JPWO2009025043A1 - Novel cross-linked polymer, method for producing the same, and use thereof - Google Patents

Abstract

Provided are a novel crosslinked polymer for producing a gel thereof, a production method thereof, and an application thereof while maintaining excellent properties such as biocompatibility and water solubility of PVLA. A crosslinked polymer obtained by reacting an Np-vinylbenzyl-D-lactone amide represented by the formula I: with a PEG derivative having a reactive double bond at each of two or more terminals, a production method thereof, and Its use.

Description

  The present invention relates to Np-vinylbenzyl-O-β-D-galactopyranosyl- (1 → 4) -D-gluconamide (hereinafter referred to as “Np-vinylbenzyl-D-lactone amide” or “ VLA ”) and a polyethylene glycol (hereinafter referred to as“ PEG ”) derivative each having a reactive double bond at two or more terminals, and a production method and use thereof.

  In recent years, there have been an increasing number of treatment examples by transplanting the liver, kidney, heart and the like to serious patients, and the number of patients who wish to be treated has also increased. However, there are currently only a limited number of patients who can receive treatment due to a lack of donors or immune rejection in transplantation treatment. As a method for solving this problem, regenerative medicine, in which cells are taken out from the patient's own tissue and proliferated and activated outside the body and returned to the body, has attracted attention, and research has been actively conducted.

  It is well known that a matrix serving as a scaffold for cells plays an important role when differentiating and proliferating cells having a function outside the body (for example, see Non-Patent Document 1). As one of these matrices, poly [Np-vinylbenzyl-D-lactone amide] (hereinafter referred to as PVLA), a synthetic sugar chain polymer with excellent biocompatibility and tissue / cell compatibility, has been studied for many years. It has been.

  PVLA is excellent in blood compatibility (see, for example, Patent Document 1), and has been found to be useful for culturing hepatocytes, and is expected to play an important role in the future development of regenerative medicine. Has been. Until now, PVLA has been used by coating a culture dish or other substrate, but it has been necessary to perform three-dimensional culture in order to put the cultured tissue into practical use. However, there has been no report on the preparation of a three-dimensional PVLA, that is, a PVLA cross-linked polymer.

PVLA is known to make polymer micelles in water and to enclose particularly lipophilic substances such as drugs (for example, see Non-Patent Document 1). In recent years, not only drugs but also many oil-soluble and health-friendly substances have been found and used in health foods and cosmetics. However, they are struggling to uniformly dissolve or disperse in water. Although it is possible to disperse these oil-soluble substances in water by PVLA, it has been difficult to increase the amount of oil-soluble substances dispersed.
JP-A-2005-112987 Mitsuaki Goto et al., Macromol. Chem. Phys., 2001, 202, 1161-1165

  Accordingly, an object of the present invention is to provide a novel cross-linked polymer for producing the gel, a method for producing the gel, and an application thereof while maintaining excellent properties such as biocompatibility and water solubility of PVLA.

  As a result of intensive studies on a crosslinked polymer capable of producing a gel while maintaining the properties of PVLA, the present inventors used PEG derivatives each having a reactive double bond at two or more ends as a crosslinking agent, A cross-linked polymer obtained by radical polymerization with Np-vinylbenzyl-D-lactone amide as a monomer component was found, and the present invention was completed. Such a crosslinked polymer forms a gel in water and can stably include an oil-soluble substance in the three-dimensional network structure formed by the crosslinking.

  That is, the present invention provides compounds of formula I:

A crosslinked polymer obtained by reacting Np-vinylbenzyl-D-lactone amide represented by
A polymer is provided in which the cross-linking agent is a PEG derivative having a reactive double bond at each of two or more terminals.

  In the present invention, the “PEG derivative having a reactive double bond at each of two or more terminals” is represented by the formula II:

[Where,
Each X is -Y-Ar-R;
R is vinyl or allyl,
Ar is a substituted or unsubstituted arylene or aralkylene;
Y is a spacer.
The cross-linked polymer is a tetrafunctional PEG derivative represented by the formula, in particular, the cross-linked polymer in which X is 4-vinylbenzylcarbamoylpentyl.

  The present invention further provides a process for the preparation of these crosslinked polymers of formula I:

The Np-vinylbenzyl-D-lactone amide represented by the formula (I) is reacted with a PEG derivative each having a reactive double bond at two or more ends in the presence of an initiator. To do.

  A PEG derivative having a reactive double bond at each of two or more ends is represented by formula II:

[Where,
Each X is -Y-Ar-R;
R is vinyl or allyl,
Ar is a substituted or unsubstituted arylene or aralkylene;
Y is a spacer.
The said manufacturing method which is a tetrafunctional PEG derivative represented by these; Especially the said manufacturing method whose X is 4-vinylbenzylcarbamoyl pentyl can also be provided.

Furthermore, the present invention relates to a photodegradation inhibitor of a fat-soluble antioxidant such as astaxanthin, coenzyme Q ₁₀ (hereinafter referred to as CoQ ₁₀ ), vitamin E or vitamin K, and the photodegradation inhibitor. Cosmetics containing can also be provided.

The crosslinked polymer obtained by the present invention forms a gel in water, and in its three-dimensional network structure, an oil-soluble substance including a fat-soluble antioxidant such as astaxanthin, CoQ ₁₀ , vitamin E, vitamin K, It is possible to stably include a practically sufficiently useful amount far exceeding the amount of PVLA polymer micelle included. That is, according to the present invention, a sufficient amount of an oil-soluble substance can be added to a composition containing water as a base material without impairing stability.

It is an experimental result which showed the deterioration rate by UV irradiation of an astaxanthin-crosslinked polymer dispersion (Example 7: indicated by ●) and an astaxanthin-water dispersion (Comparative Example 1: indicated by ▲).

  VLA represented by the formula I of the present invention is a known monomer, and can be easily produced from a commercially available raw material by, for example, the method described in JP-A-2005-112987 (the above-mentioned Patent Document 1). it can. In addition, the example of manufacture is explained in full detail as the reference example 1 to the part of the Example mentioned later.

  A PEG derivative having a reactive double bond at each of two or more terminals used as a cross-linking agent of the present invention includes a polyfunctional PEG having a functional group at two or more terminals and a compound having a reactive double bond Can be produced by introducing a compound having a reactive double bond into each terminal functional group of the multifunctional PEG according to a method known to those skilled in the art.

  In a preferred embodiment of the present invention, such a multifunctional PEG constituting the cross-linking agent of the present invention is a bifunctional PEG commercially available, for example, under the product name SUNBRIGHT® from Nippon Oil & Fats Co., Ltd. Tetrafunctional or octafunctional PEG. These are PEGs having amino, thiol or carboxy functional groups at each end, and have the following formulas IIIa-IIIc:

[Wherein, X ^{1 to} X ³ represent —CO (CH ₂ ) _m1 —COONHS, — (CH ₂ ) _m1 —COONHS, — (CH ₂ ) _m1 —NH ₂ , or — (CH ₂ ) _m1 —SH ( Here, NHS is a succinimidyl group, m1 is an integer of 1 to 5), and n is a sum of the average molecular weight (MW) of about 1,000 to 30,000. It is a number such as

  On the other hand, the compound having a reactive double bond constituting the cross-linking agent of the present invention has a carbon-carbon double bond capable of causing an addition reaction in the presence of a radical initiator in its molecule, preferably , A compound having a vinyl or allyl group. As the compound having a reactive double bond, a compound further containing an aryl moiety imparting hydrophobicity is suitable. By introducing a hydrophobic structure not only to the VLA monomer constituting the crosslinked polymer of the present invention but also to the crosslinking agent portion, the inclusion ability of the crosslinked polymer with respect to the oil-soluble substance can be enhanced. Such compounds are represented by the following formula IV:

[Where,
R is vinyl or allyl,
Ar is a substituted or unsubstituted arylene or aralkylene, in particular phenylene, benzylene or xylylene, and Y ′ is a group capable of reacting with a functional group of a polyfunctional PEG to form a covalent bond. ] Is represented. Y ′ can be appropriately selected by those skilled in the art depending on the type of the terminal functional group of the multifunctional PEG into which such a compound is introduced. For example, if the terminal functional group of the multifunctional PEG is a carboxy group (or an activated derivative thereof), Y ′ is an amino group, a hydroxy group, etc .; if the terminal functional group is an amino group, Y ′ is a carboxy group. Groups (or activated derivatives thereof), halogens and the like. Examples of the compound having a reactive double bond are 4-vinylbenzylamine, 4-vinylbenzyl chloride and the like.

  In a preferred embodiment of the present invention, the cross-linking agent is a polyfunctional PEG of the above formulas IIIa to IIIc, which has an amino or carboxy functional group at its end, and is further derivatized with a compound of the above formula IV Is obtained. The polyfunctional PEG constituting the cross-linking agent has a number of branched chains (functional groups) depending on the size of the three-dimensional network structure formed thereby and the molecular structure of the oil-soluble substance intended for inclusion. And molecular weight are appropriately selected. In a particularly preferred embodiment, the cross-linking agent is a tetrafunctional PEG of formula IIIb above, having an amino or carboxy functionality at its end, with a MW of about 10,000 to 20,000, and a terminal amino acid. Alternatively, it can be obtained by further derivatization with a compound of formula IV above with a carboxy functional group. The tetrafunctional PEG derivative so obtained has the formula II:

[Where,
Each X is -Y-Ar-R, and n is a number such that, in total, the MW is about 1,000 to 30,000;
R is vinyl or allyl,
Ar is a substituted or unsubstituted arylene or aralkylene;
Y is a spacer.
It is represented by The Y spacer is a linking moiety formed between the end group X ² of the tetrafunctional PEG of formula IIIb and Y ′ of the compound of formula IV, preferably —CO (CH ₂ ) _m1. —CONH—, — (CH ₂ ) _m1 —CONH—, —CO (CH ₂ ) _m1 —COO—, — (CH ₂ ) _m1 —COO—, — (CH ₂ ) _m1 —NH— (where m1 is And the like, particularly preferably — (CH ₂ ) _m1 —CONH— (wherein _m1 has the same meaning as described above). In a further preferred embodiment, the crosslinker is 4 of formula II, wherein X is 4-vinylbenzylcarbamoylpentyl and n is a number such that the total MW is about 10,000 to 20,000. It is a functional PEG derivative.

  The crosslinked polymer of the present invention has the formula I:

Can be obtained by reacting a PEG derivative having a reactive double bond at each of two or more terminals in the presence of an initiator. The monomer ratio between the VLA and the crosslinking agent used in the reaction may be appropriately selected according to the size of the three-dimensional network structure formed, the molecular structure of the oil-soluble substance intended for inclusion, the molecular weight of the crosslinking agent, etc. For example, it is in the range of 1: 0.005 to 1: 0.1 (weight basis), preferably 1: 0.01 to 1: 0.05. The reaction is carried out in an inert solvent such as dimethyl sulfoxide (DMSO), ethanol, or a water mixed solvent thereof under an inert atmosphere such as argon or nitrogen, and room temperature (25 ° C.) to 100 ° C., preferably 60 ° C. to 85 ° C. In the presence of an initiator in the temperature range of The initiator can be used without any particular limitation as long as it is an initiator used in a normal radical polymerization reaction. Preferably, benzoyl peroxide (BPO), 2,2-azobis (isobutyronitrile) (AIBN) is used. , Potassium persulfate or ammonium persulfate.

  The crosslinked polymer of the present invention obtained by such a reaction can be purified by a method known to those skilled in the art, for example, a method such as dialysis, if necessary.

The crosslinked polymer obtained in the present invention forms a gel in water, and in its network structure, oil-soluble substances including fat-soluble antioxidants such as astaxanthin, CoQ ₁₀ , vitamin E, vitamin K, etc. In addition, a sufficiently useful amount can be stably included. In addition, it became clear that these fat-soluble antioxidants that are susceptible to photodegradation by UV can also act as photodegradation inhibitors (examples described later), and as photodegradation inhibitors of these antioxidants Is also expected. The crosslinked polymer of the present invention is expected to be applied in the fields of pharmaceuticals, health foods, and cosmetics because it uses VLA, which is excellent in biocompatibility as a basic component, and has high water solubility. In particular, lotions, emulsions, skin gels, skin creams, oil-in-water emulsion ointments, makeup bases to which fat-soluble antioxidants such as astaxanthin, CoQ ₁₀ , vitamin E, and vitamin K are added as active ingredients The cross-linked polymer of the present invention can be blended in cosmetics of various dosage forms such as cream, emulsion foundation, hand cream, massage gel, face wash, cleansing cream, masking agent and the like.

[Reference Example 1] Synthesis of Np-vinylbenzyl-D-lactone amide (VLA)

1) Synthesis of 4-vinylbenzylamine (VBA) 1 kg of 4- (chloromethyl) styrene was dissolved in 3.2 L of DMF, and 1.2 kg of potassium phthalimide was added. This was reacted at 50 ° C. for 4 hours. After distilling off DMF using an evaporator, 4.5 L of benzene was added to dissolve the residue. Benzene was washed several times with 0.2N NaOH solution (total amount 3.25 L). Benzene was further washed several times with water (total amount 3.25 L), dried over Na ₂ SO ₄ , and then the solvent was distilled off using an evaporator. The residue was recrystallized from methanol to obtain 1.5 kg of vinylbenzylphthalimide.

1 kg of the above vinylbenzylphthalimide was dissolved in 2.7 L of ethanol in an appropriate amount of separable flask and heated to reflux under a nitrogen stream. A dropping funnel was used to add 80% hydrazine monohydrate 0.36 kg / 545 ml EtOH solution over about 40 minutes. The reaction was performed by heating to reflux for 90 minutes. After completion of the reaction, the obtained solid was collected by filtration, dissolved in KOH solution (1 kg / 6.5 L H ₂ O), and extracted with ether (total amount: 3.6 L × 3). The ether layer was further washed with 2% K ₂ CO ₃ solution and further several times with water. After the ether layer was dried with Na ₂ SO ₄ , the ether was distilled off and the residue was distilled under reduced pressure to obtain 0.45 kg of 4-vinylbenzylamine.

2) Synthesis of VLA 12 g of lactose was dispersed in 300 ml of methanol and heated to 40 ° C. To this, a methanol solution of 18 g of iodine was dropped and reacted for 40 minutes. To this was added 4N KOH methanol solution until no iodine coloration occurred. The precipitate was collected by filtration, washed several times with cold methanol, washed with ether, and once weighed. Thereafter, the obtained crystals were dissolved in a very small amount of water and applied to a proton-type ion exchange resin of Amberlite 120B, and the acidic fraction was isolated. Methanol and ethanol were added to the obtained aqueous solution for evaporation. After complete drying, methanol and ethanol were added again to dissolve and evaporate. This operation was repeated several times to produce lactose lactone.

  After 1 kg of the lactose lactone was dissolved in 5.4 L of methanol at 70 ° C., 0.4 kg of the 4-vinylbenzylamine was added thereto and reacted at 70 ° C. for 120 minutes. After completion of the reaction, 21.7 L of acetone was added to precipitate VLA. This was allowed to stand at 4 ° C. for several hours and then collected by filtration. The precipitate was recrystallized from methanol. The yield was 1.1 kg.

[Example 1] Synthesis of crosslinked polymer (No. 1) 1) Synthesis of 4VBA-PEG1 Tetrafunctional PEG (manufactured by NOF Corporation, SUNBRIGHT (registered trademark) PTE-100HS, MW 10,000; 5 g of X ² is succinimidyl carboxypentyl) was dissolved in 400 ml of chloroform, and 0.5 g of 4-vinylbenzylamine (see Reference Example 1 (1)) was added and allowed to react for 2 hours while stirring at room temperature. . Chloroform was distilled off from the reaction solution, followed by washing with diethyl ether three times to remove unreacted VBA. The washed and dried reaction product was dissolved in water, freeze-dried, and a compound in which VBA was introduced at the four ends of PEG (4VBA-PEG1: in Formula II, X is 4-vinylbenzylcarbamoylpentyl) 5 .2 g was obtained.

2) Synthesis of cross-linked polymer After dissolving 1.0 g of VLA and 20 mg of 4VBA-PEG1 in 1.5 ml of dimethyl sulfoxide (DMSO) at 60 ° C., 2,2′-azobis (isobutyronitrile) (AIBN: Tokyo) was separately prepared. 50 mg of Kasei Kogyo Co., Ltd. was dissolved in 0.5 ml of DMSO, and degassed by bubbling nitrogen gas for 10 minutes. The temperature was raised to 65 ° C. and reacted for 2 hours. After completion of the reaction, the gel product was added to 10 ml of methanol, and DMSO and the like were washed and removed. After removing the methanol under reduced pressure, the gel product was dispersed in 20 ml of water and dialyzed for 3 days in pure water using a dialysis membrane (manufactured by Sanko Junyaku Co., Ltd., UC30-32). After dialysis, freeze-dried to obtain 0.81 g of a crosslinked polymer (No. 1).

Example 2 Synthesis of Crosslinked Polymer (No. 2) 1.0 g of VLA and 50 mg of 4VBA-PEG1 prepared in Example 1 (1) were dissolved in DMSO 1.5 ml at 60 ° C., and AIBN 50 mg was separately added. Was dissolved in 0.5 ml of DMSO and degassed by bubbling nitrogen gas for 10 minutes. The temperature was raised to 65 ° C. and reacted for 2 hours. After completion of the reaction, the gel product was added to 10 ml of methanol, and DMSO and the like were washed and removed. After removing the methanol under reduced pressure, the gel product was dispersed in 20 ml of water and dialyzed for 3 days in pure water using a dialysis membrane (manufactured by Sanko Junyaku Co., Ltd., UC30-32). After dialysis, freeze-dried to obtain 0.89 g of a crosslinked polymer (No. 2).

[Example 3] Synthesis of crosslinked polymer (No. 3) 1.0 g of VLA and 20 mg of 4VBA-PEG1 prepared in Example 1 (1) were dissolved in 1.5 ml of water at 60 ° C, and separately 50 mg of AIBN. Was dissolved in 0.5 ml of ethanol and degassed by bubbling nitrogen gas for 10 minutes. The temperature was raised to 65 ° C. and reacted for 2 hours. After completion of the reaction, the gel product was washed with water to remove ethanol and the like. Further, the gel product was dialyzed in pure water for 3 days using a dialysis membrane (UC30-32, manufactured by Sanko Junyaku Co., Ltd.). After dialysis, freeze-dried to obtain 0.77 g of a crosslinked polymer (No. 3).

[Example 4] Synthesis of crosslinked polymer (No. 4) 1) Synthesis of 4VBA-PEG2 Tetrafunctional PEG (manufactured by NOF Corporation, SUNBRIGHT (registered trademark) PTE-200HS, MW 20,000; 5 g (X ² is succinimidyl carboxypentyl) was dissolved in 400 ml of chloroform, and 0.4 g of VBA was added with stirring at room temperature and reacted for 2 hours. Chloroform was distilled off from the reaction solution, followed by washing with diethyl ether three times to remove unreacted VBA. A compound in which the washed and dried reaction product was dissolved in water and freeze-dried to introduce VBA at the four ends of PEG (4VBA-PEG1: in Formula II, X is 4-vinylbenzylaminocarboxypentyl). 5.0 g was obtained.

2) Synthesis of cross-linked polymer After dissolving 1.0 g of VLA and 30 mg of 4VBA-PEG2 in 1.5 ml of DMSO at 60 ° C., 50 mg of AIBN was separately dissolved in 0.5 ml of DMSO, and nitrogen gas was bubbled for 10 minutes. I was degassed. The temperature was raised to 65 ° C. and reacted for 2 hours. After completion of the reaction, the gel product was added to 10 ml of methanol to wash and remove DMSO and the like. After removing the methanol under reduced pressure, the gel product was dispersed in 20 ml of water and dialyzed for 3 days in pure water using a dialysis membrane (manufactured by Sanko Junyaku Co., Ltd., UC30-32). After dialysis, freeze-dried to obtain 0.84 g of a crosslinked polymer (No. 4).

[Example 5] Measurement of swelling rate of crosslinked polymer 50 mg of each of the crosslinked polymers obtained in Examples 1 to 4 was placed in a glass dish, and about 10 ml of distilled water was added to each to swell in a thermostatic bath at 25 ° C for 10 days. It was. After removing excess water in the glass dish and water adhering to the gel, the swelling ratio of the crosslinked polymer was determined by weighing with a balance. The swelling rate is the following formula:
Swell ratio = weight of hydrogel / dry weight of crosslinked polymer (g / g)
Calculated from The measurement results were as shown in Table 1 below.

[Example 6] Preparation of Astaxanthin-Crosslinked Polymer Dispersion After 11.4 mg of the crosslinked polymer (No. 1) prepared in Example 1 was dispersed in 6 ml of water, a solution of astaxanthin (manufactured by Sigma) with stirring [ 0.3 mg of 1 mg / ml THF (without stabilizer)] was added dropwise to prepare a dispersion liquid. After evaporating THF under reduced pressure, the product dialyzed in water for 3 days was lyophilized to obtain a dispersion (astaxanthin dispersion). The astaxanthin dispersion was dispersed in a one-to-one mixed solvent having a volume of THF and water, and astaxanthin was transferred to the mixed solvent phase by sonication, followed by centrifugation at 7000 rpm for 5 minutes. The concentration of astaxanthin contained in the astaxanthin dispersion was calculated from the UV absorption intensity measurement at 482 nm of the supernatant. As a result, it was found that the added astaxanthin was incorporated into the 100% dispersion.

[Example 7] Preparation of coenzyme Q ₁₀ -crosslinked polymer dispersion After 15 mg of the crosslinked polymer (No. 1) prepared in Example 1 was dispersed in 12 ml of water, a solution of coenzyme Q ₁₀ (manufactured by Sigma) was stirred. 0.6 ml of (1 mg / ml THF) was added dropwise to prepare a dispersion liquid. After evaporation under reduced pressure THF, those dialyzed in water for 3 days and lyophilized to give a dispersion (Coenzyme Q ₁₀ dispersion). Coenzyme Q ₁₀ dispersion was dispersed in ethanol, after the coenzyme Q ₁₀ over the sonication were transferred to ethanol phase, and centrifuged for 5 minutes at 7000 rpm. Result of calculating the concentration of coenzyme Q ₁₀ from UV absorption intensity measurement of 274nm of the supernatant were included in the crosslinked polymer, 67% of coenzyme Q ₁₀ was added was found to have been incorporated into the gel.

[Example 8] Measurement of UV stability of astaxanthin-crosslinked polymer dispersion 9.5 mg of the astaxanthin-crosslinked polymer dispersion prepared in Example 6 was redispersed in 16 ml of water to prepare a dispersion. This dispersion was irradiated with UV under a germicidal lamp (ILA33E2 manufactured by Toshiba), and the degradation rate of astaxanthin by UV was measured. The illuminance at the UV irradiation position was 40 Lux as measured with a digital illuminometer (LX-1108 manufactured by FUSO Corporation). A part of the dispersion for each irradiation time was taken, the same amount of THF was added, and the absorbance at 482 nm was measured. The astaxanthin concentration was determined by a calibration curve of 482 nm of a mixed solution of THF and water (1 to 1). The results are shown in FIG. Astaxanthin showed long-term stability to UV light in the crosslinked polymer dispersion rather than the aqueous dispersion (see Comparative Example 1 below). That is, it was recognized that the crosslinked polymer of the present invention has an action of preventing photodegradation.

[Comparative Example 1] Measurement of UV stability of astaxanthin-water dispersion 2.3 mg of astaxanthin was dissolved in 100 ml of THF, and 16 ml of this solution was irradiated with UV under a germicidal lamp under the same conditions as in Example 8. The absorbance at 482 nm of the solution for each hour was measured, and the degradation rate of astaxanthin by UV was measured. The astaxanthin concentration was determined by a calibration curve of 482 nm of THF solution. The measurement results are shown in FIG.

[Example 9] Preparation of VK1-crosslinked polymer dispersion and dispersion of 100 mg of UV stable crosslinked polymer (No. 2) in 80 ml of water, followed by stirring with a solution of vitamin K1 (manufactured by Kanto Chemical Co., Ltd.) 4 ml of 1 mg / ml THF) was added dropwise to prepare a dispersion liquid. After THF was distilled off under reduced pressure, the product dialyzed in water for 3 days was lyophilized to obtain a dispersion (VK1 crosslinked polymer dispersion). VK1 crosslinked polymer dispersion (15 mg) was dispersed in 17 ml of water, and UV irradiation was performed under the same conditions as in Example 8. For comparison, 1 ml of 1 mg / ml THF solution of VK1 was dispersed in 16.5 ml of water to prepare an aqueous dispersion of VK1 (VK1 aqueous dispersion). The VK1 aqueous dispersion was similarly irradiated with UV. The deterioration rate of VK1 due to UV irradiation of both was measured by absorbance at 248 nm. The measurement results are shown in the table below.

  According to the present invention, oil-soluble substances such as fat-soluble antioxidants listed in the present specification can be stably blended in cosmetics, particularly cosmetics using a water-soluble base material.

Claims (9)

Formula I:

A crosslinked polymer obtained by reacting Np-vinylbenzyl-O-β-D-galactopyranosyl- (1 → 4) -D-gluconamide represented by the formula:
A polymer, wherein the crosslinking agent is a polyethylene glycol derivative having a reactive double bond at each of two or more terminals. Polyethylene glycol derivatives each having a reactive double bond at two or more ends are represented by the formula II:

[Where,
Each X is -Y-Ar-R;
R is vinyl or allyl,
Ar is a substituted or unsubstituted arylene or aralkylene;
Y is a spacer.
The crosslinked polymer according to claim 1, which is a tetrafunctional polyethylene glycol derivative represented by the formula:   The crosslinked polymer according to claim 1 or 2, wherein X is 4-vinylbenzylcarbamoylpentyl. A process for producing a crosslinked polymer according to claim 1, comprising the formula I:

Np-vinylbenzyl-O-β-D-galactopyranosyl- (1 → 4) -D-gluconamide and a polyethylene glycol derivative each having a reactive double bond at two or more terminals In the presence of an initiator. Polyethylene glycol derivatives each having a reactive double bond at two or more ends are represented by the formula II:

[Where,
Each X is -Y-Ar-R;
R is vinyl or allyl,
Ar is a substituted or unsubstituted arylene or aralkylene;
Y is a spacer.
The manufacturing method of Claim 4 which is a tetrafunctional polyethyleneglycol derivative represented by these.   The production method according to claim 4 or 5, wherein X is 4-vinylbenzylcarbamoylpentyl.   The photodegradation inhibitor of a fat-soluble antioxidant containing the crosslinked polymer according to any one of claims 1 to 3. The photodegradation inhibitor according to claim 7, wherein the fat-soluble antioxidant is selected from astaxanthin, coenzyme Q ₁₀ , vitamin E or vitamin K.   Cosmetics containing the photodegradation inhibitor according to claim 7 or 8.

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