JP2848696B2 - Oral liquid preparation - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oral liquid preparation, and more particularly, to an oral liquid preparation in which cetylpyridinium chloride as a fungicide is prevented from being inhibited from adsorbing to a tooth surface.

BACKGROUND ART Plaque control is important for preventing gingivitis, alveolar pyorrhea, and tooth decay, and various studies on chemical plaque control using bactericides such as cetylpyridinium chloride have been conducted. . Since cetylpyridinium chloride has a bactericidal action and is relatively easily adsorbed to the oral mucosa and the tooth surface, it is considered that bacteria are prevented from adsorbing on the tooth surface and, consequently, plaque formation is prevented.

However, cetylpyridinium chloride is highly reactive, and forms a salt when an anionic substance such as sodium carboxymethylcellulose used as a binder of an oral composition or sodium lauryl sulfate also used as a foaming agent is mixed, and sterilization occurs. Often the activity of the agent is lost. Inactivation is caused not only by salt formation but also by incorporation into micelles by a surfactant. Perfumes are indispensable for oral preparations, and solubilization requires a surfactant. Therefore, it is necessary to select and set the concentration of the surfactant so as not to impair the ability of the fungicide itself to adsorb to teeth and the fungicidal power. Therefore, various methods for preventing inactivation of a cationic germicide such as cetylpyridinium chloride have been proposed for oral compositions. (See Japanese Patent Application Laid-Open Nos. 64-26511 and 60-255717). However, studies on oral liquid preparations that do not impair the adsorptivity and antibacterial activity of cetylpyridinium chloride on teeth and also have the transparency (low-temperature stability) characteristic of oral liquid preparations have not been sufficiently conducted. is the current situation.

Problems to be Solved by the Invention The present inventors have conducted intensive studies for the purpose of not inhibiting the adsorption of cetylpyridinium chloride to the tooth surface, maintaining the antibacterial activity, and preventing the formation of plaque. As a result,
Surprisingly, they have found that the combination of cetylpyridinium chloride with polyoxyethylene polyoxypropylene glycol does not inhibit the adsorption of cetylpyridinium chloride to teeth, and have completed the present invention.

Means for Solving the Problems The present invention relates to cetylpyridinium chloride having a concentration at the time of use.
It is intended to provide a liquid preparation for oral cavity, characterized in that polyoxyethylene polyoxypropylene glycol is blended in an amount of 0.01 to 10% by weight.

In the present invention, cetylpyridinium chloride has a concentration of 0.0002% by weight or more, preferably 0.01% by weight, when used in the preparation.
The amount to be not less than% by weight is added. From the viewpoint of the bactericidal effect, the upper limit of the amount of cetylpyridinium chloride is not particularly limited, but considering that cetylpyridinium chloride has a bitter taste, and that when the amount is large, teeth may be colored,
Usually, 1% by weight or less is preferable.

The polyoxyethylene polyoxypropylene glycol used is preferably a water-ethanol system having a high solubilizing ability for a fragrance, having high transparency, and not inhibiting the adsorption of cetylpyridinium chloride to teeth. Polyoxyethylene polyoxypropylene glycol suitable for the above purpose is selected so that the proportion of ethylene oxide in the molecule is 70% by weight or more and the molecular weight of propylene oxide is 3000 or more. In addition, the amount of polyoxyethylene polyoxypropylene glycol is 0.01% when the concentration of the total amount of the composition is used.
The amount is to be 1.0% by weight. When the amount is too small, the solubilization of the fragrance becomes insufficient, and when the amount is too large, adsorption to teeth is inhibited.

From the viewpoint of the bactericidal action of cetylpyridinium chloride and the improvement of adsorption to teeth, it is desirable that the pH of the preparation of the present invention is 6.5 to 8.5. The oral liquid preparation of the present invention can be manufactured into a liquid preparation for concentrated or straight-type mouthwashing, dentifrice, dental treatment, etc. according to a conventional method, and other components are not particularly limited, and the tooth surface of cetylpyridinium chloride is not limited. As long as it does not inhibit adsorption or its antibacterial activity, additives usually used in this type of preparation, for example, wetting agents, sweeteners, flavors, preservatives and the like can be used, but a foaming agent and a solubilizing agent When used, anionic ones which may form a salt with cetylpyridinium chloride or polyoxyethylene sorbitan fatty acid esters which are incorporated into surfactant micelles are not preferred.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to experiments and examples, but the present invention is not limited to these examples. In the examples, “%” is “% by weight”.

Experiment 1 Adsorption experiment of cetylpyridinium chloride on tooth surface Hydroxyapatite as a model of tooth enamel
Todisk (Bio-Gel  HTP, USA Bio-Rad La
Volatiles, 13mmφ, 250mg, 1.5t / cm^TwoTablet with 6,
Sintering at 00 ° C for 6 hours) in human saliva at 37 ° C for 18 hours
What was used was used. By immersing in saliva,
Adsorb saliva mucoprotein etc. on the droxyapatite surface
To the actual tooth enamel condition wet with saliva
I let you. Try this saliva-treated hydroxyapatite disc
Take in a test tube, 0.05% cetylpyridinium chloride (Merck
1 ml of an aqueous solution was added and shaken at 37 ° C. for 30 minutes. That
Then, wash with 6 ml of water and extract solvent (50 mM sodium lauryl sulfate).
Lium, 40 mM citrate buffer pH3.0 / acetonitrile =
30/70) to extract the sample for high-performance liquid chromatography.
And High performance liquid chromatography kept at 40 ° C
Lichrosorb RP select B
B, 4.0 mmφ × 250 mm) as a separation column, and dissolve the extraction solvent.
Used as syneresis. The flow rate is 1 ml per minute and cetyl chloride
Pyridinium can be detected by measuring absorbance at 258 nm, or
Using a calibration curve made with cetylpyridium chloride standard
Quantification was performed.

Similarly, a saliva-treated apatite disk was immersed in a mixed solution in which each of the various additives shown in Table 1 was added 1.0% to 0.05% cetylpyridinium chloride, and then cetylpyridinium chloride was quantified. Among the additives, the amount of polyoxyethylene polyoxypropylene glycol was changed to 0.2, 0.6, 1.0, and 1.5% by weight, and the effect of the concentration on the amount of cetylpyridinium chloride was examined. The results are shown in Table 1.

As shown in Table 1, the adsorption of cetylpyridinium chloride on the tooth surface is inhibited by the combination of sodium lauryl sulfate as an anionic activator and polyoxyethylene sorbitan fatty acid ester as a nonionic activator.
In addition, it was confirmed that the polyoxyethylene polyoxypropylene glycol did not specifically inhibit adsorption to the hydroxyapatite disk when the blending amount was 1.0% by weight or less.

Experiment 2 A liquid preparation for oral cavity was prepared by using the following formulations with different degrees of polymerization of ethylene oxide and propylene oxide in polyoxyethylene polyoxypropylene glycol.

Ingredient Weight% Fragrance 0.3% Ethanol 10.0% Glycerin 5.0% Saccharin sodium 0.01% Cetylpyridinium chloride 0.05% Polyoxyethylene polyoxy 0.6% Propylene glycol Purified water Remaining After holding each oral liquid sample at -5 ° C for 48 hours The low-temperature stability was determined according to the following evaluation criteria. The results are shown in Table 2.

 ：: Transparency is good, and no odor is observed.

 X: Poor transparency or cage is observed.

As shown in Table 2, those in which the proportion of polyoxyethylene in the molecule is 70% by weight or more and the molecular weight of polyoxypropylene is 3000 or more are high in transparency at low temperature and excellent in low temperature stability. In addition, when the adsorption of cetylpyridinium chloride to the teeth was evaluated for samples having good low-temperature stability in the same manner as in Experiment 1, no inhibition was observed.

Experiment 3 Adjust the pH with 0.1N NaOH, 0.1N HCl, phosphate buffer,
An oral liquid preparation was prepared according to the following formulation, and the effect of pH on the amount of cetylpyridium chloride adsorbed was examined in the same manner as in Experiment 1. The results are shown in Table 3.

Ingredients Weight% Fragrance 0.3% Ethanol 10.0% Glycerin 5.0% Saccharin sodium 0.01% Cetylpyridinium chloride 0.05% Polyoxyethylene polyoxy 0.6% Propylene glycol pH adjuster Appropriate amount Purified water balance As shown in Table 3, the adsorption of cetylpyridinium chloride was not inhibited when the pH was 6.5 to 8.5 and the buffer concentration was 50 mM or less.

Experiment 4 A bactericidal test was carried out for the formulations B, C, D and E which did not inhibit the adsorption of cetylpyridinium chloride.

Take a platinum loop of Streptococcus mutans ATCC 25175, inoculate it in 10 ml of BHI medium, and in a Gas Pak at 37 ° C.
Cultured for 24 hours. After the culture, this bacterial solution was mixed with 100 ml of BHI medium, and further cultured at 37 ° C. for 20 hours. This culture solution is
The cells were centrifuged at 7000 rpm for 10 minutes to collect the cells. After washing the collected bacteria with sterile saline, dilute the bacteria with sterile saline, and adjusted to 0.2 with OD _600. Formulas B and C,
According to D and E, cetylpyridinium chloride concentration is 1ppm, 2p
The diluted sample was diluted with sterile purified water so as to be 4 ppm in pm, 0.1 ml of the diluted bacterial solution was added to 10 ml of the diluted sample, and the mixture was cultured at 37 ° C. for 5 minutes. One loop was taken from the sample and applied to a nutrient medium. This was cultured in Gas Pak at 37 ° C. for 48 hours, and the presence or absence of a colony was determined according to the following criteria. The results are shown in Table 4.

 ：: No colony was observed.

 ×: Generation of colonies was observed.

As shown in Table 4, it was confirmed that all the formulations retained the antibacterial activity of cetylpyridinium chloride.

Example 1 The following components were mixed and stirred in a conventional manner to produce a liquid preparation for oral cavity.

Ingredients Perfume 0.3% Ethanol 10.0% Sorbit 10.0% Stevia extract 0.05% Cetylpyridinium chloride 0.05% Polyoxyethylene polyoxy 0.5% Propylene glycol Purified water Remainder Example 2 The following components are mixed and stirred in a conventional manner, and A liquid preparation was prepared.

Ingredients Perfume 0.3% Ethanol 15.0% Glycerin 10.0% Saccharin sodium 0.02% Cetylpyridinium chloride 0.07% Polyoxyethylene polyoxy 0.6% Propylene glycol Remaining water Example 3 A liquid formulation was produced. When used, this was diluted 50-fold and used.

Ingredient Amount Perfume 4.0% Ethanol 20.0% Glycerin 10.0% Saccharin sodium 0.1% Cetylpyridinium chloride 2.5% Polyoxyethylene polyoxy 4.0% Propylene glycol Purified water Balance Effect of the Invention According to the present invention, cetylpyridinium chloride is applied to the tooth surface. An oral liquid preparation which does not inhibit adsorption and exhibits excellent effects in preventing plaque formation and preventing tooth decay can be obtained.

Claims (1)

(57) [Claims] (1) The ratio of cetylpyridinium chloride to polyoxyethylene in the molecule is 70% by weight or more, the molecular weight of polyoxypropylene is 3000 or more, and the concentration when used is 0.01 to 1.0% by weight. A certain amount of polyoxyethylene polyoxypropylene glycol is blended, and the pH is 6.5 to 8.5, and the buffer concentration is 50 mM or less. Liquid formulation.