] [Claim 1] An oral composition containing nordihydroguaiaretic acid.