JP3594065B2 - Dentifrice composition and method for stabilizing hydroxy-2-pyridone derivative or salt thereof - Google Patents

Description

上記式（１）において、Ｒ¹，Ｒ²はそれぞれ水素原子又は水酸基であり、かつＲ¹，Ｒ²の少なくとも一つは水酸基である。また、Ｒ³，Ｒ⁴，Ｒ⁵はそれぞれ水素原子又は一価の有機基であり、一価の有機基としてはアルキル基、アルケニル基、シクロアルキル基、ビシクロアルキル基、シクロアルキル−アルキル基、アリール基、アラルキル基、アリールアルケニル基、アリールオキシアルキル基、アリールメルカプトアルキル基、ベンズヒドリル基、フェニルスルホニルアルキル基、フリル基、フリルアルケニル基を挙げることができるが、炭素数１〜１８のアルキル基、炭素数２〜１８のアルケニル基、炭素数３〜１８のシクロアルキル基やシクロアルキル−アルキル基、ベンジル基が好ましい。
【０００８】
なお、上記式（１）のヒドロキシ−２−ピリドン誘導体は、１−ヒドロキシ−２−ピリドンあるいは３−ヒドロキシ−２−ピリドン骨格を有するが、各々互変異性体が存在する。１−ヒドロキシ−２−ピリドン骨格の場合は、２−ヒドロキシピリジン Ｎ−オキシド骨格等が異性体として存在し、３−ヒドロキシ−２−ピリドン骨格の場合は、２，３−ジヒドロキシピリジン骨格等が存在する。本発明にはこれらの異性体も含む。
【０００９】
更に、上記ヒドロキシ−２−ピリドン誘導体は、適当な塩基を用いた塩として使用することも可能である。塩の形態としてはナトリウム、カリウム、マグネシウム、カルシウム、ストロンチウム、亜鉛、銅、アルミニウム、ランタン、鉄、錫等の一価又は多価の金属塩、アンモニウム塩、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、エチレンジアミンヒドロキシルアミン類との塩、アルギニン、リジン等の塩基性アミノ酸との塩、又は塩基性アミノ酸を含む塩基性ペプチドや塩基性蛋白質との塩等が広く利用可能であり、薬学的に許容できる範囲から適宜選択できる。
【００１０】
上記式（１）のヒドロキシ−２−ピリドン誘導体又はその塩の配合量は０．０１〜１０％（重量％、以下同様）、特に０．１〜５％が好ましく、０．０１％より少ないと歯垢形成が抑制されない場合がある。また、１０％より多く配合すると使用感や配合上の問題が生じる場合がある。
【００１１】
また、ＰＯＥ・ＰＯＰエーテルとしては、ＰＯＥの重合度、ＰＯＰの重合度の異なった組み合わせの中から適宜選択できる。この場合、ＰＯＥの重合度は５〜３５０、特に２５〜３００、ＰＯＰの重合度は１０〜１００、特に３０〜７０であることが好ましい。
【００１２】
その配合量は０．１〜５．０％、特に０．５〜５．０％が好ましく、０．１％より少ないと経時による歯垢形成抑制効果低下の防止ができない場合がある。また３０％より多く配合すると使用感や配合上の問題が生じる場合がある。
【００１３】
本発明の歯磨組成物は、上記必須成分に加えて任意成分として、その他の添加剤、例えば研磨剤、粘稠剤、粘結剤、界面活性剤、甘味剤、防腐剤、有効成分等を配合でき、これら成分と水とを混合して製造できる。
【００１４】
歯磨剤の場合は、例えば研磨剤、粘稠剤、粘結剤、ＰＯＥ・ＰＯＰエーテル以外の界面活性剤、甘味剤、防腐剤、各種有効成分、色素、香料等を配合でき、これら成分と水とを混合して製造することができる。ここで研磨剤としては、沈降シリカ、シリカゲル、アルミノシリケート、ジルコノシリケート等のシリカ系研磨剤、第２リン酸カルシウム２水和物及び無水和物、ピロリン酸カルシウム、炭酸カルシウム、水酸化アルミニウム、アルミナ、炭酸マグネシウム、第３リン酸マグネシウム、ゼオライト、ケイ酸ジルコニウム、合成樹脂系研磨剤等が挙げられるが、特に沈降シリカ、水酸化アルミニウム等が好適に使用される。これらの配合量は組成物全体の２〜６０％、特に８〜４５％とすることが好ましい。
【００１５】
粘稠剤としては、グリセリン、ソルビット、プロピレングリコール、ポリエチレングリコール、キシリット、マルチット、ラクチット等、粘結剤としては、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース、カラギーナン、カーボポール、グアガム、モンモリロナイト、ゼラチン等、界面活性剤としては、アニオン界面活性剤、カチオン界面活性剤、非イオン性界面活性剤等を配合し得、具体的にはラウリル硫酸ナトリウム、α−オレフィンスルホン酸ナトリウム、Ｎ−アシルサルコシネート、Ｎ−アシルグルタメート、２−アルキル−Ｎ−カルボキシメチル−Ｎ−ヒドロキシエチルイミダゾリニウムベタイン、Ｎ−アシルタウレート、ショ糖脂肪酸エステル、アルキロールアマイド、ポリオキシエチレン硬化ヒマシ油、ポリグリセリン脂肪酸エステル、ポリオキシエチレンソルビタンモノステアレート等、甘味剤としては、サッカリンナトリウム、ステビオサイド、ステビアエキス、パラメトキシシンナミックアルデヒド、ネオヘスペリジルジヒドロカルコン、ペリラルチン等、防腐剤としては、パラ安息香酸エステル、安息香酸ナトリウム等、各種有効成分としては、フッ化ナトリウム、フッ化カリウム、フッ化アンモニウム、フッ化第１錫、モノフルオロリン酸ナトリウム等のフッ化物、正リン酸のカリウム塩、ナトリウム塩等の水溶性リン酸化合物、アラントインクロルヒドロキシアルミニウム、ヒノキチオール、アスコルビン酸、塩化リゾチーム、グリチルリチン酸及びその塩類、塩化ナトリウム、トラネキサム酸、イプシロンアミノカプロン酸、酢酸ｄｌ−トコフェロール、α−ビサボロール、クロロヘキシジン塩類、塩化セチルピリジニウム、アズレン、グリチルレチン酸、銅クロロフィリンナトリウム、グルコン酸銅等の銅化合物、乳酸アルミニウム、塩化ストロンチウム、硝酸カリウム、ベルベリン、ヒドロキサム酸及びその誘導体、トリポリリン酸ナトリウム、デキストラナーゼ、ムタナーゼ、アミラーゼ、メトキシエチレン・無水マレイン酸共重合体、ポリビニルピロリドン、エピジヒドロコレステリン、塩化ベンゼトニウム、ジヒドロコレステロール、トリクロロカルバニリド、クエン酸亜鉛、トウキ軟エキス、オウバクエキス、チョウジ、ローズマリー、オウゴン、ベニバナ等の抽出物等、香料としては、ｌ−メントール、カルボン、アネトール、リモネン等のテルペン類又はその誘導体等、着色剤としては、青色１号、黄色４号、二酸化チタン等が例示される。なお、これら成分の配合量は、本発明の効果を妨げない範囲で通常量とすることができる。
【００１６】
【発明の効果】
本発明の歯磨組成物は、ノニオン活性剤ＰＯＥ・ＰＯＰエーテルを含有することにより、ヒドロキシ−２−ピリドン誘導体又はその塩の歯垢形成抑制効果の経時安定性に優れている。
【００１７】
【実施例】
以下、実験例及び実施例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。なお、各例中の％はいずれも重量％である。
【００１８】
〔実験例〕
下記に示す組成の歯磨組成物を調製し、製剤をプラスチックチューブ容器に充填し、５０℃及び室温で２週間保存後、歯垢形成抑制率を測定した。

【００１９】
歯垢形成抑制率の測定
ストレプトコッカス・ソブリナス６７１５株を用いて、試験管内における歯垢抑制モデル試験を行った。ストレプトコッカス・ソブリナス６７１５株を３．７％ブレイン・ハート・インヒュージョン（ＢＨＩ）を用いて培養して得た培養液を遠心分離し、培養上清と菌体を得た。培養上清をメンブランフィルターで濾過し、更に、ｐＨ７．０リン酸緩衝生理食塩水（ＰＢＳ）を用いて同様にしてバッファー交換し、２０倍濃縮培養上清を得た。菌体はＰＢＳに懸濁した後、沸騰水浴中で２０分間処理して加熱死菌懸濁液とした。室温に冷却後、ＰＢＳを用いて５５０ｎｍにおける吸光度（Ａ５５０）が４．５となる加熱死菌懸濁液を調製した。ガラス試験管に２０倍濃縮培養上清１ｍｌ、加熱培養上清１ｍｌ、１０％ショ糖ＰＢＳ溶液、及び試験歯磨３倍ＰＢＳ希釈分散液の遠心分離上清３ｍｌを添加混合した。この試験管を６０度の傾斜に保って３７℃で１６時間静置培養した後、試験管壁に付着した死菌を超音波処理で分散してその懸濁液の５５０ｎｍの吸光度（Ａ５５０）を測定した。また、対照として試験歯磨遠心上清の代わりにＰＢＳを添加したものについても同様の試験を行い、下記式により歯垢形成抑制率を算出した。
歯垢形成抑制率（％）＝
〔（Ａ５５０（対照）−Ａ５５０（サンプル））／Ａ５５０（対照）〕×１００
【００２０】
【表１】

【００２１】
表１の結果のように、ＰＯＥ・ＰＯＰエーテルを配合した歯磨は、５０℃に保存しても効果の減少が少ないことが明らかであることから、ＰＯＥ・ＰＯＰエーテルは、歯磨の保存によるヒドロキシ−２−ピリドン誘導体又はその塩の歯垢形成抑制効果の減少を抑制する効果を示すことが認められた。
【００２２】

【００２３】

【００２４】

【００２６】

【００２７】

【００２８】

【００２９】

【００３０】

【００３３】

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a dentifrice composition in which the stability of a hydroxy-2-pyridone derivative or a salt thereof having a plaque inhibitory effect is enhanced, and a method of stabilizing a hydroxy-2-pyridone derivative or a salt thereof .
[0002]
Problems to be solved by the prior art and the invention
The plaque-suppressing effect of an oral composition containing a hydroxy-2-pyridone derivative or a salt thereof is described in JP-A-7-82126. However, in an oral composition such as dentifrice, the hydroxy-2-pyridone derivative or a salt thereof shows a decrease in plaque inhibitory effect over time, particularly when stored at a high temperature.
[0003]
Therefore, there is a demand for a method of preventing a decrease in the plaque-suppressing effect over time when a hydroxy-2-pyridone derivative or a salt thereof is added to an oral composition such as dentifrice.
[0004]
Means for Solving the Problems and Embodiments of the Invention
The present inventors have conducted intensive studies in order to meet the above demand, and as a result, a dentifrice composition containing a hydroxy-2-pyridone derivative or a salt thereof is added to a polyoxyethylene / polyoxypropylene block copolymer which is a nonionic activator. It has been found that by adding a coalesced compound (hereinafter referred to as POE.POP ether), a favorable result can be obtained to prevent the hydroxy-2-pyridone derivative or a salt thereof from deteriorating the plaque formation inhibitory effect. It is what led to.
[0005]
Hereinafter, the present invention will be described in more detail. The dentifrice composition of the present invention contains a hydroxy-2-pyridone derivative or a salt thereof and a nonionic activator POE.POP ether.
[0006]
In the present invention, the hydroxy-2-pyridone derivative or a salt thereof is represented by the following general formula (1).
[0007]
Embedded image

In the above formula (1), R ¹ and R ² are each a hydrogen atom or a hydroxyl group, and at least one of R ¹ and R ² is a hydroxyl group. R ³ , R ⁴ , and R ⁵ are each a hydrogen atom or a monovalent organic group, and examples of the monovalent organic group include an alkyl group, an alkenyl group, a cycloalkyl group, a bicycloalkyl group, a cycloalkyl-alkyl group, aryl group, an aralkyl group, an arylalkenyl group, an aryloxy group, an aryl mercaptoalkyl group, benzhydryl group, phenylsulfonyl group, a furyl group, there may be mentioned furyl alkenyl group, an alkyl group having 1 to 18 carbon atoms, An alkenyl group having 2 to 18 carbon atoms, a cycloalkyl group having 3 to 18 carbon atoms, a cycloalkyl-alkyl group, and a benzyl group are preferable.
[0008]
The hydroxy-2-pyridone derivative of the above formula (1) has a 1-hydroxy-2-pyridone or 3-hydroxy-2-pyridone skeleton, and each has a tautomer. In the case of a 1-hydroxy-2-pyridone skeleton, a 2-hydroxypyridine N-oxide skeleton or the like exists as an isomer, and in the case of a 3-hydroxy-2-pyridone skeleton, a 2,3-dihydroxypyridine skeleton or the like exists. I do. The present invention includes these isomers.
[0009]
Further, the above hydroxy-2-pyridone derivative can be used as a salt using an appropriate base. Examples of the salt form include sodium, potassium, magnesium, calcium, strontium, zinc, copper, aluminum, lanthanum, iron, tin and other monovalent or polyvalent metal salts, ammonium salts, monoethanolamine, diethanolamine, triethanolamine, Salts with ethylenediaminehydroxylamines, salts with basic amino acids such as arginine and lysine, or salts with basic peptides and basic proteins containing basic amino acids are widely available and pharmaceutically acceptable Can be selected as appropriate.
[0010]
The compounding amount of the hydroxy-2-pyridone derivative of the above formula (1) or a salt thereof is preferably 0.01 to 10% (% by weight, the same applies hereinafter), particularly preferably 0.1 to 5%, and if less than 0.01%. Plaque formation may not be suppressed. Further, if the content is more than 10%, there may be a problem in use feeling and formulation.
[0011]
The POE / POP ether can be appropriately selected from combinations having different degrees of polymerization of POE and POP. In this case, the degree of polymerization of POE is preferably 5 to 350, particularly 25 to 300, and the degree of polymerization of POP is preferably 10 to 100, particularly 30 to 70.
[0012]
The compounding amount is preferably from 0.1 to 5.0%, particularly preferably from 0.5 to 5.0%. If the amount is less than 0.1%, it may not be possible to prevent the plaque formation inhibitory effect from decreasing over time. In addition, if the content is more than 30%, there may be a problem in use feeling and formulation.
[0013]
The dentifrice composition of the present invention contains other additives as optional components in addition to the above essential components, such as abrasives, thickeners, binders, surfactants, sweeteners, preservatives, and active ingredients. It can be produced by mixing these components with water.
[0014]
In the case of a dentifrice, for example, an abrasive, a thickener, a binder, a surfactant other than POE / POP ether, a sweetener, a preservative, various active ingredients, a coloring matter, a flavor, and the like can be compounded. Can be mixed to produce. Examples of the abrasive include silica-based abrasives such as precipitated silica, silica gel, aluminosilicate and zirconosilicate, dibasic calcium phosphate dihydrate and anhydride, calcium pyrophosphate, calcium carbonate, calcium hydroxide, aluminum hydroxide, alumina, carbonate Examples thereof include magnesium, tribasic magnesium phosphate, zeolite, zirconium silicate, and a synthetic resin-based abrasive. In particular, precipitated silica and aluminum hydroxide are preferably used. The amount of these compounds is preferably 2 to 60%, particularly preferably 8 to 45% of the whole composition.
[0015]
As a thickener, glycerin, sorbit, propylene glycol, polyethylene glycol, xylit, maltitol, lactit, etc .; as a binder, sodium carboxymethylcellulose, hydroxyethylcellulose, carrageenan, carbopol, guar gum, montmorillonite, gelatin, etc. As the agent, an anionic surfactant, a cationic surfactant, a nonionic surfactant, or the like can be blended. Specifically, sodium lauryl sulfate, sodium α-olefin sulfonate, N-acyl sarcosinate, N- Acyl glutamate, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, N-acyl taurate, sucrose fatty acid ester, alkylol amide, polyoxyethylene hydrogenated castor oil Polyglycerin fatty acid esters, polyoxyethylene sorbitan monostearate, etc., as sweeteners, sodium saccharin, stevioside, stevia extract, paramethoxycinamic aldehyde, neohesperidyl dihydrochalcone, perillartin, etc., as preservatives, parabenzoic acid esters , Sodium benzoate, and other active ingredients include fluorides such as sodium fluoride, potassium fluoride, ammonium fluoride, stannous fluoride, and sodium monofluorophosphate; potassium salts and sodium salts of orthophosphoric acid; Water-soluble phosphate compounds, allantoinchlorohydroxyaluminum, hinokitiol, ascorbic acid, lysozyme chloride, glycyrrhizic acid and salts thereof, sodium chloride, tranexamic acid, epsilon aminocaproic acid, vinegar Acid dl-tocopherol, α-bisabolol, chlorohexidine salts, cetylpyridinium chloride, azulene, glycyrrhetinic acid, copper copper chlorophyllin sodium, copper compounds such as copper gluconate, aluminum lactate, strontium chloride, potassium nitrate, berberine, hydroxamic acid and its derivatives, tripolyline Sodium acid, dextranase, mutanase, amylase, methoxyethylene / maleic anhydride copolymer, polyvinylpyrrolidone, epidihydrocholesterine, benzethonium chloride, dihydrocholesterol, trichlorocarbanilide, zinc citrate, touki soft extract, oak extract , Fragrances such as l-menthol, carvone, anethole, limonene, etc. The derivatives thereof, as the colorant, Blue No. 1, Yellow No. 4, titanium dioxide and the like. In addition, the compounding amount of these components can be a normal amount as long as the effects of the present invention are not impaired.
[0016]
【The invention's effect】
Since the dentifrice composition of the present invention contains the nonionic activator POE.POP ether, the hydroxy-2-pyridone derivative or a salt thereof is excellent in the plaque formation inhibitory effect over time.
[0017]
【Example】
Hereinafter, the present invention will be described in detail with reference to experimental examples and examples, but the present invention is not limited to the following examples. In addition,% in each example is all weight%.
[0018]
[Experimental example]
A dentifrice composition having the composition shown below was prepared, the preparation was filled in a plastic tube container, and stored at 50 ° C. and room temperature for 2 weeks, and then the plaque formation inhibition rate was measured.

[0019]
Measurement of plaque formation inhibition rate A plaque inhibition model test in a test tube was performed using Streptococcus sobrinus 6715 strain. A culture solution obtained by culturing Streptococcus sobrinus 6715 strain using 3.7% brain heart infusion (BHI) was centrifuged to obtain a culture supernatant and cells. The culture supernatant was filtered with a membrane filter, and the buffer was further exchanged in the same manner using pH 7.0 phosphate buffered saline (PBS) to obtain a 20-fold concentrated culture supernatant. After suspending the cells in PBS, the cells were treated in a boiling water bath for 20 minutes to obtain a heat-killed suspension. After cooling to room temperature, a heat-killed bacterial suspension having an absorbance at 550 nm (A550) of 4.5 using PBS was prepared. In a glass test tube, 1 ml of a 20-fold concentrated culture supernatant, 1 ml of a heated culture supernatant, 10% of a sucrose PBS solution, and 3 ml of a centrifuged supernatant of a 3x PBS diluted dispersion of test toothpaste were added and mixed. The test tube was incubated at 37 ° C. for 16 hours while keeping the tube at an inclination of 60 °, and then the dead bacteria adhered to the test tube wall were dispersed by ultrasonic treatment, and the absorbance at 550 nm (A550) of the suspension was measured. It was measured. In addition, the same test was carried out for a control to which PBS was added instead of the test dentifrice centrifugal supernatant, and the plaque formation inhibition rate was calculated by the following equation.
Inhibition rate of plaque formation (%) =
[(A550 (control) -A550 (sample)) / A550 (control)] x 100
[0020]
[Table 1]

[0021]
As can be seen from the results in Table 1, it is clear that the effect of the dentifrice containing the POE POP ether is small even when stored at 50 ° C. It was recognized that the 2-pyridone derivative or a salt thereof exhibited an effect of suppressing a decrease in the effect of inhibiting plaque formation.
[0022]

[0023]

[0024]

[0026]

[0027]

[0028]

[0029]

[0030]

[0033]

Claims (2)

A polyoxyethylene / polyoxypropylene block in which a hydroxy-2-pyridone derivative represented by the following general formula (1) or a salt thereof has a polyoxyethylene polymerization degree of 5 to 350 and a polyoxypropylene polymerization degree of 10 to 100. A dentifrice composition comprising a copolymer in an amount of 0.1 to 5.0% by weight of the whole composition .

(Wherein, R ¹ and R ² are each a hydrogen atom or a hydroxyl group, and at least one of R ¹ and R ² is a hydroxyl group. Further, R ³ , R ⁴ and R ⁵ are each a hydrogen atom or Alkyl, alkenyl, cycloalkyl, bicycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, arylalkenyl, aryloxyalkyl, arylmercaptoalkyl, benzhydryl, phenylsulfonylalkyl, furyl And a monovalent organic group selected from furylalkenyl groups .) Polyoxyethylene having a polymerization degree of polyoxyethylene of 5-350 and a polymerization degree of polyoxypropylene of 10-100 in a dentifrice composition containing a hydroxy-2-pyridone derivative represented by the following general formula (1) or a salt thereof: -The method for stabilizing a hydroxy-2-pyridone derivative or a salt thereof, wherein the polyoxypropylene block copolymer is blended in an amount of 0.1 to 5.0% by weight of the whole composition.

(Wherein, R ¹ and R ² are each a hydrogen atom or a hydroxyl group, and at least one of R ¹ and R ² is a hydroxyl group. Further, R ³ , R ⁴ and R ⁵ are each a hydrogen atom or Alkyl, alkenyl, cycloalkyl, bicycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, arylalkenyl, aryloxyalkyl, arylmercaptoalkyl, benzhydryl, phenylsulfonylalkyl, furyl And a monovalent organic group selected from furylalkenyl groups .)