KR20240025796A - Double cross linked copolymer, preparation method thereof and patch comprising the same - Google Patents

Abstract

The present invention relates to a double cross-linked copolymer, a method for producing the same, and a patch containing the same. The double cross-linked copolymer can be used to prevent hair loss and promote hair growth due to its ability to inhibit the activity of 5α-reductase and promote hair growth, and its biodegradability is also suppressed compared to existing hyaluronic acid, so it can achieve the desired effect for a long time. In addition, by using the double cross-linked copolymer, it is possible to provide a hair loss prevention product in the form of a patch that can be easily attached and detached to the scalp, such as a microneedle, instead of the hair loss prevention product mainly used through oral medication or injection.

Description

Double cross-linked copolymer, method for producing the same, and patch containing the same {DOUBLE CROSS LINKED COPOLYMER, PREPARATION METHOD THEREOF AND PATCH COMPRISING THE SAME}

The present invention relates to a double cross-linked copolymer, a method for producing the same, and a patch containing the same.

In addition to genetic causes, hair loss also occurs due to acquired causes such as poor eating habits, stress, and drinking. Recently, the incidence of hair loss has been increasing. In particular, along with the occurrence of hair loss among women, hair loss has become a new concern among young people in their 20s. Among the currently developed hair loss-related drugs, there are two that are approved by the FDA: Minoxidil and Propecia. Minoxidil is a substance that promotes hair growth by increasing the growth stage of the hair follicle growth cycle, and shows maximum effectiveness when used consistently for about 12 to 18 months. Propecia, developed by Merck, is an oral hair loss treatment that treats hair loss by inhibiting the activity of 5α-reductase. It cannot be used for women and has the disadvantage of side effects such as loss of stamina and should be avoided by people with liver dysfunction. .

The present invention provides a double crosslinked copolymer and a method for producing the same.

The present invention provides a patch containing the above double cross-linked copolymer.

Hereinafter, the double cross-linked copolymer, its manufacturing method, and patches containing the same according to specific embodiments of the invention will be described.

According to one embodiment of the invention, there is provided a double cross-linked copolymer comprising a graft copolymer of hyaluronic acid and fucoidan, wherein the graft copolymer is chemically cross-linked and physically cross-linked to have a three-dimensional cross-linked structure.

The hair cycle can be divided into three main stages known as anagen, catagen, and telogen. During the growth phase, hair is formed as hair follicles grow deeper into the skin along with rapid proliferation of cells. The next phenomenon is the catagen phase, which is a transitional phase in which the cessation of cell division is noticeable. During this process, the hair follicles gradually degenerate and hair growth stops. In the next phase, the telogen phase, the degenerated hair follicle contains a germ that is densely packed with dermal papilla cells. The initiation of new anagen events in the telogen phase is induced by rapid cell proliferation in the embryo, expansion of the dermal papilla, and synthesis of basement membrane elements. Therefore, it is necessary to prevent hair loss or promote hair growth by promoting or extending the growth period.

As can be seen in the examples described below, the double cross-linked copolymer according to the above embodiment promotes the proliferation of dermal papilla cells and inhibits the activity of 5α-reductase, which causes hair loss, thereby preventing existing hair from falling out. It can show improvement effects such as thickening already existing hair and the effect of creating new hair.

In addition, existing hair loss prevention products are mainly used through oral medications or injections, causing problems such as side effects on the human body. However, using the double cross-linked copolymer, it is possible to provide a hair loss prevention product in the form of a patch such as a microneedle.

In this specification, hair loss prevention products are a term that encompasses products that prevent hair loss by promoting hair growth or thickening existing hair in addition to products that have the effect of preventing existing hair from falling out.

In this specification, hyaluronic acid may be used to refer to both hyaluronic acid, a salt of hyaluronic acid, or a mixture thereof. Non-limiting examples of the salt of hyaluronic acid include sodium hyaluronate.

Hyaluronic acid is a biocompatible or biocompatible substance that exists widely in nature, and N-acetylglucosamine and D-glucuronic acid form a beta-1,3-glycosidic bond. It is a linear polysaccharide continuously linked through glycosidic bonds.

These hyaluronic acids may have a high molecular weight, for example, 0.1 to 2.5 MDa, 0.5 to 2.3 MDa, 1.0 to 2.1 MDa or 1.5 to 2.0 MDa.

Hyaluronic acid is a basic component of biological tissue and is essential for cell morphogenesis, cell differentiation, and cell division, and helps heal wounds. Although hyaluronic acid is an insoluble gel in aqueous solution through ether bonds, it exhibits excellent viscoelasticity and high moisture absorption ability, so it maintains its shape for a certain period of time in the body and then decomposes and is absorbed into the body. Therefore, hyaluronic acid has the disadvantage of being quickly absorbed and decomposed by decomposition enzymes when injected into the body.

The double cross-linked copolymer according to the above embodiment graft-polymerizes hyaluronic acid with fucoidan and chemically and physically cross-links it, thereby suppressing the biodegradability of hyaluronic acid and stably producing the desired effect for a long time.

Fucoidan is a polysaccharide that exists in brown algae such as kelp and contains a sulfate group. Fucoidan is not only effective in anti-cancer, anti-inflammatory, anti-thrombotic, antioxidant, and hyperlipidemia prevention and treatment, but has also been reported to affect hair growth and hair growth. Hair loss prevention products containing fucoidan have already been introduced, but in the above embodiment, fucoidan is used in the form of graft polymerization with hyaluronic acid. In the above embodiment, by graft polymerizing fucoidan to hyaluronic acid rather than simply mixing it, fucoidan and hyaluronic acid's inherent hair loss prevention and hair growth promotion effects can be exhibited, and the biodegradability of hyaluronic acid can also be suppressed to produce the desired effect for a long time. Furthermore, it is possible to provide a product in the form of a patch that can be easily attached and detached to the scalp, such as a microneedle.

The graft copolymer may contain hyaluronic acid and fucoidan in appropriate amounts. As an example, the graft copolymer contains hyaluronic acid and fucoidan in the range of 9.9:0.1 to 6.0:4.0, 9.8:0.2 to 7.0:3.0, 9.7:0.3 to 7.3:2.7, 9.7:0.3 to 7.5:2.5, and 9.7:0.3 to 7.7. :2.3, 9.7:0.3 to 8.0:2.0, 9.7:0.3 to 8.3:1.7, 9.7:0.3 to 8.5:1.5, 9.7:0.3 to 8.7:1.7, 9.5:0.5 to 8.7:1.7 or 9.3:0.7 to 8.7:1.7 It can be included in a weight ratio of . In particular, when the weight ratio of hyaluronic acid and fucoidan is 9.7:0.3 to 8.3:1.7, 9.7:0.3 to 8.5:1.5, 9.7:0.3 to 8.7:1.7, 9.5:0.5 to 8.7:1.7 or 9.3:0.7 to 8.7:1.7. It can exhibit superior 5α-reductase activity inhibition ability.

The graft copolymer is chemically cross-linked.

As an example, the chemical crosslinking may be formed through an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent.

The acrylic compound may be a compound having a (meth)acryloyl group or (meth)acryloyloxy group.

The acrylic compound may have a reactive functional group capable of forming a chemical bond with the functional group of the graft copolymer. As an example, the acrylic compound may include at least one selected from the group consisting of a hydroxy group, an amino group, and an epoxy group as a reactive functional group capable of forming a chemical bond with the hydroxy group of the graft copolymer. As an example, the acrylic compound may include hydroxyalkyl (meth)acrylate, and the alkyl may be a straight-chain, branched-chain, or cyclic alkyl having 1 to 12 carbon atoms.

The acrylic compound can be used in an amount of 100 to 1500 parts by weight, 500 to 1000 parts by weight, or 600 to 900 parts by weight based on 100 parts by weight of the graft copolymer to achieve an appropriate crosslinking density.

The multifunctional acrylic crosslinking agent may be a compound having two or more (meth)acryloyl groups or (meth)acryloyloxy groups. For example, the multifunctional acrylic crosslinking agent may include poly(meth)acrylate of a polyol having 2 to 10 carbon atoms. Specifically, the multifunctional acrylic crosslinking agent may be poly(alkylene glycol) di(meth)acrylate, and the alkylene may be a straight-chain or branched-chain alkylene having 2 to 10, 2 to 6, or 2 to 4 carbon atoms. .

The multifunctional acrylic crosslinking agent can be used in an amount of 50 to 500 parts by weight, 100 to 300 parts by weight, or 150 to 250 parts by weight based on 100 parts by weight of the graft copolymer to achieve an appropriate crosslinking density.

The chemically cross-linked graft copolymer is also physically cross-linked to provide a dual cross-linked copolymer with a dual cross-linked system.

As an example, the physical crosslinking may be formed through chitosan.

Chitosan is a polysaccharide formed by partial deacetylation of chitin. It is a non-toxic, biocompatible, highly biodegradable polymer material with high hydrophilicity and antibacterial and hemostatic effects.

The molecular weight of chitosan used for physical crosslinking of the graft copolymer is not particularly limited, but may be, as a non-limiting example, 3 to 100 kDa.

When chitosan is added to the chemically cross-linked graft copolymer, the functional groups of hyaluronic acid and fucoidan that did not participate in the chemical cross-linking reaction form hydrogen bonds with chitosan, thereby further improving the viscoelasticity of the polymer.

More specifically, chitosan can form a strong electrostatic attraction with the negatively charged carboxyl group of hyaluronic acid, the negatively charged sulfate group and the positively charged amine group of fucoidan, thereby providing a double cross-linked copolymer with high viscoelasticity. Due to these characteristics, the double cross-linked copolymer can exhibit less biodegradability than hyaluronic acid, its main raw material, and can be provided in the form of a patch that can be attached and detached to the scalp, such as microneedles.

The chitosan can be used in an amount of 1 to 30 parts by weight, 1 to 25 parts by weight, 1 to 20 parts by weight, 1 to 15 parts by weight, or 1 to 10 parts by weight based on 100 parts by weight of the graft copolymer to achieve the above effect. In particular, referring to Examples 1 and 2 described below, when the chitosan content is 1 to 15 parts by weight or 1 to 10 parts by weight based on 100 parts by weight of the graft copolymer, it can exhibit a more excellent ability to inhibit the activity of 5α-reductase. .

Meanwhile, according to another embodiment of the invention, preparing a graft copolymer by reacting hyaluronic acid and fucoidan; Chemically crosslinking the graft copolymer by reacting the graft copolymer with an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent; and adding chitosan to the chemically crosslinked graft copolymer to physically crosslink it.

The method for producing the double cross-linked copolymer may be the method for producing the double cross-linked copolymer described above. Hyaluronic acid, fucoidan, acrylic compounds, multifunctional acrylic crosslinking agents, and chitosan have been described in detail previously and are therefore omitted here.

In the step of preparing the graft copolymer, hyaluronic acid and fucoidan are reacted to prepare the graft copolymer.

In the step of preparing the graft copolymer, a graft polymerization reaction may be performed using distilled water as a reaction solvent. And, for example, the graft polymerization reaction may be performed at room temperature for 8 to 24 hours and then further performed at 40 to 90° C. for 0.5 to 5 hours.

When the graft polymerization is completed through the step of preparing the graft copolymer, an acrylic compound having a reactive functional group can be first added to the obtained graft copolymer to induce the graft copolymer and the acrylic compound to react preferentially. Additionally, a chemical crosslinking structure can be formed by adding a multifunctional acrylic crosslinking agent to connect the acrylic compounds bonded to the graft copolymer.

In the step of chemically crosslinking the graft copolymer, an initiator may be used. Non-limiting examples of the initiator include persulfate-based initiator, azo-based initiator, hydrogen peroxide, or ascorbic acid. For example, potassium persulfate may be used as the initiator.

After chemically crosslinking the graft copolymer, chitosan can be added to physically crosslink it. In the physical crosslinking process, chitosan, a physical crosslinking agent, can be added and left to stand or stirred to induce a physical crosslinking reaction.

Meanwhile, according to another embodiment of the invention, a base film; and a plurality of protrusions present on one side of the base film, wherein the protrusions are formed of the double cross-linked copolymer.

Microneedle refers to a transdermal drug delivery system that utilizes microneedles within a few hundred micrometers in length to pass through the stratum corneum of the skin and deliver active ingredients into the dermis. Microneedles have microneedles on one side for attachment to the skin. It is provided in the form of a formed patch.

Unlike existing hair loss prevention products, the double cross-linked copolymer can be provided in the form of a patch such as microneedles without using oral medications or injections.

The base film is not particularly limited as long as it serves as a support to support a plurality of protrusions.

As an example, the base film may be a hydrocolloid film in which hydrocolloid paste is coated on one side of a polyurethane film. The hydrocolloid paste may include hydrocolloid particles and a hydrophobic elastomer to form a matrix supporting the hydrocolloid particles. Non-limiting examples of the hydrophobic elastomer include natural rubber, polyisoprene, polybutadiene, butyl rubber (e.g., a copolymer of isoprene and isobutylene) or halogenated butyl rubber, and styrene-isoprene-styrene triblock copolymer. etc. can be mentioned. The hydrocolloid particles have a network structure in which hydrophilic polymers are three-dimensionally cross-linked by physical bonds (e.g., hydrogen bonds, van der Waals forces, or hydrophobic interactions, etc.) or chemical bonds (e.g., covalent bonds). As a particle, it can exhibit a high moisture content. The hydrophilic polymers that make up these hydrocolloid particles are natural hydrophilic polymers such as pectin, gelatin, cellulose, collagen, dextran, elastin, chitin, chitosan, or sodium alginate, or synthetic hydrophilic polymers such as polyacrylic acid, polyvinyl alcohol, polyethylene glycol, It may be polyvinyl pyrrolidone, polyurethane, polyhydroxyethyl methacrylate, or silicone, or a combination thereof, and the crosslinking agent for crosslinking these hydrophilic polymers is calcium chloride, calcium sulfate, calcium nitrate, zinc nitrate, and chloride. It may be zinc, zinc sulfate, ammonium persulfate, or glutaraldehyde.

On one side of the base film, there are a number of protrusions formed from the double cross-linked copolymer. The shape, size, and number of the protrusions can be appropriately controlled depending on the usage type and size of the patch.

The patch may further include a release film to protect the protrusions formed on one side of the base film. The patch may further contain various additives known in the art to prevent hair loss or promote hair growth.

The double cross-linked copolymer according to one embodiment of the invention can be used to prevent hair loss and promote hair growth due to its ability to inhibit the activity of 5α-reductase and promote hair growth, and its biodegradability is also suppressed compared to existing hyaluronic acid, providing the desired effect for a long time. can be implemented. In addition, by using the double cross-linked copolymer, it is possible to provide a hair loss prevention product in the form of a patch that can be easily attached and detached to the scalp, such as a microneedle, instead of the hair loss prevention product mainly used through oral medication or injection.

Hereinafter, the operation and effects of the invention will be described in more detail through specific examples of the invention. However, this is presented as an example of the invention, and the scope of the invention is not limited by this in any way.

Preparation example: Preparation of chemically cross-linked copolymer

The 100 mL three-neck round bottom flask was washed and then washed once more with distilled water. Add 60 mL of distilled water, 235.7 mg of sodium hyaluronate (molecular weight: 1.8 MDa), and 23.3 mg of fucoidan (hyaluronic acid:fucoidan (weight ratio) = 9.1:0.9) into the round bottom flask and stir at room temperature at 400 rpm for more than 12 hours. did.

Afterwards, the round bottom flask was placed in an oil bath and heated. When the temperature of the reaction solution reached 75°C, the reaction solution was stirred at 75°C for 2 hours.

Afterwards, nitrogen was injected into the reaction solution at a rate of 3 mL/min for 30 minutes.

Next, the crosslinking process was performed while maintaining the temperature of the reaction solution at 75°C. 5 mL of KPS (potassium persulfate) solution was added to the reaction solution and stirred for 20 minutes. Add 2 mL (density: 1.106 g/mL at 25 ℃, 2.2 g) of 2-hydroxyethyl acrylate (2-HEA) to the reaction solution and stir for about 10 to 20 minutes. If the reaction solution becomes viscous, 500 μL (density: 1.12 g/mL at 25°C, 560 mg) of poly(ethylene glycol) diacrylate (PEGDA, number average molecular weight: 700) was added to the reaction solution and stirred for 3 hours. While the reaction was in progress, nitrogen was injected by adjusting the position of the needle on the surface of the reaction solution so that the needle supplied with nitrogen did not enter the reactant. Through the above process, a copolymer in which the graft copolymer of hyaluronic acid and fucoidan was chemically cross-linked was prepared.

Examples 1 to 3: Preparation of double crosslinked copolymers

Chitosan in the amount shown in Table 1 below was added to the chemically cross-linked copolymer prepared in the above Preparation Example and mixed appropriately to prepare a double cross-linked copolymer having both physical and chemical cross-linking.

Chitosan addition amount Control example 0 Example 1 10mg Example 2 20 mg Example 3 50mg

Test example: Characterization of double cross-linked copolymer

The properties of the double cross-linked copolymers prepared in Examples 1 to 3 and the chemically cross-linked copolymers of the control example were analyzed in the following manner, and the results are shown in Table 2.

1) Cell viability (cytotoxicity) evaluation

Cell viability was evaluated using the MTT assay method. The MTT analysis method is a water-soluble substrate called MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), which is yellow due to the action of mitochondrial dehydrogenase, and is converted to Formazan (( E,Z ), which is reddish-purple. This is a method to evaluate the metabolic activity of cells through the degree of reduction to -5-(4,5-dimethylthiazol-2-yl)-1,3-diphenylformazan).

Specifically, subcultured Human Follicle Dermal Papilla Cells (HFDPC) were dispensed into a ⁹⁶ -well plate at 1 Cultured for 24 hours.

Meanwhile, four serum free media to which the double crosslinked copolymer prepared in Examples 1 to 3 and the chemically crosslinked copolymer of the control example were added at a concentration of 200 μg/mL were used as a blank control and a negative control. Two serum-free media without any addition were prepared.

The medium of the previously cultured HFDPC was replaced with the above six mediums and further cultured under the above cell culture conditions for 24 hours.

After incubation, the MTT solution was added to only the remaining 5 media, excluding the control medium, and the 6 media were left in the dark for 2 hours. Afterwards, the supernatant was removed, and the generated formazan was completely dissolved with DMSO. The absorbance of the obtained solution at 540 nm was measured using a microplate reader (Biotek Synergy-HT, USA).

The cell survival rate was calculated using Equation 1 below. The cell viability value was defined as the average value after repeating the cell viability test three times.

[Equation 1]

Cell viability (%) = (A2 - A0) / (A1 - A0)

In Equation 1, A0 is the absorbance of the blank control group, A1 is the absorbance of the negative control group to which the MTT solution was added, and A2 is the absorbance of the group to which the cell viability test object was added.

2) Evaluation of activity inhibition ability of 5α-reductase

5α-reductase is an enzyme that reduces the male hormone testosterone and converts it into dihydrotestosterone (DHT), and is known to be a major factor causing hair loss. The expression level of 5α-reductase can be measured using real-time polymerase chain reaction (RT-qPCR). RT-qPCR is a test method that can quantitatively analyze the expression of specific mRNA by monitoring the amount of amplification product in real time by measuring the fluorescence generated during the process of amplifying the DNA product.

Specifically, subcultured dermal papilla cells (HFDPC) were dispensed into ⁶⁰ mm dishes at 5

Meanwhile, four serum free DMEM media containing the double cross-linked copolymer prepared in Examples 1 to 3 and the chemically cross-linked copolymer of the control example were added at a concentration of 200 μg/mL, and nothing was added for use as a blank control and a negative control. Two serum free DMEM media were prepared.

The medium of the previously cultured HFDPC was replaced with the above 6 mediums, and 20 nM of testosterone was added to only the remaining 5 mediums excluding the blank control medium, and the cells were cultured under the above cell culture conditions for 24 hours.

After incubation, the mRNA expression level in each sample was measured through RT-qPCR, and the activity inhibition ability of 5α-reductase was calculated by substituting it into Equation 2 below.

[Equation 2]

5α-reductase activity inhibition ability (%) = 1 - {(R2 - R0) / (R1 - R0)}

In Equation 2, R0 is the mRNA expression level of the blank control group, R1 is the mRNA expression level of the negative control group to which testosterone was added, and R2 is the mRNA expression level of the group to which the 5α-reductase activity inhibition ability test subject was added.

3) Evaluation of biodegradability inhibition efficacy

A predetermined amount of the chemical cross-linked copolymer of the control example was placed in a test tube, 0.2 M phosphate-buffered saline (pH 7.4) containing 500 U/mL of hyaluronidase was added, and the mixture was reacted at 37° C. for 48 hours.

To measure the amount of N-acetylglucosamine (NAG) decomposed through an enzymatic reaction, DMAB (p-dimethylaminobenzaldehyde) coloring reagent was added and reacted at 37°C for 30 minutes. Afterwards, the obtained reaction product was centrifuged (3,000 rpm, 10 minutes), the supernatant was taken, and the absorbance at 585 nm was measured and defined as the standard absorbance.

The biodegradability of the double cross-linked copolymers of Examples 1 to 3 was tested in the same manner as above, but the enzyme reaction time until the standard absorbance was recorded was recorded.

The enzyme reaction time until the example showed the standard absorbance was divided by 48 hours, which is the enzyme reaction time until the control example showed the standard absorbance, and was defined as the biodegradability inhibition efficacy value.

4) Evaluation of swelling degree

The degree of swelling was measured at room temperature according to Equation 3 below.

[Equation 3]

Swelling ratio = (Ws-Wd)/(Wd)

In Equation 3, Wd is the dry weight of the sample whose swelling degree is to be measured, and Ws is the weight of the swollen sample when the sample whose swelling degree is to be measured is immersed in distilled water and reaches equilibrium.

5) Viscosity evaluation

Viscosity was measured at room temperature (about 25°C) using a Brookfield Cone-Plate Viscometer equipped with a spindle size CP-40. The device was standardized within the same range as the test samples using a Viscosity Reference Standard, and the viscosity of each sample was measured three times and defined as the average.

Cell viability (%) 5α-reductase
Active inhibition capacity (%) Biodegradability inhibition effect Swelling degree Viscosity (cP) Control example 121.0000 65.7700 One 2950 15758 Example 1 127.0000 69.4500 1.20 3015 16057 Example 2 125.0000 69.7400 1.23 3028 16127 Example 3 127.0000 64.2500 1.29 3099 16278

During the anagen phase, when hair grows, hair grows through dermal papilla cells, which act as a support for the hair and provide nutrients at the same time.

Looking at Table 2 above, it is confirmed that Examples 1 to 3 show a high cell survival rate for dermal papilla cells compared to the control example. This confirms that the use of the double cross-linked copolymer according to one embodiment of the invention can promote the proliferation of dermal papilla cells and thereby promote hair growth.

In addition, it is confirmed that Examples 1 to 3 have a hair loss prevention effect due to the ability to inhibit the activity of 5α-reductase, and a biodegradability inhibition effect is also confirmed.

In particular, Examples 1 and 2 were confirmed to exhibit excellent cell viability, biodegradability inhibition ability, high swelling degree and viscosity, and high 5α-reductase activity inhibition ability.

Claims (15)

Contains a graft copolymer of hyaluronic acid and fucoidan,
The graft copolymer is a double cross-linked copolymer that is chemically and physically cross-linked to have a three-dimensional cross-linked structure.
The double crosslinked copolymer according to claim 1, which is used for preventing hair loss and promoting hair growth.
The double crosslinked copolymer of claim 1, wherein the graft copolymer includes hyaluronic acid and fucoidan in a weight ratio of 9.9:0.1 to 6.0:4.0.
The double crosslinked copolymer of claim 1, wherein the graft copolymer is chemically crosslinked with an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent.
The double crosslinked copolymer of claim 4, wherein the acrylic compound is hydroxyalkyl (meth)acrylate.
The double crosslinked copolymer of claim 4, wherein the acrylic compound is used in an amount of 100 to 1500 parts by weight based on 100 parts by weight of the graft copolymer to form a chemical crosslink.
The double crosslinked copolymer according to claim 4, wherein the multifunctional acrylic crosslinking agent is a poly(meth)acrylate of a polyol having 2 to 10 carbon atoms.
The double crosslinking copolymer according to claim 4, wherein the multifunctional acrylic crosslinking agent is used in an amount of 50 to 500 parts by weight based on 100 parts by weight of the graft copolymer to form a chemical crosslinking bond.
The double cross-linked copolymer of claim 1, wherein the graft copolymer is physically cross-linked with chitosan through hydrogen bonding.
The double crosslinked copolymer according to claim 9, wherein the chitosan is used in an amount of 1 to 30 parts by weight based on 100 parts by weight of the graft copolymer.
Preparing a graft copolymer by reacting hyaluronic acid and fucoidan;
Chemically crosslinking the graft copolymer by reacting the graft copolymer with an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent; and
A method for producing a double cross-linked copolymer, comprising adding chitosan to a chemically cross-linked graft copolymer to physically cross-link it.
The double crosslinking method of claim 11, wherein the step of preparing the graft copolymer includes reacting hyaluronic acid and fucoidan at room temperature for 8 to 24 hours, and then further reacting at 40 to 90° C. for 0.5 to 5 hours. Method for producing copolymers.
The method of claim 11, wherein the chemical crosslinking step includes first adding an acrylic compound having a reactive functional group to the graft copolymer for reaction, and then adding a multifunctional acrylic crosslinking agent to form a crosslinking bond. Method for producing a composite.
base film; and a plurality of protrusions present on one side of the base film,
The patch is formed of the double cross-linked copolymer of claim 1.
15. The patch of claim 14, wherein the base film is a hydrocolloid film.