JPS6042764B2 - Oral composition containing chlorhexidine - Google Patents

Description

Detailed Description of the Invention The present invention provides an oil-in-water type (oil-in-water type) containing chlorhexidine.
Regarding the emulsion type oral composition (hereinafter referred to as '0/W type'), more specifically, 0/W does not deactivate chlorhexidine and activates chlorhexidine to exhibit its effectiveness well. The present invention relates to an oral composition of the type.

As is well known, periodontal disease is caused by tartar, plaque, increased burden, and systemic factors. Plaque is produced when microorganisms metabolize and food particles are decomposed by microorganisms, so in order to prevent or cure periodontal disease, it is necessary to effectively suppress the growth of oral microorganisms and implement sterilization. It is necessary to measure.

In addition, when looking at the symptoms of alveolar pyorrhea, most of them are inflammatory or mixed types such as inflammatory and atrophic.
In order to prevent, cure or alleviate these diseases,
Correct brushing using toothpaste and, in some cases, treatments such as scaling are required, but in addition, drug therapy includes the use of bactericides to suppress and kill microbial growth, and the prevention of inflammatory diseases with anti-inflammatory agents. , cure or remission is required.

For this reason, several oral compositions containing bactericides and anti-inflammatory agents as active ingredients have been known and actually used for the purpose of preventing, curing, or relieving periodontal diseases. There are various problems with this type of oral composition.

In other words, chlorhexidine is considered to be the best method for killing oral microorganisms, and for this reason, chlorhexidine is often used as a disinfectant. However, chlorhexidine is generally easily deactivated and has a sterilizing power of 11,100 to 111,000, which is less than its original sterilizing power.
is also said to decrease. (Although there are some ointments that have been devised to prevent this deactivation, they have not yet been able to sufficiently prevent the deactivation of chlorhexidine.For example, currently commercially available ointments containing chlorhexidine contain Escherichia coli and yellow grapevine. The minimum bactericidal concentration for microorganisms such as cocci and Bacillus subtilis is 50 to 100 p in terms of rehexidine concentration.
pm, clearly chlorhexidine was deactivated in the ointment,
Its bactericidal power is lowered to 1110-1130 compared to that of chlorhexidine alone. ) Therefore, even if chlorhexidine is blended into an oral composition, there are problems such as the bactericidal effect being easily lost in the composition, so in order to exert a sufficient bactericidal effect, it is necessary to Chlorhexidine must be incorporated in relatively large amounts. but,
Mixing a large amount of a bactericidal agent (chlorhexidine) is highly likely to cause side effects such as oral irritation and sensitization, so it is important to mix as little as possible to achieve sufficient effects. Conventionally, ointments containing chlorhexidine have been of water-in-oil type (hereinafter referred to as "W/0 type").

) Most of the ointments are emulsion type, and in the past, measures were often taken to prevent the deactivation of chlorhexidine in these types of ointments (however, as mentioned above, sufficient prevention of deactivation has not been achieved. ) but W/0
When using a molded ointment especially in the oral cavity, it has poor affinity for the gums and oral mucosa and is very uncomfortable to use.
When used in the oral cavity, it is necessary to increase the feeling of use, so
/W type. However, 0
/ W-type emulsion type ointment. When preparing chlorhexidine, since chlorhexidine is a cationic fungicide,
Previously, highly hydrophilic surfactants with nonionic ethylene oxide added thereto were sometimes used, but using only this type of surfactant resulted in deactivation of chlorhexidine. However, it has not necessarily been possible to exhibit sufficient microbial growth inhibition and bactericidal effects.

In view of the above circumstances, the present inventors used chlorhexidine, which itself has excellent bactericidal and microbial growth inhibiting effects,
As a result of intensive research in order to obtain oral compositions such as O/W emulsion type oral ointments that do not lose their activity or lose their activity even when mixed with chlorhexidine and have good medicinal effects even when mixed in small amounts, we have found that chlorhexidine 0/W emulsion type oral composition containing zorbitan fatty acid ester,
Alternatively, when polyoxyethylene sorbitan fatty acid ester is blended alone, the minimum bactericidal concentration against microorganisms such as Escherichia coli, Staphylococcus aureus, and Bacillus subtilis is significantly higher than, for example, an aqueous solution of chlorhexidine in which chlorhexidine is dissolved at the same concentration. Increased sterilizing power by 1120
Although the deactivation of chlorhexidine is significant, when sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester are simultaneously added to an O/W oral composition containing chlorhexidine, chlorhexidine There is no deactivation of chlorhexidine, and on the contrary, the synergistic effect of both of the above active agents occurs, activating chlorhexidine, and the bactericidal power is improved rather than that of an aqueous solution of chlorhexidine alone, and it has an excellent bactericidal effect and microbial growth inhibiting effect. Therefore, a small amount of chlorhexidine can provide sufficient medicinal efficacy, and it can be used safely without the risk of side effects such as oral irritation or sensitization, and it has good affinity for the gingiva and oral mucosa. It was discovered that there is no discomfort when applied and the usability is very good, leading to the creation of the present invention.

That is, the present invention can activate chlorhexidine by using sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester in combination, and is effective in treating pyorrhea, gingivitis, bad breath, and other periodontal diseases. An O/W emulsion-type chlorhexidine-containing oral cavity that can inhibit the growth of oral microorganisms that are thought to be the cause of periodontal diseases, and enhance the bactericidal effect, and can be suitably used for the prevention, cure, and remission of these periodontal diseases. The present invention provides a composition for use. The present invention will be explained in detail below.

In the chlorhexidine-containing oral composition according to the present invention, as chlorhexidine, its hydrochloride or gluconate is usually used.

Further, the blending amount thereof is preferably 0.0001 to 1.0% (weight %, same hereinafter), particularly 0.01 to 0.3% of the total. If the amount of chlorhexidine is within this range, it will exhibit good bactericidal and microbial growth inhibiting effects,
Moreover, there is no risk of causing primary stimulation or sensitization stimulation. In the present invention, the chlorhexidine is blended with chlorhexidine.
/W type oral composition contains sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester. In this case, the sorbitan fatty acid ester is usually represented by the following general formula (1) (where R is a hydrogen group or One (C
H2) m-CH3 represents an alkyl group where m=8 to 20.

) is used, and the polyoxyethylene sorbitan fatty acid ester is usually represented by the following general formula (2) (where R is the same as in formula (1), and n=
There are 10 to 25.

) is used. Furthermore, the zorbitan fatty acid ester has a hydrophilic-lipophilic ratio (HL, B) of 2.
~8, and the polyoxyethylene sorbitan fatty acid ester is HI. B is 10 to 16. The blending amount of the sorbitan fatty acid ester is generally 0.01 to 10%, preferably 0.1 to 5% in the oral composition, and the blending amount of the polyoxyethylene sorbitan fatty acid ester is 0.01 to 20%. , preferably 0.05 to 10
%.

If the amount of both of these active agents is less than 0.01%, it will be difficult to make an ointment with moldability, and if the amount of zorbitan fatty acid ester is less than 1%, it will be difficult to make an ointment with moldability.
If the amount of polyoxyethylene sorbitan fatty acid ester is more than 20%, the ointment becomes too hard and may not be able to withstand actual use in the oral cavity. Therefore, it is preferable that the amounts of both of the active agents be within the above-mentioned ranges. The blending ratio of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester is preferably 1:2 to 1:10 by weight, thereby making it possible to more reliably measure the activation of chlorhexidine. Oral compositions such as oral ointments according to the present invention contain various essential components such as chlorhexidine, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester depending on the type of oral composition to be prepared. It is prepared by adding ingredients such as higher alcohols, thickeners, fragrances, sweeteners, active agents, etc., and preparing it in the form of an O/W emulsion by a conventional method.

In the oral composition thus obtained, chlorhexidine is not inactivated in the composition, chlorhexidine is activated by the synergistic action of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester, and chlorhexidine alone is activated. The minimum sterilizing concentration against various microorganisms is lower than that of an aqueous solution, and the sterilizing power is improved.

Therefore, even in a small amount of chlorhexidine, which is free from the risk of side effects, it exhibits its medicinal efficacy well and reliably exhibits its growth inhibiting and bactericidal effects on microorganisms that cause periodontal diseases such as alveolar pyorrhea. , it can be successfully used for the prevention, treatment, and remission of these periodontal diseases. In addition, since this oral composition only needs to contain a small amount of chlorhexidine as described above, there is no risk of side effects such as oral irritation and sensitization stimulation, and as shown in Example 1 below, it is effective against mice and rats. The LD5O value was 10y/Kg or more in acute toxicity tests on rats, and no damage was observed in tests on rat gingiva, so it can be used safely.

Moreover, since this composition is in O/W type and has hydrophilic properties, it has good affinity for the gingiva and oral mucosa, does not cause any discomfort in the circulatory cavity during use, and has an excellent feeling of use. have.

In addition, the mixture of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester is compatible with other ointment ingredients, and is also compatible with chlorhexidine, fragrances, etc., so the oral composition has good stability and long-lasting properties. It can withstand storage for a long period of time, does not deteriorate in quality or medicinal efficacy of chlorhexidine, and fully exhibits the bactericidal and microorganism growth inhibiting effects of chlorhexidine in the oral cavity. Next, experimental examples will be shown to specifically explain the features of the present invention.

Experimental Example 1 In vitro experiment 0.1% by weight of chlorhexidine was added to an ointment base with the following composition, and 1% by weight of sorbitan monostearate was added to this.
and polyoxyethylene sorbitan monostearate (
O/W emulsion type ointment for the oral cavity (sample number 1) obtained by blending 5% by weight of sorbitan monostearate (n = 20), O/W type ointment (sample number 1) obtained by blending 1% by weight of sorbitan monostearate ( For Sample No. 2) and O/W ointment (Sample No. 3) obtained by blending 5% by weight of polyoxyethylene sorbitan monostearate, the minimum bactericidal concentration against the bacterial species shown in Table 1 was determined by in vitro experiments. Examined.

In addition, the minimum bactericidal concentration of currently commercially available ointments containing chlorhexidine against various microorganisms was similarly investigated.

Furthermore, as a control, 0.01% by weight of chlorhexidine
Using an aqueous solution (sample number 7), its minimum bactericidal concentration was investigated. Table 1 shows the results of the minimum bactericidal concentration in each ointment when converted to chlorhexidi]/concentration.

As is clear from the above results, O/W emulsion type ointments obtained by blending sorbitan fatty acid ester or polyoxyethylene sorbitan fatty acid ester alone with an ointment base containing chlorhexidine, as well as commercially available ointments containing chlorhexidine, In both cases, the minimum bactericidal concentration against various microorganisms was quite high, and the chlorhexidine was deactivated in the ointment, resulting in a significant decrease in its bactericidal activity. It was found that the minimum bactericidal concentration is lower than that of chlorhexidine alone (chlorhexidine aqueous solution), and that chlorhexidine is activated by the synergistic action of the two active agents in combination, and has extremely excellent bactericidal activity. . Experimental Example 2 Clinical Trial An O/W emulsion type ointment with the following composition was prepared and administered twice in the morning and evening (A) to 112 patients with pyorrhea and gingivitis. 5y/time) was applied to the teeth and gums for 4 weeks.

As a result, an improvement in redness and swelling was observed in 75% of patients, suppression of bleeding and drainage in 80% of patients, and a remission or healing effect on periodontal disease was observed. In addition, inhibition of tartar and plaque deposition was observed in more than 80% of patients. In general, more than 80% of the causes of periodontal disease are plaque.
Considering that this is caused by the decomposition of microbial metabolites and food debris by microorganisms, the results of the above clinical tests indicate that there is no deactivation of chlorhexidine in the ointment according to the present invention. On the contrary, chlorhexidine was activated, and chlorhexidine successfully exerted its growth-inhibiting and bactericidal effects on oral microorganisms, which was recognized to indicate that the cause of periodontal disease was eliminated. It has been reported that the ointment has good affinity for the gums and oral mucosa and does not cause discomfort when applied.

As explained above, according to the present invention, the inactivation of chlorhexidine is reliably prevented, its activation is successfully achieved, and the growth inhibition and bactericidal effect of oral microorganisms can be improved, and the use It has a good texture and can withstand long-term storage, and can be effectively used for the prevention, cure, or remission of periodontal diseases caused by microorganisms.

Examples are shown below.

Example 1 An O/W emulsion type ointment having the following composition was prepared by a conventional method.

Example 2 An O/W emulsion type ointment having the following composition was prepared by a conventional method.

All of the ointments according to the above examples had excellent bactericidal effects, in which the efficacy of chlorhexidine was well exhibited.

In addition, as a result of conducting an acute toxicity test on mice and rats for the ointment of Example 1, the LD5O value was 10.
y or more/K9, and no damage was observed in the results of examining the effects on the gingiva of rats.

Example 3 An O/W emulsion type ointment having the following composition was prepared by a conventional method.

This product effectively treats periodontal disease when used twice in the morning and evening, has good storage stability, provides a good feeling of use even after being stored at room temperature for two months, and has a minimum bactericidal concentration of chlorhexidine. The bactericidal activity was also maintained at a good level with a concentration of 1 ppm.

Claims (1)

[Scope of Claims] 1. An oil-in-water emulsion type chlorhexidine-containing oral composition characterized by using a combination of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester. 2 The blending amount of sorbitan fatty acid ester is 0.01 to 1
0% by weight, the blending amount of polyoxyethylene sorbitan fatty acid ester is 0.01 to 20% by weight, and the content of chlorhexidine is 0.0001 to 1% by weight.
The oral composition according to claim 1. 3 The blending ratio of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester is 1 as a weight ratio.
The composition for oral cavity according to claim 1 or 2, wherein the ratio is from 2 to 1:10.