JPH01238543A - Composition for oral cavity application - Google Patents

Abstract

PURPOSE:To provide a composition for oral cavity application, containing a compound having calmodulin-inhibiting action, suppressing the activity of Ca- calmodulin-dependent enzyme participating in oral cavity diseases and useful for the prevention and remedy of periodontosis while keeping the safety and applicability in good state. CONSTITUTION:The objective composition contains, as an active component, one or more compounds selected from a compound having inhibiting action against calmodulin which is an intracellular Ca-ion receptor protein and an activation factor of a Ca-calmodulin-dependent phosphorase (e.g. trifluoperazine, fluphenazine or prenylamine) and a compound having selective activity to the Ca channel of a salcolemma of cardiac muscle, blood vessel and various smooth muscles and having calcium antagonistic action to suppress the increase in free Ca ion in cytoplasm (e.g. verapamil, flunarizine, nifedipine or cinnarizine). The amount of the above active component in the composition is usually 0.00001-10wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an oral composition, particularly an oral composition used for preventing and curing periodontal diseases.

[Conventional technology] Conventionally, anti-inflammatory agents such as allantoin and glycyrrhizic acid, anti-plasmin agents such as ε-aminocaproic acid and tranexamic acid, hinokitiol, and sodium chloride have been used to treat periodontal diseases such as periodontitis and pyorrhea. Formulated oral compositions have been used.

[Problems to be solved by the invention] ′ However, all of these are insufficiently effective, cannot exhibit their effects due to relationships with other ingredients, have problems with stability, and have problems with the system in which they are blended. There were problems such as poor usability, and it was not always satisfactory.

The present invention was made in view of the problems of the prior art described above, and its purpose is to provide an oral composition that is highly effective in preventing and treating periodontal diseases, and is also safe and easy to use. It is about providing.

In order to achieve the above objective, the present inventors conducted extensive research in order to obtain a substance that has an excellent effect on periodontal diseases.As a result, the behavior of Ca in periodontal cells has a great influence on periodontal diseases. I found that I was giving. As a substance that controls the behavior of Ca in periodontal cells and prevents and treats periodontal diseases, it also has good safety and usability.
Calcilla 11 and compounds with calmodulin inhibitory effects
The present invention was completed by focusing on compounds that have antagonistic effects.

[Means for Solving the Problems] That is, the invention according to claim 1 is an oral composition characterized by containing one or more compounds selected from compounds having a calmodulin inhibitory effect.

Moreover, the invention according to claim 2 is an oral composition characterized by containing one or more compounds selected from compounds having calcium antagonistic action.

Hereinafter, the configuration of the present invention will be explained in detail.

Power 1- I S Officer Δ
Calmodulin is an intracellular calcium ion receptor protein, and was discovered by Kakiuchi et al. in 1970 as an activator of calcium-calmodulin-dependent phosphogesterase.

Its molecule 1 is a 16,500 thermostable acidic protein. Later, it was revealed that it also acts as an activator of various enzymes, and is involved in many biological reactions such as cyclic nucleotide metabolism, calcium ion transport, smooth muscle contraction, cell secretion phenomena, cell movement, cell division, and glycogen metabolism. It has come to be considered as a regulating factor.

However, its application to the field of oral compositions was completely unknown.

In the present invention, a "compound having a calmodulin inhibitory effect", that is, a calmodulin inhibitor,
Refers to all compounds that bind to calmodulin, selectively inhibit enzymes activated by calcium ions and calmodulin, and can prevent and treat periodontal diseases such as periodontitis and alveolar leakage in mammals. do.

Specifically, phenothiazine, thioxanthin, butyrophenone, diphenylbutylamine, dibenzodiazepine, benzodiazepine 5, dibenzazebin, naphthalenesulfonamide, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, trifluoperazine. , chlorpromazine, preniramine, butaclamol, amitributyline, felodibine, vinblastine, vincristine, fluphenazine, pimozide, medazebam, protributyrin, (1-[bis(p-chlorophenyl)methyl]-3-[2,4-dichloro-β( 2
, 4-dichlorobenzyloxy)phenethyl]imidazolinium chloride, flubenxol, chlorpromazine, heroperidol, chlordiazepoxide, tetracaine, lidocaine, dibucaine, desibramine, clozavin, plummethacin, fentolamine, imibramine, penperidol and the like.

On the other hand, "compounds with calcium antagonistic effects", that is, calcium antagonists, were discovered by Fleckenstein in 1969 during electrophysiological research on myocardial contraction.
It is a group of compounds that act competitively with calcicum, including verapamil, and research and clinical applications regarding this drug have since made remarkable progress.

These calcium antagonists act selectively on calcium channels in the sarcolemma of various smooth muscles, including myocardium and blood vessels, thereby increasing the influx of extracellular calcium ions into the cells and the cytoplasmic accumulation of stored calcium in the sarcoplasmic reticulum. It is thought that the increase in free calcium ions in the cytoplasm is suppressed by inhibiting the release of calcium ions into the cytoplasm.

Clinically, the suppressing and relaxing effects of muscle cell contraction based on pharmacological effects are thought to be involved in the expression of anti-myocardial ischemic effects, anti-arrhythmic effects, and antihypertensive effects.

There have been reports of its anti-arteriosclerotic effect, peripheral circulation improving effect, anti-gastric ulcer effect, etc., and its indications are being further expanded.

However, its application to the field of oral compositions was completely unknown.

In the present invention, a calcium antagonist refers to a calcium channel that is mainly membrane voltage dependent in vivo, that is, a channel that operates by depolarization of the cell membrane and allows extracellular calcium ions to flow into the cell, and a channel that allows extracellular calcium ions to flow into the cell from an intracellular calcium storage site. refers to all compounds that can inhibit the movement of calcium ions in mammals and prevent and treat periodontal diseases such as periodontitis and alveolar pyorrhea.

Specifically, the following compounds are included.

(1) 1,4-Dihydropyridine derivatives Preferred examples include nifedipine, nicardipine, nildipine, nimodipine, nisoldipine, nitrendipine, milvadipine, dazodibine, and felodipine.

(2) N-Methyl-N-homoveratrilamine derivatives Preferred examples include verapamil, gallopamil, and thiavamil.

(3) Benzothiazepine derivatives Preferred are diltiazem and the like.

(4) Piperazine derivatives, preferably cinnarizine, lidoflazine, flunarizine and the like.

(5) Diphenylpropyramine derivatives Preferable examples include prenylamine, telocilin, and fencilline.

(6) Benzothiazole Posbonate derivatives Preferably diethyl-4-(benzothiazol-2-yl)benzylphosphonate, hostezyl, and the like.

(7) Bebridil derivative Preferably, Bebridil and the like are used.

(8) Perhexyline derivative Preferably, perhexyline or the like is used.

C1 The amount of the calmodulin inhibitor or calcium antagonist, which is the active ingredient in the present invention, added to the oral composition is usually 0.00001-10 (wt%), preferably 0.0001-5 (wt%). , more preferably 0
．． 0 l-1 (wt%).

If it is less than 0.00001%, the effect of the present invention cannot be sufficiently obtained, and if it exceeds 10%, it is disadvantageous in terms of formulation cost.

In addition to the essential components of the calmodulin inhibitor or calcium antagonist, the oral composition of the present invention may also contain water, a humectant, an abrasive, a binder, an interface, etc., depending on the type of the oral composition. Ingredients normally used in oral compositions, such as active agents, lower alcohols, sweeteners, fragrances, preservatives, antifungal agents, pigments, or drugs such as bactericidal agents, anti-inflammatory agents, breath odor removers, and fluorine compounds, can be added. can.

Further, the dosage form of the oral composition of the present invention is arbitrary, and can be used in toothpaste, powdered toothpaste, moist toothpaste, double layer such as water double layer, oral pasta, mouthwash, mouth freshener, chewing gum, etc. It can also be used.

Furthermore, an oral composition containing a calmodulin inhibitor and a calcium antagonist is also possible.

[Example] Next, the present invention will be explained in more detail with reference to Examples.

Note that the present invention is not limited to this.

−shi ψ l −raw 1
1 First, in order to investigate the effect of the oral composition of the present invention using a calmodulin inhibitor on periodontal disease, the following comparative test was conducted.

The composition of the toothpaste used in the comparative test is shown in Table 1 below. The toothpaste was produced by a conventional method.

(Leaving space below) Implementation Group 1-2 Table 1 (Amount %) Then, the 30 patients with periodontal disease were divided into 3 groups of 10 patients each so that the severity of symptoms was the same in each group. Each group was made to brush for 3 minutes three times a day for 14 days using the toothpastes of Example 1.2 and Comparative Example 1, respectively.

During this period, the use of other oral compositions was prohibited, and no particular instructions on brushing were given.

The effectiveness against periodontal disease was evaluated using the following criteria.

Rating: Significant effect on periodontal disease: 3. Significant effect on periodontal disease: 2. Slight effect on periodontal disease: 1. The 20 results for which no effect was found are shown in Table 2 below.The numbers in the table are the average scores of 10 people in each group.

Table 2"; 2 As is clear from Table 2, Examples 1 and 2 in which 0.0001 to 0.01 trifluoberazine were blended.
It is understood that Comparative Example 1 has a better therapeutic effect on periodontal diseases than Comparative Example 1.

Other examples are shown below, and all of them showed excellent improvement effects on periodontal diseases as a result of similar practical tests.

Hidadabioka l Toothpaste weight 1% Silicic anhydride 20.0 Sorbitol 50.0 Carrageenan
, 0.5 Sodium carboxymethyl cellulose 1.0 Sodium lauryl sulfate 1. 8 Satucalin Sodium
0.08 Methyl paraoxybenzoate 0
．． 2 Fragrance 0.9 Flufenazine 0.1 Purified water
Remainder Example j2 Oral pasta weight% Vaseline 10.0 Propylene glycol 7.0 Stearyl alcohol
10.0 Polyethylene glycol 1500 3
0.0 Hinokitiol 0. 1 naphthalene sulfonamide o, oot polyethylene glycol 400 remainder bukotabibendama mouthwash ethyl alcohol 10.0 saccharin sodium 0.05 fragrance
0.8 Polyoxyethylene (20 mol) Sorbitan laurate 1.0 Phenothiazine 0.05 Purified water
Remnant Light Blood Saturday Daytime Refreshing Agent (Sub 1) - Type) Ethyl Alcohol 40.0 Saccharin Sodium 0. 1 sorbitol
10.0 fragrance
1.0 Polyoxyethylene (60 mol) Hydrogenated castor oil 0. 7 Chlorhexidine hydrochloride 0.05 Prenylamine
0.0001 purified water
Remaining amount ±l Chewing gum Gum base 25.0 Calcium carbonate 2.0 Fragrance
1. 0 steel chlorophyll 0
．． 05 aminotributyrin 0.005 sorbit powder balance 5
J-, -r Next, an oral composition using a calcium antagonist will be explained.

First, in order to examine the effects of oral compositions using calcium antagonists on the prevention and treatment of periodontal diseases, the following comparative test was conducted in the same manner as in the case of calmodulin inhibitors.

First, Table 3 shows the composition of the toothpaste used in the test.

(Margin below) Table 3 (% by weight) The 30 patients with periodontal disease were divided into 3 groups of 10 patients each so that the severity of symptoms was the same in each group. Each group was made to brush for 3 minutes three times a day for 14 days using the toothpastes of Examples 8 and 9 and Comparative Example 2, respectively. this! During the first period, the use of other oral compositions was prohibited, and no particular instructions on brushing were given.

The results are shown in Table 4 below.

Note that the evaluation method is similar to that when using the calmodulin inhibitor described above.

Table 4 As is clear from Table 4 above, Examples 8 and 9 containing 0.0001 to 0.01 of nicardipine hydrochloride are more effective against periodontal disease than Comparative Example 2. be understood.

Other examples are shown below, and all of them showed excellent improvement effects on periodontal diseases as a result of similar practical tests.

Satosumi Satosumi Toothpaste Weight% Silicic anhydride 20.0 Sorbitsu 50.0 Carrageenan
0.5 carboxymethyl cellulose sodium J, i.

Sodium lauryl sulfate 1. 8 Satucalin sodium 0.08 Methyl paraoxybenzoate 0. 2 fragrance
0.9 Diltiazem hydrochloride 0. 1
Purified Water Refreshing Makeup 411
- Oral Pasta Weight % Vaseline 10.0 Propylene Glycol 7.0 Stearyl Alcohol
1000 polyethylene glycol 1500
30.0 Hinokitiol 0. 1 flunarizine o, ooi polyethylene glycol 400 residual evil eye 1 fima 1 mouthwash ethyl alcohol 10.0 saccharin sodium 0.05 fragrance
0.8 Polyoxyethylene (20 mol) Sorbitan laurate 1.0 Nifedipine
0.05 purified water
Zanbe Mitodo Eyu Mouth freshener (spray type) Ethyl alcohol 40.0 Saccharin sodium 0. 1 sorbitol
1000 fragrances
1.0 Polyoxyethylene (60 mol) Hydrogenated castor oil 0. 7 Chlorhexidine hydrochloride 0.05 Cinnarizine
o, oooiM Seisui Zanbe Mi JfV Milk 1", Chewing Gum Gum Base 25.0 Calcium Carbonate 2.0 Fragrance
1.0 steel chlorophyll 0
．． 05 Verapamil hydrochloride 0.005 Sorbit powder Balance [Effects of the Invention] Since the present invention is constructed as described above, it exhibits the effects as described below.

According to the invention as claimed in claim 1, since a calmodulin inhibitor is blended into the oral composition, the activity of calcium-calmodulin-dependent enzymes closely related to oral diseases is suppressed, and safety and usability are maintained favorably. While doing so, it is possible to effectively prevent and treat oral diseases.

According to the invention as claimed in claim 2, since a calcium antagonist is blended into the oral composition, an increase in intracellular free calcium ion concentration, which is closely related to oral diseases, is suppressed, and safety and usability are improved. It is possible to effectively prevent and treat oral diseases while maintaining the oral health.

Patent applicant: Shiseido Co., Ltd.

Claims (2)

[Claims] (1) An oral composition comprising one or more compounds selected from compounds having a calmodulin inhibitory effect. (2) An oral composition characterized by containing one or more compounds selected from compounds having calcium antagonistic effects.