CN1443072A - Compositions containing ascorbyl phosphate - Google Patents

Abstract

A composition comprising ascorbic acid phosphate, characterized by comprising: ascorbic acid phosphate ester or a salt thereof; (B) an anionic surfactant; and (C) one or more sugar alcohols selected from the group consisting of a mono-sugar alcohol having 4 or more carbon atoms, an oligosaccharide alcohol and a reduced starch syrup; wherein the calcium and aluminium ion sources are present in an amount of less than 10% by weight of the total composition and the composition has a pH of 8.0 or more after storage for 1 month at 25 ℃.

Description

Compositions containing ascorbyl phosphate

technical field

The present invention relates to an oral and external composition containing ascorbyl phosphate.

Background technique

It is known that ascorbyl phosphate and salts thereof play an important role in developing enzyme activities in vivo, and have various physiological activities. In particular, it has been recognized that they act as a coenzyme for prolyl and lysyl hydroxylases and are essential for collagen synthesis. In recent years, attention has been paid to an ester or salt of an antioxidant vitamin that removes excess active oxygen generated in the body and prevents oxygen imbalance in living tissue. Also, these esters and salts are known to have various physiological activities.

So far, a large number of compositions containing ascorbyl phosphate and salts thereof have been proposed, including cosmetics (Japanese Patent Publication No. Sho 62-298508 and Japanese Patent Publication No. Hei3-63208), whitening cosmetics (Japanese Patent Publication No. Sho 63-243014 and Japanese Patent Publication No. Hei 1-305009 and No. 3-133914), oral cavity containing agent (Japanese Patent Publication No. Sho 62-96408), bath agent (Japanese Patent Publication No. Sho 62-96410) , oral compositions (Japanese Patent Publication Nos. Hei 2-292210, 2-292211 and 4-173727), external preparations for skin (Japanese Patent Publication Nos. Hei 3-34908, 7-206632 and 8-133951) and the like.

However, when ascorbyl phosphate or its salts are formulated into various types of compositions, they become unstable due to the influence of calcium, metals, microorganisms and pH, with the attendant problem that they are converted into ascorbic acid and phosphoric acid. Therefore, there is a need to keep the composition stable.

To combat this, add antioxidants or chelating agents to the formula. Also, in order to minimize its contact with water, research has been conducted to convert this composition into powder or granules (Japanese Patent Laid-Open No. Hei7-252127). However, in the composition formulated with ascorbyl phosphate and its salts, it is necessary not only to stabilize the formulated ascorbyl phosphate, but also to enable them to achieve higher physiological activity in application.

In this regard, formulations with good applicability, such as pastes, liquids or creams, should be selected so as to maintain proper foamability and dispersibility. At the same time, while maintaining the structure of ascorbyl phosphate and its salts in these preparations, the esters or salts should be absorbed by the living body to which they are applied. There is a need to develop a technology wherein in such an aqueous formulation an ascorbyl phosphate or a salt thereof can be stably formulated to exhibit this efficacy.

Detailed Description of the Invention

It is an object of the present invention to provide a composition formulated with ascorbyl phosphate and its salts in a stable and active state.

In order to achieve the above object, the present inventors have carried out in-depth research and found that when an anionic surfactant and one or more are selected from monosaccharide alcohols, oligosaccharides and oligosaccharides containing 4 or more carbon atoms, Sugar alcohols and sugar alcohols of reduced starch syrup, when formulated in compositions containing ascorbyl phosphate or salts thereof, the content of sources of calcium and aluminum ions is limited to less than 10% of the total composition (herein weight percent, The same below), and its initial pH value is adjusted to not less than 8.0, preferably 8.5 to 9.5, after storing this composition at 25°C for more than one month, the stability of the composition containing this ascorbyl phosphate , increasing with time. In addition, after long-term storage, the residual rate of ascorbyl phosphate or its salt in the composition can be effectively prevented from decreasing, so as to ensure its effectiveness. Although the initial pH is adjusted to 8.0 or above, especially 8.5 to 9.5, the pH of many compositions formulated with ascorbyl phosphate or its salts will change within a month when stored at around room temperature after preparation. large variations, and in some cases the pH will drop below 8.0. Stable formulations of ascorbyl phosphate and its salts cannot be obtained when the pH is 8.0 or below after storage at 25°C for one month. We have thus found that the pH of the composition after storage at 25°C for one month is important for the stability and active state of formulations of ascorbyl phosphate and salts thereof.

Brief Description of the Drawings [Attachment 1]

Accompanying drawing 1 (A), 1 (B) and 1 (C) are the schematic diagrams showing the state of anterior tooth gingiva respectively, wherein accompanying drawing 1 (A) shows the state not suffering from gingivitis, and accompanying drawing 1 (B) shows suffering from The state of mild degree of gingivitis, Figure 1(C) shows the state of having appreciable degree of gingivitis.

The best way to carry out the invention

The present invention will now be described in more detail.

The composition of the present invention is characterized by containing (A) ascorbyl phosphate or its salt, (B) anionic surfactant and (C) selected from monosaccharide alcohols, oligosaccharide alcohols and reduced starches containing 4 or more carbon atoms One or more sugar alcohols of a syrup in which the source of calcium and aluminum ions is less than 10% of the total composition and the composition has a pH of 8.0 or above after storage at 25°C for one month.

Ascorbyl phosphates refer to those esters in which one or more hydroxyl groups at any of the 2, 3, 5 and 6 positions of ascorbic acid are esterified with a compound such as phosphoric acid and polyphosphate. Examples include ascorbyl-2-phosphate, ascorbyl-3-phosphate, ascorbyl-6-phosphate, ascorbyl-2-polyphosphate, and the like. Salts of these esters include, for example, alkali metal salts and alkaline earth metal salts, such as sodium, potassium, calcium, magnesium, and the like. Of course, in compositions for the oral cavity, magnesium salts and sodium salts of ascorbyl phosphate are preferred from the standpoint of prevention and treatment of periodontal diseases.

Its amount is 0.001 to 10%, preferably 0.01 to 5%, of the total composition. If the amount is too small, the potency cannot be expressed satisfactorily. Larger amounts may reduce availability.

Second, the purpose of using anionic surfactants is to provide the composition with a suitable degree of foaming power and dispersibility. Although it has been recognized that the addition of anionic surfactants will reduce the stability of ascorbyl phosphate or its salts, according to the present invention, if anionic surfactants are formulated, they can be combined by storing the composition at 25°C for one month. Maintaining the pH of the product at or above 8.0 overcomes this while successfully obtaining a stable formulation of ascorbyl phosphate or a salt thereof.

The anionic surfactants used in the present invention are those commonly used known to those of ordinary skill in the art, including, for example, alkyl sulfates, polyoxyethylene alkyl sulfates, α-sulfo fatty acid esters, α-olefinic Sulfonate, Alkyl or Hydroxyalkyl Ether Carboxylate, N-Acylated Taurine, N-Acylated Glycine, N-Acylated Aspartic Acid, N-Acylated Sarcosine, N-Acylated Glutaric acid, monoalkyl phosphate, alkyl amido ether sulfate, alkyl (poly) glyceryl ether sulfate, alkyl (poly) glyceryl ether carboxylate, secondary amide type N-acyl amino acid salt, tartrate alkyl amide, alkylamide malate, alkylamide citrate, alkyl (poly) glycerol sulfonate, monoglyceride succinate, etc. Among them, alkyl sulfates are preferable.

The amount of an anionic surfactant is suitably selected, usually from 0.1 to 10%, preferably from 0.5 to 3%, of the total composition.

The composition of the present invention should also be formulated with one or more ingredients selected from monosaccharide alcohols, oligosaccharide alcohols and reduced starch syrups containing not less than 4 carbon atoms. Examples of monosaccharide alcohols having 4 or more carbon atoms include erythritol, xylitol, mannitol, sorbitol, galactitol, iditol and the like. Examples of oligosaccharide alcohols include maltitol, lactitol, palatinit, maltotriitol, isomaltotriitol and the like. Reduced starch syrup includes, for example, a low saccharified reduced starch syrup, a high saccharified reduced starch syrup, a reduced maltose syrup, and the like. These may be used alone, or two or more kinds may be used in combination.

Although the amount of these sugar alcohols may be 1 to 80%, preferably 5 to 60%, of the total composition, these sugar alcohols are formulated in a ratio of 0.5 or more, more preferably 0.5 to 2.0, compared to the amount of water in the composition. The ratio of 0.75 to 1.5 is most preferred. This allows the ascorbyl phosphate or salt thereof to more effectively exert its effects.

It should be noted that glycerin is a monosaccharide alcohol with 3 carbon atoms, which does not have such an effect as above.

In carrying out the present invention, the content of calcium ion source and aluminum ion source is less than 10%, preferably not more than 1%, especially preferably not more than 0.1% of the total composition, this calcium ion source and aluminum ion source are for example a kind of calcium-containing compound , such as calcium hydrogen phosphate, calcium triphosphate, calcium pyrophosphate, etc., and an aluminum-containing compound, such as aluminum hydroxide, etc. It is very particularly preferred that these calcium- and aluminum-containing compounds are not formulated at all. If the calcium-containing compound is present in larger amounts, ascorbyl phosphate or its salt reacts with calcium to form an insoluble calcium salt. If the aluminum-containing compound is present in a relatively large amount, the decomposition of ascorbyl phosphate or its salt will be accelerated due to the action of aluminum. The above-mentioned disadvantages are overcome when the content of the calcium-containing compound and an aluminum-containing compound is limited to less than 10% of the total composition.

The composition of the present invention can be used for various purposes, such as oral and external purposes, and its formulation can be selected in various dosage forms. Preferably the composition is presented as a paste, liquid, cream and the like.

Depending on the end use and the form of the preparation, known ingredients can be used to further formulate the compositions of the present invention together with the above-mentioned components. For example, provided oral compositions can be a dentifrice, such as toothpaste, liquid dentifrice, or others; a cream for massaging the gums; a surface wipe or mouthwash. In this dentifrice, abrasives, binders, sweeteners, flavor enhancers and various types of active ingredients can be formulated in usual amounts.

Preferred abrasives include silica abrasives such as silica gel, precipitated silica, aluminosilicates, zirconosilicates (titanium-bound silica), and the like. Magnesium carbonate, bentonite, methyl polymethacrylate, and the like can also be formulated.

Binders that can be formulated include one or more carrageenans; cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, and the like; alginic acid derivatives such as seaweed sodium phosphate, propylene glycol alginate, etc.; gums such as xanthan gum, gellan gum, tranganth gum, carrageenan gum, etc.; synthetic adhesives, such as polyvinyl alcohol, sodium polyacrylate, carboxyvinyl polymer, etc. etc.; and inorganic binders such as silica gel, propolis, laponite, etc.

The humectant includes, if necessary, glycerin, propylene glycol, polyethylene glycol and the like in addition to the above-mentioned sugar alcohols. Surfactants that can be formulated include nonionic surfactants, such as decaglyceryl laurate, myristoyl diethanolamide, etc., in addition to the aforementioned anionic surfactants, and amphoteric surfactants such as betaines.

Fragrance enhancers include menthol, anethole, carvone, eugenol, decyl alcohol, citronellol, alpha-terpineol, eucalyptol, linalool, ethyl linalool, vanillin, thyme phenol, peppermint oil, spearmint oil, wintergreen oil, clove oil, eucalyptus oil, etc., which can be formulated alone or in combination of two or more. Also, sweeteners such as sodium saccharin, perillatin, thaumatin, and the like can be formulated.

In the practice of the present invention, one or more known active ingredients may also be formulated, including cationic fungicides such as chlorhexidine, benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride, decalinium chloride, etc.; phenolic compounds, such as triclosan, hinokitiol, biozole, etc.; enzymes, such as dextranase, mutanase, lysozyme, amylase, protease, lysin, SOD etc.; alkali metal monofluorophosphates such as sodium monofluorophosphate, potassium monofluorophosphate, etc.; fluorides such as sodium fluoride, stannous fluoride, etc.; tranexamic acid, ε-aminocaproic acid, allantoin , dihydrocholestanol, glycyrrhizic acid, glycyrrhetinic acid, glycyrrhizic phosphate, chlorophyll, sodium chloride, xylitol, zinc chloride, water-soluble inorganic phosphate compounds, vitamin A, vitamin B, vitamin E and its derivatives.

The initial pH of the composition of the present invention should be adjusted so that after storage at 25°C for 1 month, the pH is 8.0 or above, preferably 8.0 to 9.5, particularly preferably 8.5 to 9.5. The reason why the stated pH is not a starting value but the pH after 1 month of storage is that for most compositions the pH changes considerably within 1 month of preparation at near room temperature , and finally stabilized. Therefore, the inventors of the present invention noticed that the pH value after storage at 25° C. for 1 month is important.

In this case, the change in pH differs depending on the type of ingredients formulated. For example, when formulating silica gel, the pH is higher than after 1 month storage at 25°C, but when formulating precipitated silica, the opposite is true and the pH drops. Thus, in order to adjust the initial pH so that the pH after storage at 25° C. for 1 month reaches a predetermined pH, the initial pH is set higher or lower than the predetermined storage 1 depending on the formulation of the composition. pH levels after months. If necessary, use a technique in which the relationship between the initial pH and the pH after storage at 25°C for 1 month can be determined from a pilot test. It should be noted that the pH can be adjusted by using a commonly used pH adjuster, for this purpose sodium hydroxide or potassium hydroxide is usually applied and a water-soluble salt of citrate, phosphate, Carbonates, bicarbonates, etc.

The ascorbyl phosphate-containing compositions of the present invention can be formulated with an ascorbyl phosphate or salt thereof in a stable and active state which exhibits effective efficacy after prolonged storage.

Example

Experimental Examples, Examples, and Comparative Examples are described to specifically illustrate the present invention, but the present invention should not be construed as being limited to the following Examples. Experimental example

A dentifrice containing the following formulation was prepared. Use the dentifrice prepared for 1 to 3 months, and apply it for a week to observe the improvement effect of gingivitis. More specifically, 10 normal healthy subjects each used each of the following dentifrices A and B for more than one week, and then stopped oral cleaning for 2 days, self-evaluated the state of gingivitis, and filled out a questionnaire. It should be noted that the interval between the use of different dentifrices is one week or more. In the results of the questionnaire, the gingiva of the upper and lower jaws of the anterior teeth were observed, and represented by dots in the following manner, referring to accompanying drawings 1(A) to 1(C). The results are shown in Table 1.

0: No gingivitis (Fig. 1(A))

1: Mild gingivitis was observed (Fig. 1(B))

2: Gingivitis to a perceivable degree was observed (Fig. 1(C))

In the drawings, X represents a tooth, Y represents a gingiva, and Z represents a site of gingivitis.

Dentifrice A Dentifrice B Magnesium L-Ascorbic Acid-2-Phosphate 0.3% 0.3% Precipitated Silica 15% 15% Propylene Glycol 3.5% 3.5% Carboxymethylcellulose 1.5% 1.5% Butylparaben 0.1 % 0.1% Sodium Saccharin 0.2% 0.2% Flavor Enhancer 1% 1% Sodium Lauryl Sulfate 1.5% 1.5% Titanium Dioxide 0.5% 0.5% Citric Acid 0.1% 0.1% 70% Sorbitol Solution 50% -85% Glycerin- 0% Sodium Hydroxide 0.3% 0.35% Purified Water Balance Total 100.0% 100.0% pH value (initial) 8.93 8.96 pH value (after 1 month storage at 25°C) 8.58 8.60 Moisture content with sugar alcohol ratio ( weight ratio) 0.76 0

Table 1 evaluation points at the start of the test After 10 days of the dentifrice test 2 days after stopping oral hygiene point 2 1 0 2 1 0 2 1 0 Number of subjects Dentifrice A 0 3 7 0 0 10 0 2 8 Dentifrice B 0 4 6 0 1 9 0 5 5 Examples 1 to 5, Comparative Examples 1 to 4

Dentifrices having the same formulations below, in which the components shown in Table 2 (silicon dioxide, sorbitol or glycerin) were formulated in the manner shown in Table 2, were prepared respectively. The pH of each resulting dentifrice was measured immediately after preparation and after storage at 25° C. for 1 month, 6 months and 18 months, respectively. In addition, for a dentifrice product stored in a constant temperature room at 60°C for more than 1 month, a dentifrice product stored in a constant temperature room at 40°C for more than 6 months, and a dentifrice product stored in a constant temperature room at 25°C Determination of the residual rate of magnesium ascorbyl phosphate in dentifrice products stored in the laboratory for more than 18 months. The results are shown in Table 2. The same formula: L-2-phosphate magnesium 0.3 % propylene glycol 3.5 carboxymethyl cellulose 1.5-pair of hydroxybenzoate 0.1 glycogen 0.2 sodium sodium sodium sodium sodium 1.5 titanium dioxide 0.1 hydroxide hydroxide Sodium Appropriate amount (approximately 0.3%) Silica Table 2 Sorbitol Table 2 Glycerin Table 2 Purified water Total balance 0 %

Table 2 project Example comparative example 1 2 3 4 5 1 2 3 4 Types of silica A A B B B B A B B amount of silica 11% 11% 11% 11% 11% twenty one% 11% 16% 16% Sorbitol amount (70%) 50% 45% 50% 45% 20% 40% 50% - 30% Sugar Alcohol/Water Ratio 0.78 0.65 0.78 0.65 0.29 0.67 0.78 0 0.60 Glycerin content (85%) - - - - 20% - - 40% - initial pH value 7.68 8.11 8.91 8.80 8.88 8.40 7.11 8.81 7.65 pH value after storage at 25°C for 1 month 8.25 8.78 8.62 8.53 8.56 7.65 7.80 8.46 7.42 pH value after 6 months storage at 25°C 8.36 8.86 8.62 8.51 8.52 7.62 7.87 8.42 7.41 pH value after 18 months storage at 25°C 8.48 8.90 8.60 8.49 8.51 7.63 7.91 8.40 7.44 Residual rate after 18 months storage at 25°C 95.1% 96.5% 97.0% 95.4% 92.2% 88.2% 89.6% 77.6% 80.6% evaluate ○ ○ ○ ○ △ x x x x Silica Type A: Silica Silica Type B: Precipitated Silica Example 6 Toothpaste Propylene Glycol 5% 70% Sorbitol 50 Carrageenan 1.2 Sodium Saccharin 0.2 Sodium Lauryl Sulfate 1.2 Ethylparaben Ester 0.1 Magnesium ascorbic acid-2-phosphate 0.2 Citric acid monohydrate 0.2 Silicic zirconate 18 Silicic anhydride (Tokuyama Co.) 3 Flavoring agent 0.9 Sodium hydroxide Appropriate amount Purified water Residue total 100% Initial pH value 9.2825°C Example 7 Toothpaste Macrogol 400 5% 70% Sorbitol 40 Xanthan Gum 1.1 Xylitol 10 Sodium Lauryl Sulfate 0.9 Diethanolamide Myristate 0.9 Palm Acid 0.5 Sodium Ascorbyl-2-Phosphate 1 Citric Acid Monohydrate 0.5 Ethylparaben 0.1 Aluminosilicate 20 Flavor Enhancer 1 Purified Water Balance Total 100% Initial pH 8.7 Store at 25°C for 1 month After pH 8.92 Example 8 Toothpaste Propylene Glycol 400 4% Sorbitol Solution (60%) 40 Carboxymethylcellulose 2 Sodium Saccharin 0.15 Sodium Lauryl Sulfate 1 Sodium Lauroyl Sarcosinate 0.2 Sodium Benzoate 0.5 Ammonium Cyclomic Acid 0.05 Magnesium Ascorbyl-2-Phosphate 0.05 Sodium Tartrate 0.02 Titanium-Bound Silica 20 Pyrogenic Silica 1 Flavor Enhancer 1 Sodium Hydroxide qs Purified Water Balance Total 100% Initial pH 9.0525°C Store 1 Month After pH value 8.61 Example 9 toothpaste propylene glycol 5% sorbitol solution (60%) 60 sodium alginate 3 sodium saccharin 0.15 sodium lauryl sulfate 1 butyl p-hydroxybenzoate 0.5 triclosan 0.1 ascorbic acid-2- Sodium Phosphate 1 Sodium Tripolyphosphate 1 Sodium Myristate 0.2 Silica Gel 20 Flavor Enhancer 1 Sodium Hydroxide Appropriate amount Purified Water Remainder Total 100% Initial pH value 7.91 pH value after 1 month storage at 25°C is 8.58 Example 10 Toothpaste Sodium Polyacrylate 0.5% Xanthan Gum 0.5 Propylene Glycol 570% Sorbitol Solution 50 Sodium Saccharin 0.1 Sodium Benzoate 0.3 Sodium Lauryl Sulfate 1.5 Tranexamic Acid 0.1 Magnesium Ascorbic Acid-2-Phosphate 0.5 Triethanolamine 2.5 Tartaric Acid 2dl- α-tocopherol 0.2 Cork tree bark extract 0.05 Sodium fluoride 0.2 Silica gel 10 Precipitated silica 10 Flavor enhancer 1 Sodium carbonate Appropriate amount Purified water Balance total 100% pH 8.68 Example 11 Mouthwash Ethanol 10% Glycerin 5 Sorbitol 5 Mannitol 3 Maltitol (Maltitol) 3 Polyethylene oxide (60) Hardened Castor Oil 1.0 Sodium Lauryl Sulfate 0.1 Ascorbic Acid-2 -Magnesium Phosphate 0.2 Tocopheryl Acetate 0.05 Flavor Enhancer 0.3 Purified Water Residue Total 100% Initial pH 8.44 pH 8.49 after 1 month storage at 25°C Example 12 Oral Paste Cetyl Alcohol 20% Squalane Alkane 5P.OE (40) Hardened Castor Oil 0.1 Xylitol 8 Sorbitan Monooleate 1 Sodium Lauryl Sulfate 0.2 Glycyrrhizic Acid 0.1 Sodium Saccharin 0.6 Sodium Ascorbyl Phosphate 0.3 Citric Acid 0.5 Silicic Anhydride 3 Fragrance 0.3 Potassium Hydroxide Appropriate amount of purified water, total balance 100%, initial pH value 8.25, pH value after storage for 1 month at 25°C is 8.38

Claims (3)

1. a compositions that contains ascorbic acid phosphoric acid esters is characterized in that containing: (A) ascorbic acid phosphoric acid esters or its salt; (B) anion surfactant; And (C) one or more are selected from the sugar alcohol of the pure and mild reduction starch syrup of monosaccharide alcohol, oligosaccharide with 4 or more a plurality of carbon atoms; Wherein the content in calcium and aluminium ion source is less than 10 weight % of total composition, and 25 ℃ store 1 month down after, the pH value of said composition is 8.0 or higher.

2. according to the compositions of claim 1, one or more the wherein contained sugar alcohols and the weight ratio of water are not less than 0.5.

3. according to the compositions of claim 1 or 2, wherein said compositions is to be used for the compositions that use in the oral cavity.

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