JP4559764B2 - Chitosan-based composite, method for producing the chitosan-based composite, and external preparation for skin and cosmetics containing the chitosan-based composite - Google Patents

Description

The present invention, a derivative and an inorganic substance of key chitosan, skin formulated complexed by hydrogen bonds or ionic bonds, and the like, and key chitosan-based composite, a method of manufacturing of the complex, as well as key chitosan Composites It relates to external preparations and cosmetics.

  As is well known, chitin is a substance obtained from crustaceans and filamentous fungi, and chitosan is a substance obtained by deacetylating this chitin. This chitin, chitosan, or a derivative thereof has a skin repair effect, antibacterial activity, and the like. -It has been put into practical use as a raw material for cosmetics and functional food because it has various effects and functions such as antifungal properties, artificial skin, and moisture retention, as well as physiological activity, and it has also been developed in various other technical fields. Research has been done. However, these chitin, chitosan, or derivatives thereof are not sufficient in terms of action and affinity for living bodies.

  That is, physiological effects such as antibacterial properties and biological repairing effects are mainly derived from charged amino groups of chitin, chitosan, or derivatives thereof, but the activity decreases due to the formation of polyion complexes by proteins present in the living body, Or the modification | denaturation by the Maillard reaction of monosaccharides, such as glucose which exists in a biological body, may occur, and the problem arose in the point of stability, durability, and the effect | action with respect to an actual biological body.

Therefore, in view of such problems, studies have been made to form a complex with another substance such as chitin, chitosan, or a derivative thereof so as not to form a polyion complex with proteins in the living body. ing. For example, silicon is often found in sites related to growth in living organisms, and is highly compatible with living organisms. As shown in Non-Patent Document 1 below, application studies to biocompatible complexes are also being studied.
Functional Materials September 1984 Issue

From the viewpoint of complexing with silicon, an application such as the following Patent Document 1 in which a complex is produced by reacting multimeric silicon alkoxide with chitosan as a silicon raw material has been proposed. There is a problem that a strong reaction occurs with an amino group important for the active action, resulting in a decrease in the physiological activity effect.
Japanese Examined Patent Publication No. 7-64953

The present invention has been made to solve such conventional problems, stability, persistence high and contains a key chitosan-based composites and the complex was enhanced activity for actual biological It is an object to provide an external preparation for skin and cosmetics.

The present inventors have revealed that an extensive investigation to solve the above problems, and derivatives of key chitosan, by compounding the inorganic oxide, the stability of the derivatives of key chitosan increases the persistence, the The present inventors have found that the problem can be solved and have completed the present invention.

That is, the invention of claim 1, wherein an invention relating to key chitosan Composites, partially myristoylation chitosan pyrrolidone carboxylate as derivatives of chitosan, chitosan lactate, or a carboxymethyl chitosan, as an inorganic oxide It is characterized by comprising silica or zinc oxide .

Furthermore the invention of claim 2, in key chitosan-based composite according to claim 1 Symbol placement, silica or zinc oxide, characterized in that an average particle diameter of 0.5μm or less of fine particles. Furthermore the invention of claim 3, wherein, in the key chitosan-based composite according to claim 1 or 2 wherein the derivative of the key chitosan is characterized in that it presents a 20-100% amino group content.

Furthermore the invention of claim 4, wherein, in the key chitosan-based composite according to any one of claims 1 to 3, an average molecular weight of derivatives of key chitosan is characterized in that it is a 1000 to 5000000.

Furthermore invention according to claim 5, be made of partially myristoylation chitosan pyrrolidone carboxylate as derivatives of key chitosan, chitosan lactate and or carboxymethyl chitosan, and sol silica or zinc oxide as an oxidizing sol of the inorganic It is characterized by. Of claim 6 further according to the method of manufacturing the key chitosan Composites invention, partially myristoylated chitosan pyrrolidone carboxylate as derivatives of key chitosan, chitosan lactate, or a carboxymethyl chitosan, as an oxidizing sol of the inorganic It is characterized by being produced by mixing silica or zinc oxide sol in a hydrophilic solvent.

Furthermore, the invention according to claim 7 relating to the external preparation for skin contains the chitosan complex according to any one of claims 1 to 5 . Furthermore the invention of claim 8 according to the cosmetic is characterized by containing a key chitosan-based composite according to any one of claims 1 to 5.

According to the present invention, as described above, by complexing with an inorganic oxide derivative of key chitosan, it is possible to suppress the reduction efficacy by proteins and monosaccharides present in the living body, whereby the heat stability, etc. Maillard reaction inhibiting effect can be obtained, stability and sustainability and key chitosan composites with enhanced activity for actual living body, and skin external preparation, it has become possible to provide a cosmetic.

The inorganic oxide contained in the complex of the present invention, silica, zinc oxide Ru is used. As the inorganic oxide to be combined, for example, a particulate oxide sol such as colloidal silica or colloidal zinc oxide is preferably used. The average particle size in the oxide sol is desirably 1 to 500 nm.

Derivatives of key chitosan contained in the complex of the present invention, from the viewpoint of compounding the above inorganic oxide and hydrogen bond or ionic bond, etc., it is preferable to use an average molecular weight from 1000 to 5000000, as described above . The average molecular weight in this case is, for example, GPC-HPLC coupled with a data module GPC cartridge [gel filtration chromatography column: TSK-gel-G3000WXL + TSK-gel-G2500PWXL manufactured by Tosoh Corporation, solvent: 0.4M acetic acid-acetic acid Na buffer (pH = 4.8)] Measured by revealing molecular weight distribution by analysis. As the molecular weight standard, chitosan oligosaccharide (molecular weight: 413,1006), dextran sulfate (molecular weight: 5000, 8000) and pullulan molecular weight standard are used. The average molecular weight can also be obtained from a viscosity measurement method or the like.

Further , as the chitosan derivative, it is preferable to use a derivative having an amino group content of 20 to 100%. Chitosan is a highly deacetylated product of chitin, which is a natural polysaccharide, and it is preferable to synthesize derivatives based on deacetylated chitin that exhibits a degree of deacetylation of 50 to 100%.

Derivatives of key chitosan, chitosan lactate, using carboxymethyl chitosan.

Moreover, what introduce | transduced 0.1-50.0% partial fatty acid groups, such as a C4-C20 acyl group, is also used. A substance obtained by partially introducing 0.1 to 50.0% of a fatty acid group having 4 to 20 carbon atoms into an amino group or a hydroxyl group is preferable because the composite action with an inorganic oxide or an inorganic acid salt is further enhanced. From this viewpoint, those in which a fatty acid group having 8 to 20 carbon atoms is partially introduced are more preferable. Specifically, partially myristoylated chitosan pyrrolidone carboxylate (product name: PM-chitosan: Pierce Co., Ltd.) is used .

Here, “partial introduction” indicates how much fatty acid groups such as acyl groups are introduced per residue of the constituent monosaccharide. “Partial introduction of 0.1 to 50.0% of fatty acid groups” "and in the case of chitosan, the hexosamine 1000 residues is a constituent monosaccharide, fatty acid group means that it is introduced to 500 pieces. Thus derivatives of key chitosan fatty acid group is introduced portion of such an acyl group having 4 to 20 carbon atoms shows an amphipathic.

Coexistence ratio of the inorganic oxide, a derivative of chitosan is not particularly limited with respect to derivatives 100 parts by volume of the key chitosan, the volume ratio of the inorganic oxide is desirably 1 to 50 parts by volume.

· The chitosan-based composite of the invention, the hydroxyl group of an amino group or an acetyl group and an inorganic oxide in key chitosan derivative is formed interact. Sol obtained key chitosan complexes and their conjugates, since the stability and functionality increases, ion complex forming low protects efficacy, function and the amino group while improving its sustainability . The key chitosan composite sol of the present invention high stability with a hydrophilic solvent, is difficult to occur aggregation and separation by freezing and temperature changes.

  Skin external preparations and cosmetics containing the composite of the present invention can effectively exhibit functional effects such as moisture retention flexibility, antibacterial properties, skin repair effects, anti-aging, and anti-wrinkles. Moreover, according to the form of a skin external preparation, the component generally used with cosmetics and an external preparation other than the said essential component can be mix | blended in the range which does not inhibit the effect of this invention. For example, polyhydric alcohols such as butylene glycol, dipropylene glycol and glycerin, higher alcohols such as cetanol and behenyl alcohol, nonpolar oils such as liquid paraffin and squalane, ester oils such as isopropyl palmitate and isopropyl myristate, Examples include vegetable oils such as wheat germ oil and olive oil, silicon compounds such as trimethylsiloxysilicic acid and methylphenylpolysiloxane, and fluorine compounds such as perfluoropolyether. Moisturizing and softening agents, antioxidants, astringents, whitening agents, antibacterial agents, anti-inflammatory agents, UV absorbers, UV scattering agents, vitamins, enzymes, etc. Ingredients such as cosmetic raw material standards, Japanese pharmacopoeia, official standards for food additives, and the like.

  Regardless of the dosage form of the external preparation for skin and cosmetics containing the complex of the present invention, it can be provided in the form of preparations such as lotion, emulsion, pack, emulsified lotion and cream. For example, it can be provided as a preparation such as a creamy skin care agent, an emulsion makeup base, an emulsified mascara or a foundation.

  Although the compounding quantity of the composition with respect to the skin external preparation or cosmetics in this invention is not specifically limited, 0.0005-5 mass% is preferable by dry solid weight in the whole quantity, such as an external preparation. This is because if the amount is less than 0.0005% by mass, the effect of the present invention may not be sufficiently obtained. From this viewpoint, 0.001 to 3 mass% is more preferable.

  Examples of the present invention will be described below.

Example 1
An organic synthesizer (Tokyo Rika) was added to 3.3 g of 30% colloidal silica solution (30%, isopropanol dispersion) to 100 g of 2% partially myristoylated chitosan pyrrolidone carboxylate (average molecular weight: about 600,000 containing 60% ethanol). A translucent dispersion having a nano-size dispersoid was obtained by stirring reaction at 100 rpm in an instrument made by PPV-3000) at 40 ° C. for 15 hours. The reaction solution was centrifuged (10000 rpm, 20 min) to obtain a composite sol (average particle size: about 250 nm). The obtained composite sol was concentrated with an evaporator and freeze-dried to obtain a white powder. FT-IR analysis as shown in FIG. 1 from (reflection type), amide I (1660 cm ^-1), showed an absorption peak of the amide II (1580 cm ^-1), as compared to the partial myristoylation chitosan pyrrolidone carboxylate The peak strength was significantly reduced. Furthermore, since the absorption peak (1573 cm ⁻¹ ) attributed to the amide group is shifted about 7 cm ⁻¹ to the high wavenumber side, complexation due to the interaction between the charged amino group and silica was confirmed.

(Example 2)
Add 2Og of 30% colloidal silica solution (30%, isopropanol dispersion) to 100g of 2% chitosan lactate (average molecular weight: about 80,000, containing 60% ethanol), organic synthesizer (Tokyo Rika Kikai, PPV- 3000), a translucent dispersion having a nanosize dispersoid was obtained by stirring reaction at 100 ° C. for 12 hours at 40 ° C. The reaction solution was centrifuged (10000 rpm, 20 min) to obtain a composite sol (average particle size: about 100 nm). The obtained composite sol was concentrated with an evaporator and freeze-dried to obtain a white powder. FT-IR analysis from (reflection type) analysis, the amide I (1660 cm ^-1), showed an absorption peak of the amide II (1583cm ^-1), as compared to the chitosan lactate peak - the click strength is significantly reduced. Furthermore, since the absorption peak (1573 cm ⁻¹ ) due to the amide group is shifted by about 10 cm ⁻¹ to the high wavenumber side, complexation due to the interaction between the charged amino group and silica was confirmed.

(Example 3)
Organic synthesizer (manufactured by Tokyo Rika Kikai Co., Ltd., PPV) was added to 3.3 g of 30% colloidal zinc oxide solution (30%, isopropanol dispersion) to 100 g of 2% carboxymethyl chitosan (average molecular weight: about 150,000, containing 50% ethanol) -3000), a semitransparent dispersion having a nano-size dispersoid was obtained by stirring at 40 ° C. for 10 hours at 100 rpm. The reaction solution was centrifuged (10000 rpm, 20 min) to obtain a composite sol (average particle size: about 200 nm). The obtained composite sol was concentrated with an evaporator and freeze-dried to obtain a white powder. FT-IR analysis from (reflection type) analysis, the amide I (1660 cm ^-1), showed an absorption peak of the amide II (1580 cm ^-1), peak compared to carboxymethyl chitosan - click intensity was significantly reduced. Furthermore, since the absorption peak (1572 cm ⁻¹ ) attributed to the amide group is shifted about 8 cm ⁻¹ to the high wavenumber side, complexation due to the interaction between the charged amino group and zinc oxide was confirmed.

Example 4
The composite sols of Example 1 and Example 2 were obtained from appearance and particle size distribution in 2 months under conditions of 45 ° C. and 25 ° C., and the time-dependent change after two freeze-thaw treatments. As a result, the composite sol of the present invention was highly stable and no change in appearance and particle size distribution was observed.

(Comparative Example 1)
In the same manner as in Example 1, in the case where hyaluronic acid and collagen were reacted instead of the chitosan derivative, aggregation / separation was observed in all systems, and a stable composite sol was not formed.

(Example 5)
In this example, the inhibitory action of the Maillard reaction was examined. The Maillard reaction is a non-enzymatic reaction in which an amino group and a reducing sugar such as glucose are converted into an aldehyde to be browned. 500 mg of glucose was added to 100 ml of a 1% aqueous solution of the complex described in Example 3, and browning due to treatment at 80 ° C. for 2 hours was determined using the change in absorbance at 420 nm as an index. As a result, when not complexed, the absorbance increased from 0.05 to 0.45, and a remarkable browning change was observed, whereas the complex solution described in Example 3 showed almost no browning change. This is probably because the Maillard reaction that reduces the functionality of the chitosan derivative is suppressed because the amino group is protected by complexation.

(Example 6)
Antibacterial evaluation was examined. The antibacterial effect was obtained by diluting the composite sols of Examples 1 and 3 with physiological saline (10 times) and inoculating MRSA (methicillin-resistant Staphylococcus aureus) having high resistance against the antibacterial agent over time. It was calculated from the change. When not complexed, it died after 90 minutes, whereas the complexed sol died after 60 minutes, which improved the antibacterial activity against MRSA. Moreover, when not complexed, a decrease in antibacterial property due to the coexistence of biological protein (BSA, skin-derived keratin) was observed, whereas the complexed sol did not exhibit a decrease in antibacterial property.

(Example 7)
Hydroxyl radical scavenging action with strong cytotoxicity and DNA damage action among active oxygen was examined. The reaction composition is 40 mM phosphate buffer (pH 7.2), 0.26 mM ascorbic acid, 0.15 mM Fe EDTA, 0.6 mM hydrogen peroxide, 2 mM salicylic acid and the hybrid sol of Examples 1 and 2 diluted with purified water (50 times) The total amount was 400 ml, and hydroxy radicals were generated by the ascorbic acid-hydrogen peroxide system. After incubating at 25 ° C. for 90 minutes, hydroxylated salicylic acid was derivatized, and radicals were detected from the absorbance at 510 nm. For the control, purified water was added instead of the sample, and for the blank, a solution excluding ascorbic acid, Fe EDTA, and hydrogen peroxide was used. As a result, the hydroxy radical scavenging rates of the composite sols of Examples 2 and 3 were 31% and 39%, respectively, and had an excellent scavenging effect.

(Example 8)
Lotion 1 (wt%)
(1) Ethanol 5.0
(2) Butylene glycol 3.0
(3) Glycerin 3.0
(4) Methylparaben 0.2
(5) Complex of Example 1 0.2
(6) Purified water remaining

Example 9
Lotion 2 (wt%)
(1) Ethanol 5.0
(2) Butylene glycol 3.0
(3) Glycerin 3.0
(4) Methylparaben 0.2
(5) Complex of Example 3 0.2
(6) Purified water remaining

(Comparative Example 1)
Lotion 3 (wt%)
(1) Ethanol 5.0
(2) Butylene glycol 3.0
(3) Glycerin 3.0
(4) Methylparaben 0.2
(5) Chitosan lactate (average molecular weight: approx. 100,000) 0.2
(6) Purified water remaining

(Comparative Example 2)
Lotion 4 (wt%)
(1) Ethanol 5.0
(2) Butylene glycol 3.0
(3) Glycerin 3.0
(4) Methylparaben 0.2
(5) Hyaluronic acid (average molecular weight: about 500,000) 0.2
(6) Purified water remaining

(Comparative Example 3)
Lotion 5 (wt%)
(1) Ethanol 5.0
(2) Butylene glycol 3.0
(3) Glycerin 3.0
(4) Methylparaben 0.2
(5) Purified water remaining

(Test Example 1)
Tests on skin viscoelasticity improvement and wrinkle improvement were conducted. Lotion was applied to the outer part of the forearm of 12 men and women (average age: 38.5 years) for 6 weeks (twice / day). In the measurement, it was measured after rinsing for 20 minutes in an environment of 22 ° C and 50% humidity after washing. Skin viscoelasticity was determined using a cut meter (C / K) and stratum corneum water content was determined using SKIKON-200EX (manufactured by IBI S). Further, after collecting a replica of the evaluation site, the shadow produced by the halogen lamp irradiation was taken into a CCD camera (manufactured by Keyence Corporation), and the average depth of wrinkles was determined by image analysis. The results are shown in Table 1.

表１において、皮膚粘弾性の項目の◎は向上率が20％以上であることを示し、○は向上率が10〜20％であることを示し、△は向上率が５〜10％であることを示し、×は向上作用が認められなかったことを示す。また、角層水分量の項目の◎は向上率が40％以上であることを示し、○は向上率が20〜40％であることを示し、△は向上率が10〜20％であることを示し、×は向上作用が認められなかったことを示す。さらに、シワ改善の項目の◎はシワの平均深さが30％以上浅くなることを示し、○はシワの平均深さが20〜30％浅くなることを示し、△はシワの平均深さが10〜20％浅くなることを示し、×は改善作用が認められなかったことを示す。

In Table 1, ◎ in the item of skin viscoelasticity indicates that the improvement rate is 20% or more, ○ indicates that the improvement rate is 10 to 20%, and Δ indicates that the improvement rate is 5 to 10%. X indicates that no improving effect was observed. In addition, ◎ of the stratum corneum moisture content indicates that the improvement rate is 40% or more, ○ indicates that the improvement rate is 20 to 40%, and △ indicates that the improvement rate is 10 to 20%. And x indicates that no improving effect was observed. Furthermore, ◎ in the item of wrinkle improvement indicates that the average depth of wrinkles is 30% or more shallow, ○ indicates that the average depth of wrinkles is 20-30% shallower, and △ indicates the average depth of wrinkles. It shows that it becomes shallower by 10 to 20%, and x indicates that no improving action was observed.

  As is apparent from Table 1, in Examples 8 and 9, it was found that the skin viscoelasticity, skin moisture content, and wrinkle improving action were superior to those of Comparative Examples 1 to 3.

Next, a prescription example is shown.
[Formulation Example 1] Skin care cream (wt%)
(1) Cetanol 5.0
(2) Propyl myristate 3.0
(3) Squalane 10.0
(4) POE sorbitan monostearate 3.5
(5) Composite of Example 2 0.5
(6) Glycerin 5.0
(7) Propylene glycol 3.0
(8) Methylparaben 0.1
(9) Purified water remaining

  O / W type cream was prepared by emulsification by heat treatment (7000 rpm, 1 min) after adding heat-dissolved components (1) to (4) to the heat-treated water phase composition of (5) to (9) did.

[Formulation Example 2] Emulsification lotion (wt%)
(1) Liquid paraffin 1.0
(2) Propyl myristate 1.0
(3) POE sorbitan monolaurate 3.0
(4) Hybrid sol described in Example 3 10.0
(5) Butylene glycol 10.0
(6) Licorice flavonoid 0.2
(7) Rosemary extract 2.0
(8) Phenoxyethanol 0.1
(9) Purified water remaining

  What was obtained by heating and dissolving the components (1) to (4) to the heat-treated water phase compositions (4) to (9) was added and emulsified by homomixer treatment to prepare an emulsion lotion.

· The chitosan-based composite of the invention, for the active oxygen suppressing, particular wrinkles, and skin aging such as age spots, skin roughness, suppressing the influence of a high hydroxyl radicals to skin cell damage, such as inflammatory acne skin peel external preparation Can be widely applied to cosmetics.

An IR analysis chart for confirming a composite state of a charged amino group and silica.

Claims (8)

Partially myristoylation chitosan pyrrolidone carboxylate as derivatives of chitosan, chitosan lactate, or carboxymethyl chitosan, silica or consisting of zinc oxide, characterized in key chitosan Composites as inorganic oxides. The silica or zinc oxide and an average particle diameter of 0.5μm or less of particulate claim 1 key chitosan-based composite according. The partial myristoylation chitosan pyrrolidone carboxylate, chitosan lactate, or carboxymethyl chitosan, key chitosan-based composite according to claim 1 or 2 showing a 20-100% amino group content. The partial myristoylation chitosan pyrrolidone carboxylate, chitosan lactate, or carboxymethyl key chitosan-based composite according to any one of claims 1 to 3 average molecular weight of chitosan is 1000 to 5000000. Partially myristoylation chitosan pyrrolidone carboxylate as derivatives of chitosan, chitosan lactate, or carboxymethyl chitosan and, key chitosan composite body characterized by comprising a sol of silica or zinc oxide as an oxidizing sol of the inorganic. Producing by mixing partially myristoylated chitosan pyrrolidone carboxylate, chitosan lactate or carboxymethyl chitosan as a derivative of chitosan and silica or zinc oxide sol as an inorganic oxide sol in a hydrophilic solvent method of manufacturing a key chitosan-based composite characterized by. Skin external agent characterized in that it contains a key chitosan-based composite according to any one of claims 1 to 5. Cosmetic characterized by containing a key chitosan-based composite according to any one of claims 1 to 5.

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