JP5083493B2 - Moisturizer and external preparation for skin using the same - Google Patents

Description

The present invention relates to a moisturizing agent for use in a skin external preparation such as pharmaceuticals, quasi drugs, and cosmetics.

Skin protects the body from external stimuli by its barrier function.
The skin consists of the epidermis, dermis and subcutaneous tissue from the outside, and keratin is present in the outermost layer of the epidermis.
The stratum corneum is the part where cells consisting of 10 to 20 stratum corneum cells finally reach, and the more outside, the more dead cells without nuclei are seen, but they retain moisture and prevent drying, etc. The barrier function of the stratum corneum is greatly related to the beauty of the skin.
In the keratinocytes, there are natural moisturizing factors such as amino acids, urea, and lactic acid, and these bind to water to retain moisture and maintain skin flexibility.
In general, external factors such as dryness, ultraviolet rays, aging, aging, visceral diseases, stress, etc. cause the skin's keratinous water content to decrease, resulting in reduced skin barrier function, rough skin, dry skin, It is said to cause dermatitis.
Therefore, in the cosmetics field and the dermatology field, it is essential to develop a moisturizing agent that maintains the amount of keratin water.

As conventional humectants, for example, polyhydric alcohols such as glycerin, amino acids, urea, collagen, natural fats and oils such as jojoba oil, olive oil, squalane, chondroitin sulfate, hyaluronic acid and the like are often used.
In particular, it is said that hyaluronic acid has an excellent moisturizing effect.
Furthermore, although the effect is inferior to that of hyaluronic acid, its use as a moisturizing agent such as alginic acid, chitosan, chitin derivatives, etc., which are cheaper as an alternative, has been studied. (See Patent Document 1)

JP-A-11-139554

However, these moisturizers may not be sufficient in terms of the irritation to the skin when used for a long time, and the sustainability and stability of the effect.
Moreover, there are many problems when considering the stable supply of raw materials and the cost.
Many of these moisturizers have a high aqueous solution viscosity, and there are restrictions on the content of active ingredients and those that cannot be stably dissolved in a system in which various salts and other ingredients are mixed. Many.

In order to solve the problems of the prior art, the present invention has high water solubility and excellent moisturizing performance while taking advantage of the inherent advantages of polysaccharides that have little adverse effects on the environment and the human body and can be stably supplied. The present invention provides a humectant and an external preparation for skin using the same.

The invention according to claim 1 is based on polyuronic acid obtained by selectively converting a primary hydroxyl group of the polysaccharide to a carboxyl group or a salt thereof by oxidizing the polysaccharide, and the polyuronic acid is cellulose, chitin, A humectant characterized by oxidizing starch or pullulan.

The invention according to claim 2 is characterized in that the polyuronic acid oxidizes a polysaccharide consisting of N-acetylglucosamine or glucose using 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (TEMPO). The humectant according to claim 1, wherein

The invention according to claim 3 is the humectant according to claim 1 or 2, wherein the polyuronic acid has a weight average molecular weight in the range of 5,000 to 200,000.

The invention according to claim 4 is characterized in that a part or all of the carboxyl group of the polyuronic acid is desalted and has a free carboxyl group. It is a moisturizer described in the item.

Invention of Claim 5 contains the moisturizer of any one of Claim 1 thru | or 4, It is the outside of the skin characterized by the above-mentioned.

Polyuronic acid derived from natural polysaccharides with a uronic acid residue whose structure is controlled, such as the position of carboxyl group introduction, by using a polysaccharide modified by introducing a carboxyl group by oxidation and imparting hydrophilicity Therefore, it is possible to provide a moisturizing agent having high safety, water solubility, and sufficient moisturizing properties.

Polyuronic acid, which is the main component of the humectant of the present invention, is obtained by oxidation of polysaccharides.
When a polysaccharide containing glucose or N-acetylglucosamine is used as the polysaccharide before oxidation, the polyuronic acid obtained by oxidation has a structure containing glucuronic acid or N-acetylglucosaminouronic acid.
These glucuronic acid and N-acetylglucosamine are contained in hyaluronic acid, chondroitin and the like, have a very high affinity for living bodies, and are also present in skin and other organs.
Examples of polysaccharides containing glucose and N-acetylglucosamine include water-soluble polysaccharides such as starch, pullulan, and hyaluronic acid, and cellulose and chitin. It is preferable to use raw materials such as starch, cellulose, chitin and the like because they can be water-solubilized with little change in the procurement of raw materials, cost, expected function, and structure.
Moreover, it is more preferable that raw material polysaccharide is a cellulose or chitin from a viewpoint of the high moisturizing performance of the obtained polyuronic acid and biocompatibility.

The weight average molecular weight of the polyuronic acid which is the main component of the humectant of the present invention is in the range of 5,000 to 1,000,000, and a more preferable weight average molecular weight is 5,000 to 50, 000 range.
Furthermore, in addition to the uniform chemical structure, when the molecular weight is within this range, the viscosity is low when it is made into an aqueous solution, and it can be dissolved at a high concentration, so that it can function efficiently. Can do.
Moreover, it is thought that a part penetrate | invades skin and can improve the water retention of skin not only from a keratin surface but from the inside.

When only the primary hydroxyl group at the 6-position of cellulose is selectively oxidized, polyuronic acid having β-1,4-linked glucuronic acid as a constituent monosaccharide is obtained.
Glucuronic acid also exists in vivo as a constituent monosaccharide of chondroitin and hyaluronic acid, and is considered to be greatly involved in its moisture retention performance.
Chitin is a polysaccharide formed by β-1,4-bonding N-acetylglucosamine, which is also present in the body as a constituent monosaccharide of hyaluronic acid.
However, chitin cannot be dissolved in water as it is and cannot be used as a humectant. Therefore, by selectively oxidizing only the primary hydroxyl group at the 6-position to form a polysaccharide having a uronic acid structure, water solubility can be imparted to chitin. Further, this chitin oxide has a carboxyl group released in a considerable proportion. Even if it exists in a state, the state dissolved in water can be maintained.

In order to obtain these polyuronic acids, a selective oxidation method from polysaccharides is effective.
Various methods have been studied as the method for oxidizing polysaccharides, and an oxidation method that has a high selectivity for the oxidation of primary hydroxyl groups and can obtain a uniform structure as much as possible should be taken.
A method for oxidizing cellulose or chitin using nitrogen dioxide or the like is also known, but from the viewpoint of reagent toxicity and oxidation selectivity, an oxidation method using a co-oxidant in the presence of an N-oxyl compound is known. preferable.
This selective oxidation method can control the degree of oxidation and can oxidize almost all the 6-positions of the pyranose ring to a carboxyl group without oxidizing the 2nd and 3rd positions of the pyranose ring. It is possible to carry out an oxidation reaction.

As the N-oxyl compound, 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (hereinafter, TEMPO) is preferably used.
Examples of the oxidizing agent include halogens, hypohalous acids, halous acids and perhalogen acids, or salts thereof, halogen oxides, nitrogen oxides, peroxides and the like that can promote the target oxidation reaction. Any oxidizing agent can be used as long as it is an agent.
Furthermore, when the oxidation reaction is carried out in the presence of bromide or iodide, the oxidation reaction can proceed smoothly even under mild conditions, and the carboxyl group introduction efficiency can be greatly improved.
Among these, it is particularly preferable to use TEMPO as the N-oxyl compound and perform an oxidation reaction using sodium hypochlorite as an oxidizing agent in the presence of sodium bromide.

When this method is used, the reaction temperature is not higher than room temperature, more preferably not higher than 5 ° C., for the purpose of improving the selectivity of oxidation of the constituent monosaccharides to primary hydroxyl groups and suppressing side reactions. desirable.
Furthermore, it is preferable to keep the inside of the system alkaline during the reaction.
At this time, the pH is preferably 9 to 12, more preferably 10 to 11.

Further, in this oxidation method, the degree of oxidation can be controlled by the amount of the oxidant and the amount of alkali added when the pH is kept constant.
For example, when an alkali is added in an equimolar amount with a sugar residue, almost all primary hydroxyl groups at the 6-position of the pyranose ring are oxidized to carboxylic groups via aldehyde groups, and water-soluble polyuronic acid is obtained.

In addition, when a highly crystalline polysaccharide such as cellulose or chitin is used as a raw material, in order to obtain a polyuronic acid that is uniform and highly water-soluble or has good dispersibility, the crystallinity such as regeneration treatment may be used as a pretreatment. It is preferable to perform a process for reducing the temperature.
As the regeneration treatment of cellulose, a known regeneration treatment method such as a cupra ammonium method or a viscose method can be used.
In addition, the chitin regeneration treatment is not limited as long as the crystallinity of the chitin after regeneration is reduced, and examples thereof include an alkali regeneration treatment.
After dipping chitin in a high-concentration alkali, it becomes a viscous liquid by diluting under low temperature while adding ice.
When neutralized by adding hydrochloric acid thereto, flaky chitin precipitates.
The obtained chitin is almost amorphous, which is sufficiently washed with water and not dried or freeze-dried, and then subjected to an oxidation reaction to suppress molecular weight reduction as much as possible, and almost all pyranose ring positions 6 Only the primary hydroxyl group can be oxidized to a carboxyl group.

Alternatively, chitosan which is a deacetylated product of chitin may be used as a raw material, and a material that is N-acetylated under a uniform reaction may be subjected to an oxidation reaction.
For example, after dissolving chitosan in acetic acid and diluting with methanol, it is easily N-acetylated by adding 1.5 to 3 times the molar amount of acetic anhydride relative to the amount of amino groups in the chitosan, and again chitin The chemical structure can be restored.
By passing through this operation, the well-washed water is not dried or freeze-dried and subjected to an oxidation reaction, so that only the primary hydroxyl group at the 6-position is oxidized with high selectivity as in the case of alkali-regenerated chitin.
Furthermore, in this case, it is also possible to control the degree of N-acetylation of the oxidation raw material by the amount of acetic anhydride added.
Therefore, it is also possible to obtain polyuronic acid having N-acetylglucosamine, glucosamine and uronic acid obtained by oxidizing them as constituent monosaccharides.

Polyuronic acid obtained by these methods often exists as a salt such as sodium. The humectant of the present invention is characterized by having a free carboxyl group in which a part or all of the carboxyl groups of these polyuronic acids are desalted.
The skin generally has a slightly acidic nature.
By desalting polyuronic acid, these aqueous solutions also show weak acidity, so they have high affinity for the skin and high moisturizing performance, so they are suitable for use as moisturizing agents.
As a desalting method, a general method can be applied. For example, an inorganic acid or an organic acid is dropped into an aqueous solution of polyuronic acid sodium salt obtained by the above oxidation method to make the pH weakly acidic and then isolated. Thus, the desired partially desalted polyuronic acid can be obtained.
Alternatively, an ion exchange resin or the like can be used.
Moreover, the target partially dechlorinated polyuronic acid can be obtained by mixing a salt obtained by desalting almost all of the carboxyl groups of polyuronic acid with an undesalted polyuronic acid.

These carboxyl groups are highly reactive compared to hydroxyl groups and the like, and have high water solubility or hydrophilicity. Therefore, they are very effective as a raw material for secondary modification, and polysaccharides that have been derivatized before and after oxidation are also available. It can be used as a humectant.
In addition, a synergistic effect by mixing with various other components, which is also effective in the use of conventional humectants, can be expected.
In particular, the polyuronic acid of the present invention is highly water-soluble and can be dissolved at a high concentration, and it is easy to use because it is hardly gelled or insolubilized by addition of other components such as salt and alcohol.

The moisturizing agent of the present invention can be obtained as a powder, but when used, it can be used by forming a liquid, film, sheet, or gel of an aqueous solution, or impregnating a film or sheet. It can also be used.

Hereinafter, the present invention will be described in detail based on examples. The present invention is not limited to such an embodiment.

10 g of starch was dissolved by heating in 400 g of distilled water and cooled.
A solution prepared by dissolving 0.18 g of TEMPO and 2.5 g of sodium bromide in 100 g of distilled water was added to this solution, and 104 g of an 11% strength sodium hypochlorite aqueous solution was added dropwise to initiate the oxidation reaction.
The reaction temperature was always kept below 5 ° C.
During the reaction, the pH in the system was lowered, but a 0.5 N NaOH aqueous solution was sequentially added to adjust the pH to 10.75.
Then, when the amount of alkali added corresponding to 100% of the number of moles of the primary hydroxyl group at the 6-position was reached, ethanol was added to stop the reaction.
This solution was added to 2.5 L of ethanol with stirring to obtain a precipitate.
The precipitate was further washed several times with a mixed aqueous solution of water / acetone = 1/7 to remove the reaction reagent and by-products, further washed with acetone, and then dried to obtain a white powder.
100 g of this powder was suspended in water and passed through a column filled with 70 mL of an ion exchange resin (organo Corporation: Amberlite IR120) regenerated into H-type for desalting treatment.
The treated aqueous solution was freeze-dried to obtain 8.7 g of a polyuronic acid white powder prepared from starch.

The product was dissolved in 0.2N-NaOH aqueous solution, and the molecular weight of the aqueous solution neutralized with 0.2N-HCl aqueous solution was measured in terms of standard pullulan by connecting GPC columns PWXL-6000 and PWXL-3000.
The weight average molecular weight of polyuronic acid was 120,000.

Using Benize manufactured by Asahi Kasei Kogyo Co., Ltd. as regenerated cellulose, 10 g of regenerated cellulose is suspended in 400 g of distilled water, and a solution of 0.18 g of TEMPO and 2.5 g of sodium bromide dissolved in 100 g of distilled water is added to a temperature of 5 ° C. or lower. Cooled down.
To this, 104 g of an aqueous 11% sodium hypochlorite solution was added dropwise to initiate the oxidation reaction.
The reaction temperature was always kept below 5 ° C.
During the reaction, the pH in the system was lowered, but a 0.5 N NaOH aqueous solution was sequentially added to adjust the pH to 10.75.
Then, when the alkali addition amount corresponding to 100% of the number of moles of the primary hydroxyl group at the 6-position was reached, ethanol was added to stop the reaction.
The reaction solution was poured into 1 L of ethanol to precipitate the product, which was sufficiently washed with a solution of water: acetone = 1: 7 to obtain sodium polyuronic acid.
Hydrochloric acid was added to a 5% aqueous solution of polyuronic acid sodium salt to obtain an aqueous solution having a pH of 3.
After stirring for 3 hours, this solution was mixed with excess ethanol with stirring and then left overnight to obtain a precipitate.
This product was sufficiently washed with a solution of water: acetone = 1: 7, dehydrated with acetone, and dried under reduced pressure at 40 ° C. to obtain polyuronic acid which is an oxide of cellulose.
The weight average molecular weight of polyuronic acid was 25,000.

10 g of chitin manufactured by Wako Pure Chemical Industries, Ltd. was immersed in 150 g of 45% aqueous sodium hydroxide solution and stirred at room temperature or lower for 2 hours.
The surroundings were cooled with ice water or the like, and 850 g of crushed ice was added with stirring.
Chitin is almost dissolved by this alkali treatment.
After neutralizing with hydrochloric acid, washing thoroughly with water and not drying, the raw material for oxidation was used.
A solution prepared by dissolving 0.08 g of TEMPO and 1.0 g of sodium bromide in 50 g of distilled water was added to 200 g of the suspension having a regenerated chitin concentration of 2.5% and cooled to 5 ° C. or lower.
An 11% sodium hypochlorite aqueous solution (35 g) was added dropwise thereto to initiate the oxidation reaction.
The reaction temperature was always kept below 5 ° C. During the reaction, the pH in the system was lowered, but a 0.5 N NaOH aqueous solution was sequentially added to adjust the pH to 10.75.
When the amount of alkali added corresponding to 100% of the total number of moles of the primary hydroxyl group at the 6-position is reached, ethanol is added to stop the reaction, and the reaction solution is put into 1 L of ethanol. The product was precipitated, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, and dried under reduced pressure at 40 ° C. to obtain 5.2 g of white polyuronic acid sodium salt. .
Furthermore, this polyuronic acid sodium salt was made into 5% aqueous solution, and the polyuronic acid was obtained from the chitin by processing with an ion exchange resin like Example 1. FIG.
The weight average molecular weight of polyuronic acid was 13,000.

<Comparative Example 1>
Sodium alginate viscosity 100 to 150 cps.

<Comparative example 2>
Sodium hyaluronate (sodium hyaluronate).

<Comparative Example 3>
Glycerin.

(Preparation of moisture retention evaluation measurement sample)
1 wt% aqueous solution of Examples 1-3 and Comparative Examples 1-3 was produced | generated.

(Moisturizing evaluation 1)
Each moisture retention evaluation measurement sample was set in a test tube so that the water level was 5 cm, and stored in an environmental test chamber at 40 ° C. and 25% RH for 150 minutes, and the water level at that time was confirmed.

The water level of the sample using Comparative Example 3 was 3.4 cm, the water level of the sample using Comparative Example 2 was 3.7 cm, the water level of the sample using Comparative Example 1 was 3.6 cm, and the sample using Example 3 The water level is 4.0 cm, the water level of the sample using Example 2 is 4.0 cm, the water level of the sample using Example 1 is 3.8 cm, and the sample using Examples 1 to 3 is Comparative Example 1. Better moisture retention performance was shown than the samples using ~ 3.

(Moisturizing evaluation 2)
Each moisturizing evaluation measurement sample was applied to the inner side of the lower arm of a subject (female, 30s).
After excessive moisture was lightly suppressed with cotton, the moisture content of the skin 500 seconds after application was measured with a moisture checker MY-707S (SCARA Co., Ltd.).

The moisture content of the skin of the sample using Comparative Example 3 is 50%, the moisture content of the skin of the sample using Comparative Example 2 is 55%, and the moisture content of the skin of the sample using Comparative Example 1 is 52%. The skin moisture content of the sample using 3 is 58%, the skin moisture content of the sample using Example 2 is 65%, and the skin moisture content of the sample using Example 1 is 56%. The samples using 1-3 showed better moisture retention performance than the samples using Comparative Examples 1-3.

The moisturizing agent of the present invention and the external preparation for skin using the same impart high hydrophilicity and exhibit sufficient moisturizing performance while taking advantage of the inherent advantages of polysaccharides that have less adverse effects on the environment and the human body. It can also be used as a skin cream.

Claims (5)

The main component is polyuronic acid obtained by selectively converting the primary hydroxyl group of the polysaccharide to a carboxyl group or a salt thereof by oxidizing the polysaccharide, and the polyuronic acid oxidizes any of cellulose, chitin, starch or pullulan. A moisturizing agent characterized by comprising The polyuronic acid is obtained by oxidizing a polysaccharide consisting of N-acetylglucosamine or glucose using 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (TEMPO). Item 2. A humectant according to Item 1. The humectant according to claim 1 or 2, wherein the polyuronic acid has a weight average molecular weight in the range of 5,000 to 200,000. The moisturizer according to any one of claims 1 to 3, wherein a part or all of the carboxyl group of the polyuronic acid is desalted and has a free carboxyl group. An external preparation for skin comprising the moisturizer according to any one of claims 1 to 4.