JP2010202522A - Salt-resistant thickener and cosmetic comprising the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To develop a new salt-resistant thickener exhibiting sufficient viscoelasticity at possible concentration of a salt or a drug compounded with a cosmetic, by using crosslinked hyaluronic acid gel. <P>SOLUTION: The thickener contains the crosslinked hyaluronic acid gel. The method for producing the crosslinked hyaluronic acid gel comprises: (1) a step of stirring and mixing a mixture containing hyaluronic acid, a crosslinking agent and water under an acidic or alkaline condition; (2) a step of carrying out a crosslinking reaction of the mixture; (3) and a step of crushing the mixture into slurry. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a novel thickener and a cosmetic containing the same, and specifically to a salt-resistant thickener containing a crosslinked hyaluronic acid gel slurry and a cosmetic containing the thickener.

  In some cases, a thickener is added to the cosmetic for the purpose of improving the comfort of the cosmetic and imparting a high-class feeling. However, viscoelasticity of a thickener that has been conventionally blended in cosmetics such as gum arabic and sodium carboxymethylcellulose is reduced in the presence of a salt or a drug.

  In cosmetics, various salts may be blended as moisturizers, depigmenting agents, amino acids, and vitamins. Therefore, for use in the field of cosmetics, it is necessary to develop a thickener having salt resistance that does not lose viscoelasticity even in the presence of these salts.

  The hyaluronic acid solution has viscoelasticity and may be used as a thickener. However, since the hyaluronic acid solution exhibits spinnability, there is a problem in terms of the comfort of cosmetics. Further, the viscosity of the hyaluronic acid solution decreases as the salt concentration in the solution increases. The crosslinked hyaluronic acid gel described in Patent Literature 1 has a low crosslinking rate and exhibits excellent viscoelasticity. However, since crosslinked hyaluronic acid gel has the property of maintaining a constant volume dimension, it can be used for applications such as tissue-enhancing substances injected into the body, but it can be used as a thickener for cosmetics as it is. I can't.

International Publication WO2006 / 051950

  There is a need to develop new salt tolerant thickeners that can utilize cross-linked hyaluronic acid gels to exhibit sufficient viscoelasticity at concentrations of salts or drugs that may be incorporated into cosmetics.

  The present invention provides a thickener comprising a crosslinked hyaluronic acid gel. The method for producing the crosslinked hyaluronic acid gel includes a step of stirring and mixing a mixture containing hyaluronic acid, a crosslinking agent and water under acid or alkaline conditions, (2) a step of performing a crosslinking reaction of the mixture, and (3) Crushing the mixture into a slurry.

  In the thickener of the present invention, the method for producing the crosslinked hyaluronic acid gel may include a step of immersing the mixture in an immersion liquid and causing the mixture to swell between step (2) and step (3).

  In the thickener of the present invention, the crosslinking agent may be selected from the group consisting of divinyl sulfone, 1,4-butanediol diglycidyl ether, and ethylene glycol diglycidyl ether.

  The present invention provides a cosmetic comprising the thickener of the present invention.

  The cosmetic of the present invention may contain 4-methoxysalicylic acid potassium salt and / or ascorbic acid-2-glucoside.

The graph which shows the relationship between the storage elastic modulus (G ') and salt concentration of a crosslinked hyaluronic acid gel slurry. The graph which shows the relationship between the swelling rate of a crosslinked hyaluronic acid gel slurry, and salt concentration. The graph which shows the relationship between the storage elastic modulus (G ') and salt concentration of a crosslinked hyaluronic acid gel slurry. The graph which shows the relationship between the storage elastic modulus (G ') of 1% hyaluronic acid solution, and salt concentration. The graph which shows the relationship between the storage elastic modulus (G ') and salt concentration of a 1% syntarene L solution. The bar graph which shows the storage elastic modulus (G ') of bridge | crosslinking hyaluronic acid gel slurry. The bar graph which shows the storage elastic modulus (G ') of a 1% hyaluronic acid and a solution of Sinteral L. The bar graph which shows the storage elastic modulus (G ') of a 0.2% hyaluronic acid and a Sinterale L solution.

  In the present specification, the “thickening agent” refers to a composition blended in the composition for the purpose of imparting viscoelasticity to products such as cosmetics, foods, beverages, and pharmaceuticals.

  In the present specification, “salt resistance” means a property in which the viscoelasticity of the solution is not easily lowered even if the salt concentration in the solution containing the thickener is increased within a range where it may be blended in cosmetics. Say.

  As used herein, “threadability” refers to the property that when a part of the solution is separated, the surface of the solution extends into a thread shape without being cut.

  The hyaluronic acid used in the present invention can be obtained, for example, by an isolation extraction method from animal tissues such as a chicken crown or a fermentation method using a microorganism. In addition, as the hyaluronic acid of the present invention, commercially available hyaluronic acid such as Biohyaro 12 (Shiseido Co., Ltd.), hyaluronic acid (Kibun Food Chemifa Co., Ltd.) and the like can be used. The molecular weight of the hyaluronic acid of the present invention is not particularly limited, but is preferably 100,000 or more, more preferably about 500,000 to 3,000,000.

  The hyaluronic acid used in the method for producing the crosslinked hyaluronic acid gel of the present invention includes a derivative and / or salt of hyaluronic acid. In the present specification, hyaluronic acid is a derivative of hyaluronic acid covalently bonded to an atomic group such as an ester group, an ether group, an acetyl group, an amide group, an acetal group, or a ketal group at a functional group such as a hydroxyl group or a carboxyl group. What you did. In the present specification, the salt of hyaluronic acid and its derivatives includes metal salts and amine salts of hyaluronic acid and its derivatives. The metal salt may include an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt, or the like. The amine salt may include a triethylamine salt, a benzylamine salt, or the like.

  In the method for producing the crosslinked hyaluronic acid gel of the present invention, hyaluronic acid may be contained in the mixture at a concentration of, for example, 5 to 20 w / v%, preferably 10 to 20 w / v%.

  In the present invention, as a crosslinking agent for hyaluronic acid gel, the hyaluronic acid molecule has two or more functional groups that can form a covalent bond by reacting with a reactive functional group such as hydroxyl group, carboxyl group, or acetamide group. A polyfunctional compound can be used. Specifically, the crosslinking agent used in the present invention is an alkyl diepoxy compound such as 1,3-butadiene diepoxide, 1,2,7,8-diepoxyoctane, 1,5-hexadiene diepoxide and the like. And diglycidyl ethers such as ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, bisphenol A diglycidyl ether, divinyl sulfone, and epichlorohydrin. Preferably, the crosslinking agent is selected from the group consisting of divinyl sulfone, 1,4-butanediol diglycidyl ether, and ethylene glycol diglycidyl ether. The cross-linking agent is more preferably divinyl sulfone. In the method for producing the crosslinked hyaluronic acid gel of the present invention, two or more kinds of crosslinking agents may be used in combination.

  In the present invention, the concentration of the crosslinking agent of the hyaluronic acid gel is, for example, 0.02 to 1 w / v%, preferably 0.05 to 0.5 w / v%, or, for example, 0.02 to 2 w / w%. is there.

  In the method for producing a crosslinked hyaluronic acid gel of the present invention, the acid or alkali condition is a pH condition of the mixture of the present invention set for the purpose of increasing the reactivity of hyaluronic acid during the crosslinking reaction, and as an acidic condition Means pH 1 to 5 conditions and alkaline conditions are pH 10 to 14 conditions. The mixture containing hyaluronic acid, a crosslinking agent and water of the present invention is suitable as an acid such as hydrochloric acid or sulfuric acid, a base such as sodium hydroxide or potassium hydroxide, or a phosphate, quaternary ammonium salt or the like. Using a suitable buffer, the mixture is stirred and mixed under the conditions of pH 1 to 5 or pH 10 to 14 and subjected to a crosslinking reaction.

  Stirring in the method for producing a crosslinked hyaluronic acid gel of the present invention may be performed by a method of stirring the hyaluronic acid in the mixture without physically cutting it. Specifically, the agitation method includes agitation by a rotation-revolution mixer, agitation by a bread dough kneading device or a moistening device, agitation by squeezing with a human hand, and the like. As the rotation-revolution mixing apparatus, for example, an apparatus described in JP-A No. 61-290946 can be used.

  When the crosslinking reaction in step (2) of the method for producing a crosslinked hyaluronic acid gel of the present invention is carried out by forming the mixture stirred and mixed in step (1) and allowing to stand at room temperature for 3 to 24 hours. There is. The molding of the mixture may be performed by pushing the gel-like mixture into a previously prepared mold, or may be performed by appropriately shaping the gel-like mixture with a human hand.

  The crushing in step (3) of the method for producing a crosslinked hyaluronic acid gel of the present invention may be carried out using a commercial or research and development pulverizer depending on the weight and volume of the gel to be crushed. .

  In the present specification, the “cosmetics” refers to those having a mild action, such as application to the skin, application, and the like for the purpose of cleansing the body and making the appearance beautiful. The cosmetics of the present invention include basic cosmetics, makeup cosmetics, medicinal cosmetics, toiletry products and the like.

  Moreover, the cosmetics of this invention may contain chemical | medical agents, such as fats and oils, a moisturizer, a whitening agent, a pigment | dye, a fragrance | flavor, a nutrient, an antibacterial agent, antioxidant, a ultraviolet absorber, for example. The whitening agent includes 4-methoxysalicylic acid potassium salt, and the nutrients and antioxidants include ascorbic acid-2-glucoside.

  In the present specification, the “immersion liquid” is a liquid for washing and swelling the crosslinked hyaluronic acid gel by immersing the mixture of the present invention after the crosslinking reaction. The immersion liquid includes, but is not limited to, physiological saline and isotonic phosphate buffer. The said immersion liquid may further contain the effective salt or chemical | medical agent of the cosmetics of this invention.

  The present invention will be described in detail by the following examples, but the present invention is not limited to these examples.

1. 1. Examination of salt resistance of crosslinked hyaluronic acid gel slurry 1-1. Method (Preparation of crosslinked hyaluronic acid gel slurry)
Add 4.95 mL of 0.1N NaOH aqueous solution and 50 μL of divinyl sulfone solution diluted 16.67 times with dimethyl sulfoxide (3 μL as divinyl sulfone) to a small glass mortar with a diameter of 65 mm and stir well, 0.8 g Of hyaluronic acid (Bio-Hyaro 12 (Shiseido Co., Ltd.)) was further added. The above mixture was stirred with a pestle to obtain a translucent gel-like mixture. The gel mixture was placed in the bottom of a sterilized polyethylene bag (length 100 mm, width 70 mm), and then formed into a rod shape (length 70 mm, diameter 10 mm). This was allowed to stand at room temperature for 4 hours to carry out a crosslinking reaction to obtain a rod-like gel. The rod-shaped gel was taken out from the polyethylene bag, weighed, immersed in 1 L of sterile physiological saline and allowed to stand for 24 hours. Thereafter, the rod-shaped gel was immersed in 1 L of isotonic phosphate buffer (pH 6.8) and allowed to stand at room temperature for 5 days to wash and swell the rod-shaped gel. The weight of the swollen rod gel after the 5 day washing and swelling process was measured. The rod-shaped gel was divided into four pieces, and the weight of each gel piece (the piece weight immediately after the division) was measured, and then 0%, 0.9%, 1.8%, 2.7% NaCl, respectively. The sample was dipped in a phosphate buffer solution containing 2 days and allowed to stand for 2 days, and the weight of each gel fragment (fragment weight after swelling) was measured. Thereafter, the gel fragment was crushed to obtain a crosslinked hyaluronic acid gel slurry. A series of operations was performed using a sterilizing instrument and a sterilizing reagent in order to avoid microbial contamination, and the gel preparation operation was performed in a clean bench.

(Calculation of swelling rate)
For each of the crosslinked hyaluronic acid gel slurries, the percentage obtained by dividing the fragment weight after swelling by the fragment weight immediately after the division is the swelling ratio of the gel fragment immersed in the phosphate buffer having the respective NaCl concentration.

(Measurement of viscoelasticity)
The obtained crosslinked hyaluronan gel slurry was measured for viscoelasticity. The measurement of viscoelasticity was performed using a rheometer (Rheolyst AR1000-N: TA Instruments). Storage elastic modulus (G ′) and loss elastic modulus (G ″) were measured under the conditions of 25 ° C. and frequency of 0.1 Hz to 10 Hz. When displaying viscoelasticity measurement results below, G ′ at a frequency of 1 Hz was used.

1-2. Results The theoretical final hyaluronic acid concentration of the cross-linked hyaluronic acid gel slurry (Lot 3041) that could be prepared by the above procedure was about 2.5 w / w%. The results of measuring the viscoelasticity and swelling rate of cross-linked hyaluronic acid gel slurries containing NaCl at different concentrations (0%, 0.9%, 1.8%, 2.7%) are shown in FIGS.

  FIG. 1 is a graph showing the relationship between the storage elastic modulus (G ′) and salt concentration of a crosslinked hyaluronic acid gel slurry (lot 3041). G ′ of the cross-linked hyaluronic acid gel slurry not containing NaCl was about 1000 Pa, but G ′ of the cross-linked hyaluronic acid gel slurry containing 0.9% NaCl exceeded 2000 Pa, and when NaCl was included, G ′ was about doubled. Increased. The G 'of the cross-linked hyaluronic acid gel slurry did not change significantly even when the NaCl concentration increased beyond 0.9%. From this result, it was found that the cross-linked hyaluronic acid gel slurry did not show a great change in viscoelasticity even when the salt concentration was increased, and had high salt resistance.

  FIG. 2 is a graph showing the relationship between the swelling rate and salt concentration of the crosslinked hyaluronic acid gel slurry (lot 3041). Although the swelling rate of the crosslinked hyaluronic acid gel slurry containing no NaCl was about 160%, the swelling rate of the crosslinked hyaluronic acid gel slurry containing 0.9% NaCl was about 100%, and the swelling rate of the gel slurry containing NaCl was slightly higher. Declined. The swelling rate of the cross-linked hyaluronic acid gel slurry did not change significantly even when the NaCl concentration increased beyond 0.9%.

2. 2. Examination of salt tolerance of cross-linked hyaluronic acid gel slurry, hyaluronic acid solution and sinterene L solution 2-1. Method The crosslinked hyaluronic acid gel slurry containing NaCl at different concentrations (0%, 0.9%, 1.8%, 2.7%) is described in Example 1 except that the added amount of hyaluronic acid is 0.5 g. It was prepared according to the method. The theoretical final hyaluronic acid concentration of the resulting crosslinked hyaluronic acid gel slurry (Lot 3042a) was about 1.1 w / w%. As a comparative example, a 1% hyaluronic acid solution containing NaCl with different concentrations (0%, 0.9%, 1.8%, 2.7%) and different concentrations (0%, 0.9%, 1% 0.8%, 2.7%) of 1% Cintalen L (Wako Pure Chemical Industries, Ltd.) solution containing NaCl was prepared according to a conventional method. The viscoelasticity of the prepared crosslinked hyaluronic acid gel slurry, hyaluronic acid solution and synthalene L solution was measured according to the method described in Example 1.

  2-2. result

  FIG. 3 is a graph showing the relationship between the storage elastic modulus (G ′) of the crosslinked hyaluronic acid gel slurry (lot 3042a) and the salt concentration. G ′ of the cross-linked hyaluronic acid gel slurry containing no NaCl was about 40 Pa, but G ′ of the cross-linked hyaluronic acid gel slurry containing 0.9% NaCl was about 140 Pa. Increased. The value of about 140 Pa was 30 times or more and 2 times or more, respectively, as compared with 1% hyaluronic acid containing 0.9% NaCl and G ′ of the sinterene L solution. (See FIGS. 4 and 5.) Also, the G 'of the cross-linked hyaluronic acid gel slurry did not change significantly as the salt concentration increased beyond 0.9%.

  FIG. 4 is a graph showing the relationship between storage elastic modulus (G ′) and salt concentration of a 1% hyaluronic acid solution. The G ′ of the hyaluronic acid solution containing no NaCl was about 6 Pa, but the G ′ of the hyaluronic acid solution containing 0.9% NaCl was about 4 Pa, and the G ′ slightly decreased when containing NaCl. The G 'of the hyaluronic acid solution decreased as the salt concentration increased above 0.9%.

  FIG. 5 is a graph showing the relationship between the storage elastic modulus (G ′) and the salt concentration of 1% sinterene L solution. The G ′ of the synthalene L solution containing no NaCl was about 70 Pa, but the G ′ of the synthalene L solution containing 0.9% NaCl was about 60 Pa, and G ′ decreased when containing NaCl. The G 'of the syntaren L solution decreased as the salt concentration increased above 0.9%.

  From the results shown in FIGS. 3 to 5, the hyaluronic acid solution and the sinterene L solution have low salt resistance, but the cross-linked hyaluronic acid gel slurry has a higher viscosity than the hyaluronic acid solution or sinteral L solution containing the same concentration of salt. In addition to the elasticity, the viscoelasticity did not change greatly even when the salt concentration increased, indicating that the salt resistance was high.

3. Examination of salt resistance and drug resistance of cross-linked hyaluronic acid gel slurry, hyaluronic acid solution, and syntarene L solution Examples of components commonly used in cosmetics and the like include 4-methoxysalicylic acid potassium salt (4MSK) and ascorbic acid-2-glucoside The viscoelasticity of the thickener containing (AA2G) was examined.

3-1. Method A crosslinked hyaluronic acid gel slurry was prepared containing 2% 4MSK, 2% AA2G or 0.9% NaCl, or none of these. Regarding the preparation method, the amount of hyaluronic acid added was 0.4 g, and after dividing the rod-shaped gel into 4 pieces, 0% or 0.9% NaCl, 2% 4MSK, 2 The method described in Example 1 was followed except that the sample was immersed in a phosphate buffer containing 1% AA2G and allowed to stand for 2 days. The theoretical final hyaluronic acid concentration of the resulting crosslinked hyaluronic acid gel slurry was about 1.1 w / w%. As a comparative example, a 1% or 0.2% solution of hyaluronic acid or sinteral L with or without 2% 4MSK, 2% AA2G or 0.9% NaCl was prepared. The viscoelasticity of the prepared crosslinked hyaluronic acid gel slurry, hyaluronic acid solution and synthalene L solution was measured according to the method described in Example 1.

3-2. Results FIG. 6 is a bar graph showing the storage modulus (G ′) of the crosslinked hyaluronic acid gel slurry. G ′ of the crosslinked hyaluronic acid gel slurry containing 2% 4MSK, 2% AA2G, and 0.9% NaCl was about 90 Pa, about 80 Pa, and about 60 Pa, respectively. G ′ of the acid gel slurry was about 20 Pa, and G ′ increased in the presence of salt or drug.

  FIG. 7 is a bar graph showing the storage modulus (G ′) of 1% hyaluronic acid or sinterene L solution. G ′ of 1% hyaluronic acid solution containing 2% 4MSK or AA2G was about 30 Pa, but G ′ of 1% hyaluronic acid solution not containing any of the above components was about 40 Pa. G 'decreased slightly when the drug was included. In addition, G ′ of 1% of syntalne L solution containing 2% of 4MSK or AA2G was about 60 Pa, but G ′ of 1% of synthalene L solution not containing any of the above components was about 80 Pa. G 'decreased slightly in the presence of salt or drug.

  FIG. 8 is a bar graph showing the storage modulus (G ′) of 0.2% hyaluronic acid or sinterene L solution. G ′ of 0.2% hyaluronic acid solution containing 2% 4MSK or AA2G was below 0.1 Pa, but G ′ of 0.2% hyaluronic acid solution containing none of the above components was about At 0.5 Pa, G ′ decreased significantly in the presence of salt or drug. In addition, G ′ of 0.2% of the synthalene L solution containing 2% of 4MSK and AA2G was about 1.5 Pa and about 0.5 Pa, respectively. G ′ of the L solution exceeded 3 Pa, and G ′ significantly decreased in the presence of salt or drug.

  From the results shown in FIGS. 6 to 8, it was found that the hyaluronic acid solution and the sinterene L solution have low viscoelasticity and low salt resistance and drug resistance in the presence of salt or drug. Moreover, it turned out that a crosslinked hyaluronic acid gel slurry does not fall viscoelasticity in presence of a salt or a chemical | medical agent, and salt resistance and chemical | medical agent resistance are high.

4). Examination of Spinnability of Crosslinked Hyaluronic Acid Gel Slurry and Hyaluronic Acid Solution The spinnability of the crosslinked hyaluronic acid gel slurry and hyaluronic acid solution prepared in Examples 1 to 3 was visually evaluated during the working steps of Examples 1 to 3. . As a result, the hyaluronic acid solution had spinnability, but the crosslinked hyaluronic acid gel slurry did not have spinnability.

  The cross-linked hyaluronic acid gel slurry showed very high viscoelasticity as compared with a hyaluronic acid solution containing the same concentration of salt or a Citalene L solution. Since the viscoelasticity of the cross-linked hyaluronic acid gel slurry did not change significantly with increasing salt or drug concentration, the cross-linked hyaluronic acid gel slurry has salt resistance and drug resistance. Further, the crosslinked hyaluronic acid gel slurry was not spinnable, unlike the hyaluronic acid solution. Therefore, the crosslinked hyaluronic acid gel slurry can be utilized as a salt-resistant thickener. It is expected that a product that is comfortable to use can be provided by using a thickener containing a crosslinked hyaluronic acid gel slurry in a cosmetic formulation.

Claims (5)

  (1) a step of stirring and mixing a mixture containing hyaluronic acid, a crosslinking agent and water under acid or alkaline conditions; (2) a step of performing a crosslinking reaction of the mixture; and (3) crushing the mixture into a slurry. A thickening agent comprising a crosslinked hyaluronic acid gel produced by a method comprising the steps of:   The thickener according to claim 1, characterized in that the method comprises a step of swelling the mixture between step (2) and step (3).   The thickener according to claim 1 or 2, wherein the cross-linking agent is selected from the group consisting of divinyl sulfone, 1,4-butanediol diglycidyl ether, and ethylene glycol diglycidyl ether.   A cosmetic comprising the thickener according to any one of claims 1 to 3.   The cosmetic according to claim 4, comprising 4-methoxysalicylic acid potassium salt and / or ascorbic acid-2-glucoside.