WO2024038936A1 - Cross-linked copolymer, preparation method thereof, and patch comprising same - Google Patents
Cross-linked copolymer, preparation method thereof, and patch comprising same Download PDFInfo
- Publication number
- WO2024038936A1 WO2024038936A1 PCT/KR2022/012430 KR2022012430W WO2024038936A1 WO 2024038936 A1 WO2024038936 A1 WO 2024038936A1 KR 2022012430 W KR2022012430 W KR 2022012430W WO 2024038936 A1 WO2024038936 A1 WO 2024038936A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cross
- copolymer
- graft copolymer
- linked
- hyaluronic acid
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 4
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 34
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/738—Cross-linked polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
Definitions
- the present invention relates to a crosslinked copolymer, a method for producing the same, and a patch containing the same.
- Minoxidil is a substance that promotes hair growth by increasing the growth stage of the hair follicle growth cycle. It 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 5 ⁇ -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 crosslinked copolymer and a method for producing the same.
- the present invention provides a patch containing the crosslinked copolymer.
- a cross-linked copolymer in which a graft copolymer of hyaluronic acid and fucoidan is three-dimensionally cross-linked is provided.
- the hair cycle can be divided into three main stages known as anagen, catagen, and telogen.
- anagen catagen
- telogen a transitional phase in which the cessation of cell division is noticeable.
- the hair follicles gradually degenerate and hair growth stops.
- 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.
- the cross-linked copolymer according to the above embodiment promotes the proliferation of dermal papilla cells and inhibits the activity of 5 ⁇ -reductase, which causes hair loss, thereby preventing existing hair from falling out. It can show improvement effects such as thickening existing hair and the effect of creating new hair.
- hair loss prevention products are mainly used through oral medications or injections, causing problems such as side effects on the human body.
- a hair loss prevention product in the form of a patch such as a microneedle.
- 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.
- 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.
- 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.
- 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 cross-linked copolymer according to the above embodiment graft-polymerizes hyaluronic acid with fucoidan and cross-links it three-dimensionally, 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.
- the graft copolymer may contain hyaluronic acid and fucoidan in appropriate amounts.
- 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 .
- 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:
- the ratio is 1.7 or 9.3:0.7 to 8.7:1.7, it can exhibit a more excellent ability to inhibit the activity of 5 ⁇ -reductase.
- the graft copolymer is three-dimensionally cross-linked.
- the 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.
- 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.
- 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.
- the multifunctional acrylic crosslinking agent may include poly(meth)acrylate of a polyol having 2 to 10 carbon atoms.
- 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 method for producing the crosslinked copolymer may be the method for producing the crosslinked copolymer described above.
- Hyaluronic acid, fucoidan, acrylic compounds, and multifunctional acrylic crosslinking agents have been described in detail previously and are therefore omitted here.
- hyaluronic acid and fucoidan are reacted to prepare 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.
- 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.
- a three-dimensional crosslinking structure can be formed by adding a multifunctional acrylic crosslinking agent to connect the acrylic compounds bonded to the graft copolymer.
- an initiator may be used.
- the initiator include persulfate-based initiator, azo-based initiator, hydrogen peroxide, or ascorbic acid.
- potassium persulfate may be used as the initiator.
- the method for producing the crosslinked copolymer may be performed as a one-pot synthesis process in which a continuous chemical reaction is performed in one reactor.
- a base film and a plurality of protrusions present on one side of the base film, wherein the protrusions are formed of the crosslinked 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.
- the 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.
- 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.
- 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.
- physical bonds e.g., hydrogen bonds, van der Waals forces, or hydrophobic interactions, etc.
- chemical bonds e.g., covalent bonds
- 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.
- natural hydrophilic polymers such as pectin, gelatin, cellulose, collagen, dextran, elastin, chitin, chitosan, or sodium alginate
- protrusions formed from the crosslinked 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 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 5 ⁇ -reductase and promote hair growth, and its biodegradability is also suppressed compared to existing hyaluronic acid, providing the desired effect for a long time. It can be implemented.
- 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.
- the 100 mL three-neck round bottom flask was washed and then washed once more with distilled water.
- 60 mL of distilled water, sodium hyaluronate (molecular weight: 1.8 MDa), and fucoidan were added in the amounts shown in Table 1 below, and then stirred at room temperature at 400 rpm for more than 12 hours.
- 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.
- 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.
- 2 mL (density: 1.106 g/mL at 25 °C, 2.2 g) of 2-hydroxyethyl acrylate (2-HEA) was added to the reaction solution and stir for about 10 to 20 minutes. If the reaction solution becomes viscous, 500 ⁇ L (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.
- PEGDA poly(ethylene glycol) diacrylate
- Hyaluronic acid Fucoidan Weight ratio of hyaluronic acid:fucoidan Example 1 235.7mg 12.4mg 9.5:0.5
- Example 2 235.7mg 26.2 mg 9.0:1.0
- Example 3 235.7mg 41.6mg 8.5:1.5
- Example 4 235.7mg 58.9mg 8.0:2.0
- Example 5 235.7mg 78.6mg 7.5:2.5 Control example 235.7mg - 10.0:0
- MTT MTT analysis method
- MTT water-soluble substrate
- E,Z Formazan
- 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).
- HFDPC Human Follicle Dermal Papilla Cells
- the medium of the previously cultured HFDPC was replaced with the above eight mediums and further cultured under the above cell culture conditions for 24 hours.
- the MTT solution was added to only the remaining 7 media, excluding the control medium, and the 8 media were left in a darkened state 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 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.
- 5 ⁇ -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 5 ⁇ -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.
- subcultured dermal papilla cells were dispensed into 60 mm dishes at 5
- serum free DMEM media to which the cross-linked copolymer prepared in Examples 1 to 5 and the hyaluronic acid of the control example were added at a concentration of 200 ⁇ g/mL, and two media to which nothing was added for use as a blank control and a negative control. Serum free DMEM medium was prepared.
- the medium of the previously cultured HFDPC was replaced with the above eight mediums, and 20 nM of testosterone was added only to the remaining seven mediums excluding the blank control medium, and the cells were cultured under the above cell culture conditions for 24 hours.
- 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
- R2 is the mRNA expression level of the group to which the 5 ⁇ -reductase activity inhibition ability test subject was added.
- a predetermined amount of hyaluronic acid from 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 reaction was performed at 37°C for 48 hours.
- N-acetylglucosamine (NAG) decomposed through an enzymatic reaction 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 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.
- Examples 1 to 5 show a high cell survival rate for dermal papilla cells compared to the control example. This confirms that using the cross-linked copolymer according to one embodiment of the invention can promote the proliferation of dermal papilla cells and thereby promote hair growth.
- Examples 1 to 5 have a hair loss prevention effect due to the ability to inhibit the activity of 5 ⁇ -reductase, and a biodegradability inhibition effect is also confirmed.
- Examples 1 to 3 showed excellent cell viability and biodegradation inhibition ability while showing a high ability to inhibit the activity of 5 ⁇ -reductase.
- Examples 1 and 2 showed a higher ability to inhibit the activity of 5 ⁇ -reductase, and Example 2 It is confirmed that it shows the best effect in all aspects.
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Abstract
The present invention relates to a cross-linked copolymer, a preparation method thereof, and a patch comprising same. The cross-linked copolymer inhibits the activity of 5α-reductase and promotes hair growth, and thus can be used for preventing hair loss and promoting hair growth, and is less biodegradable than conventional hyaluronic acid, and thus can implement desired effects for a long time. In addition, if the cross-linked copolymer is used, a patch-form hair loss prevention product having convenient attachability/detachability to/from the scalp, like that of microneedles, can be provided instead of a hair loss prevention product mainly used through oral medicine or injection.
Description
본 발명은 가교 공중합체, 이의 제조 방법 및 이를 포함하는 패치에 관한 것이다.The present invention relates to a crosslinked copolymer, a method for producing the same, and a patch containing the same.
탈모는 유전적 원인 외에도 잘못된 식습관, 스트레스, 음주 등의 후천적 원인으로도 발생한다. 최근에는 탈모의 발생률이 증가하고 있는 추세이다. 특히, 여성들의 탈모 발생과 더불어 20 대 젊은 층에서도 탈모가 새로운 고민거리가 되었다. 현재 개발된 탈모 관련 약물 중 FDA에서 인정한 약물로는 미녹시딜과 프로페시아 2 가지가 있다. 미녹시딜은 모낭의 성장 주기 중 성장 단계를 늘려 줌에 따라 모발 성장을 촉진시키는 물질로 12 내지 18 개월 정도 꾸준히 사용했을 때 최대 효과를 보인다. Merck사에서 개발된 프로페시아는 경구용 탈모 치료제로 5α-reductase의 활성을 저해함으로써 탈모를 치료하는 원리로, 여성에게는 사용할 수 없으며 정력 감퇴 등의 부작용과 간기능 이상이 있는 사람은 피해야 하는 단점이 있다.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 in 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. It 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. .
본 발명은 가교 공중합체 및 이의 제조 방법을 제공한다. The present invention provides a crosslinked copolymer and a method for producing the same.
본 발명은 상기 가교 공중합체를 포함하는 패치를 제공한다. The present invention provides a patch containing the crosslinked copolymer.
이하 발명의 구체적인 구현예에 따른 가교 공중합체, 이의 제조 방법과 이를 포함하는 패치 등에 대해 설명하기로 한다. Hereinafter, a cross-linked copolymer according to a specific embodiment of the invention, a method for manufacturing the same, and a patch containing the same will be described.
발명의 일 구현예에 따르면, 히알루론산과 후코이단의 그래프트 공중합체가 3 차원적으로 가교 결합된 가교 공중합체가 제공된다. According to one embodiment of the invention, a cross-linked copolymer in which a graft copolymer of hyaluronic acid and fucoidan is three-dimensionally cross-linked is provided.
모발 주기는 성장기, 퇴행기, 휴지기로 알려진 3 개의 주요 단계들로 나눌 수 있다. 성장기에는 세포의 빠른 증식과 함께 피부 안으로 깊이 모낭이 성장하면서 모발 형성이 이루어진다. 다음 현상은 퇴행기인데 이것은 세포 분열의 중단이 두드러지는 과도기이며, 이 과정에서 모낭은 점차 퇴행하며 발모가 중단된다. 다음 현상인 휴지기에서는 퇴행 모낭은 조밀하게 찬 모유두세포를 갖는 배(germ)를 포함한다. 휴지기에서 새로운 성장기 현상의 개시는 상기 배에서 빠른 세포 증식, 모유두의 팽창 및 기저막 요소의 합성에 의해 유도된다. 따라서, 성장기의 촉진 또는 연장에 의해 탈모를 방지하거나 발모를 촉진하는 것이 필요하다. 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.
상기 일 구현예에 따른 가교 공중합체는 후술하는 실시예에서도 확인할 수 있듯이 모유두세포의 증식을 촉진하고 탈모를 유발하는 5α-reductase의 활성을 저해함에 따라 이미 존재하고 있는 모발이 빠지지 않게 하는 효과, 이미 존재하는 모발을 굵게 하는 등의 개선 효과, 새로운 모발을 생성하는 효과 등을 나타낼 수 있다. As can be seen in the examples described later, the 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 existing hair and the effect of creating new hair.
또한, 기존의 탈모 방지 제품은 주로 경구 약품이나 주사를 통해 이용되어 인체 부작용 등의 문제를 초래하였는데, 상기 가교 공중합체를 이용하면 마이크로니들과 같은 패치 형태의 탈모 방지 제품을 제공할 수 있다. 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 cross-linked copolymer, it is possible to provide a hair loss prevention product in the form of a patch such as a microneedle.
본 명세서에서 탈모 방지 제품은 기존의 모발이 빠지지 않게 하는 효과를 가지는 제품 외에도 발모를 촉진하거나, 기존의 모발을 굵게 하여 탈모를 예방할 수 있는 제품까지 아우르는 용어이다. 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.
본 명세서에서 히알루론산은 히알루론산, 히알루론산의 염 또는 이들의 혼합물을 모두 지칭하는 의미로 사용될 수 있다. 상기 히알루론산의 염의 비제한적인 예로는 히알루론산 나트륨 등을 들 수 있다. 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.
히알루론산은 자연에 널리 존재하는 생친화성 또는 생체 적합성(biocompatible) 물질로서, N-아세틸글루코사민(N-acetylglucosamine)과 D-글루쿠론산(D-glucuronic acid)이 beta-1,3-글리코시드결합(glycosidic bond)을 통해 연속적으로 연결된 선형 다당류(linear polysaccharide)이다.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.
이러한 히알루론산은 고분자량을 가지며, 예를 들어, 0.1 내지 2.5 MDa, 0.5 내지 2.3 MDa, 1.0 내지 2.1 MDa 또는 1.5 내지 2.0 MDa의 분자량을 가질 수 있다. 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.
히알루론산은 생체 조직의 기본 구성 성분으로 세포의 형태 형성, 세포 분화, 세포 분열에 필수적인 물질이며, 상처를 회복시키는데 도움을 준다. 히알루론산은 에테르 결합을 통해서 수용액 상에서 불용성의 겔이면서도 우수한 점탄성과 높은 수분 흡수 능력을 보이고 있어 생체 내에서 일정 시간 동안 형체를 유지하다 분해되어 체내로 흡수된다. 따라서, 히알루론산은 체내에 주입 시 분해 효소에 의해 빨리 흡수, 분해되는 단점이 있다.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.
상기 일 구현예에 따른 가교 공중합체는 이러한 히알루론산을 후코이단과 그래프트 중합하고 3 차원적으로 가교 결합함에 따라 히알루론산의 생분해성이 억제되어 장시간 원하는 효과를 안정적으로 나타낼 수 있다. The cross-linked copolymer according to the above embodiment graft-polymerizes hyaluronic acid with fucoidan and cross-links it three-dimensionally, thereby suppressing the biodegradability of hyaluronic acid and stably producing the desired effect for a long time.
후코이단(fucoidan)은 다시마와 같은 갈조류에 존재하며, 황산기를 함유한 다당류이다. 후코이단은 항암, 항염, 혈전 억제, 항산화, 고지혈증 예방 및 치료 등에 효과적일 뿐 아니라 모발의 성장 및 육모에 영향을 주는 것으로 보고된 바 있다. 후코이단이 배합된 탈모 방지 제품 등은 이미 소개된 바 있으나, 상기 일 구현예에서는 후코이단을 히알루론산과 그래프트 중합한 형태로 사용한다. 상기 일 구현예에서는 후코이단을 단순 배합하는 것이 아닌 히알루론산에 그래프트 중합함에 따라 후코이단 및 히알루론산 고유의 탈모 방지 및 모발 성장 촉진 효과를 나타낼 수 있고, 히알루론산의 생분해성도 억제하여 장시간 원하는 효과를 나타낼 수 있으며, 더 나아가 마이크로니들과 같이 두피에 간편하게 탈부착할 수 있는 패치 형태의 제품을 제공할 수 있다. 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.
상기 그래프트 공중합체는 히알루론산과 후코이단을 적절한 함량으로 포함할 수 있다. 일 예로, 상기 그래프트 공중합체는 히알루론산과 후코이단을 9.9:0.1 내지 6.0:4.0, 9.8:0.2 내지 7.0:3.0, 9.7:0.3 내지 7.3:2.7, 9.7:0.3 내지 7.5:2.5, 9.7:0.3 내지 7.7:2.3, 9.7:0.3 내지 8.0:2.0, 9.7:0.3 내지 8.3:1.7, 9.7:0.3 내지 8.5:1.5, 9.7:0.3 내지 8.7:1.7, 9.5:0.5 내지 8.7:1.7 또는 9.3:0.7 내지 8.7:1.7의 중량비로 포함할 수 있다. 특히, 후술하는 실시예 1 내지 5를 참고하면, 히알루론산과 후코이단의 중량비가 9.7:0.3 내지 8.3:1.7, 9.7:0.3 내지 8.5:1.5, 9.7:0.3 내지 8.7:1.7, 9.5:0.5 내지 8.7:1.7 또는 9.3:0.7 내지 8.7:1.7 인 경우 더욱 우수한 5α-reductase의 활성 저해능을 나타낼 수 있다. 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, referring to Examples 1 to 5 described below, 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: When the ratio is 1.7 or 9.3:0.7 to 8.7:1.7, it can exhibit a more excellent ability to inhibit the activity of 5α-reductase.
상기 그래프트 공중합체는 3 차원적으로 가교 결합된다. The graft copolymer is three-dimensionally cross-linked.
일 예로, 상기 가교 결합은 반응성 관능기를 가지는 아크릴계 화합물과 다관능성 아크릴계 가교제를 통해 형성될 수 있다. As an example, the crosslinking may be formed through an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent.
상기 아크릴계 화합물은 (메트)아크릴로일((meth)acryloyl)기 또는 (메트)아크릴로일옥시((meth)acryloyloxy)기를 가지는 화합물일 수 있다. The acrylic compound may be a compound having a (meth)acryloyl group or (meth)acryloyloxy group.
상기 아크릴계 화합물은 상기 그래프트 공중합체의 관능기와 화학적 결합을 형성할 수 있는 반응성 관능기를 가지는 것일 수 있다. 일 예로, 상기 아크릴계 화합물은 상기 그래프트 공중합체의 히드록시기와 화학적 결합을 형성할 수 있는 반응성 관능기로서 히드록시기, 아미노기 및 에폭시기로 이루어진 군에서 선택된 1 종 이상을 포함할 수 있다. 일 예로, 상기 아크릴계 화합물로는 히드록시알킬 (메트)아크릴레이트 등을 들 수 있으며, 상기 알킬은 탄소수 1 내지 12의 직쇄, 분지쇄 또는 고리형 알킬일 수 있다. 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.
상기 아크릴계 화합물은 상기 그래프트 공중합체 100 중량부에 대하여 100 내지 1500 중량부, 500 내지 1000 중량부 또는 600 내지 900 중량부로 사용하여 적절한 가교 밀도를 구현할 수 있다. 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.
상기 다관능성 아크릴계 가교제는 2 이상의 (메트)아크릴로일기 또는 (메트)아크릴로일옥시기를 가지는 화합물일 수 있다. 일 예로, 다관능성 아크릴계 가교제로는 탄소수 2 내지 10의 폴리올의 폴리(메트)아크릴레이트 등을 들 수 있다. 구체적으로, 상기 다관능성 아크릴계 가교제는 폴리(알킬렌 글리콜) 디(메트)아크릴레이트일 수 있으며, 상기 알킬렌은 탄소수 2 내지 10, 2 내지 6 또는 2 내지 4의 직쇄 또는 분지쇄 알킬렌일 수 있다. 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. .
상기 다관능성 아크릴계 가교제는 상기 그래프트 공중합체 100 중량부에 대하여 50 내지 500 중량부, 100 내지 300 중량부 또는 150 내지 250 중량부로 사용하여 적절한 가교 밀도를 구현할 수 있다. 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.
한편, 발명의 다른 일 구현예에 따르면, 히알루론산과 후코이단을 반응시켜 그래프트 공중합체를 제조하는 단계; 및 상기 그래프트 공중합체를 반응성 관능기를 가지는 아크릴계 화합물과 다관능성 아크릴계 가교제와 반응시켜 상기 그래프트 공중합체를 가교시키는 단계를 포함하는 가교 공중합체의 제조 방법이 제공된다. Meanwhile, according to another embodiment of the invention, preparing a graft copolymer by reacting hyaluronic acid and fucoidan; and crosslinking the graft copolymer by reacting the graft copolymer with an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent.
상기 가교 공중합체의 제조 방법은 앞서 설명한 가교 공중합체의 제조 방법일 수 있다. 히알루론산, 후코이단, 아크릴계 화합물 및 다관능성 아크릴계 가교제에 대해서는 앞서 상세히 설명하였으므로 여기에서는 생략한다. The method for producing the crosslinked copolymer may be the method for producing the crosslinked copolymer described above. Hyaluronic acid, fucoidan, acrylic compounds, and multifunctional acrylic crosslinking agents have been described in detail previously and are therefore omitted here.
상기 그래프트 공중합체를 제조하는 단계에서는 히알루론산과 후코이단을 반응시켜 그래프트 공중합체를 제조한다. In the step of preparing the graft copolymer, hyaluronic acid and fucoidan are reacted to prepare the graft copolymer.
상기 그래프트 공중합체를 제조하는 단계에서는 반응 용매로서 증류수를 사용하여 그래프트 중합 반응을 수행할 수 있다. 그리고, 상기 그래프트 중합 반응은, 예를 들면, 상온에서 8 내지 24 시간 동안 수행된 후, 40 내지 90 ℃에서 0.5 내지 5 시간 동안 추가로 수행될 수 있다. 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.
상기 그래프트 공중합체를 제조하는 단계를 통해 그래프트 중합이 완료되면 얻어진 그래프트 공중합체에 반응성 관능기를 가지는 아크릴계 화합물을 먼저 투입하여 그래프트 공중합체와 아크릴계 화합물이 우선적으로 반응하도록 유도할 수 있다. 그리고, 다관능성 아크릴계 가교제를 투입하여 그래프트 공중합체에 결합된 아크릴계 화합물들을 서로 연결함으로써 3 차원적인 가교 결합 구조를 형성할 수 있다. 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 three-dimensional crosslinking structure can be formed by adding a multifunctional acrylic crosslinking agent to connect the acrylic compounds bonded to the graft copolymer.
상기 그래프트 공중합체를 가교시키는 단계에서는 개시제가 사용될 수 있다. 상기 개시제의 비제한적인 예로는 과황산염계 개시제, 아조계 개시제, 과산화수소 또는 아스코르빈산 등을 들 수 있다. 일 예로, 상기 개시제로는 과황산칼륨이 사용될 수 있다. In the step of 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.
상기 가교 공중합체의 제조 방법은 하나의 반응기에서 연속적인 화학 반응을 수행하는 단일 합성(one-pot synthesis) 공정으로 수행될 수 있다. The method for producing the crosslinked copolymer may be performed as a one-pot synthesis process in which a continuous chemical reaction is performed in one reactor.
한편, 발명의 또 다른 일 구현예에 따르면, 기재 필름; 및 상기 기재 필름의 일면에 존재하는 다수의 돌기를 포함하며, 상기 돌기는 상기 가교 공중합체로 형성된 패치가 제공된다. 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 crosslinked copolymer.
마이크로니들(Microneedles)이란 피부의 각질층을 통과하여 피내로 유효 성분을 전달하기 위해 수백 마이크로미터 길이 이내의 미세 바늘을 활용하는 경피 약물 전달 시스템을 일컫는 것으로, 피부에 부착할 수 있도록 일면에 미세 바늘이 형성된 패치 형태로 제공된다. 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.
상기 가교 공중합체는 기존의 탈모 방지 제품과 달리 경구 약품이나 주사를 이용하지 않고 이러한 마이크로니들과 같은 패치 형태로 제공될 수 있다. Unlike existing hair loss prevention products, the cross-linked copolymer can be provided in the form of a patch such as microneedles without using oral medications or injections.
상기 기재 필름은 다수의 돌기를 지지하는 지지체 역할을 하는 것이면 특별히 한정되지 않는다. The base film is not particularly limited as long as it serves as a support to support a plurality of protrusions.
일 예로, 상기 기재 필름은 폴리 우레탄 필름의 일면에 하이드로콜로이드 페이스트가 코팅된 하이드로콜로이드 필름일 수 있다. 상기 하이드로콜로이드 페이스트는 하이드로콜로이드 입자와 이를 지지하는 매트릭스를 형성하기 위한 소수성 탄성 중합체를 포함할 수 있다. 상기 소수성 탄성 중합체의 비제한적인 예로는, 천연고무, 폴리이소프렌, 폴리부타디엔, 부틸고무(예를 들어, 이소프렌과 이소부틸렌의 공중합체) 또는 할로겐화 부틸고무, 스티렌-이소프렌-스티렌 삼블럭 공중합체 등을 들 수 있다. 상기 하이드로콜로이드 입자는 친수성 고분자가 물리적 결합(예를 들어, 수소 결합, 반데르발스 힘 또는 소수성 상호 작용 등) 또는 화학적 결합(예를 들어, 공유 결합)에 의해 3 차원적으로 가교되어 망상 구조를 갖는 입자로서 높은 함수율을 나타낼 수 있다. 이러한 하이드로콜로이드 입자들을 구성하는 친수성 고분자는 천연 친수성 고분자로서 펙틴, 젤라틴, 셀룰로오스, 콜라겐, 덱스트란, 엘라스틴, 키틴, 키토산 또는 알긴산 나트륨이거나, 혹은 합성 친수성 고분자로서 폴리아크릴산, 폴리비닐 알코올, 폴리에틸렌 글리콜, 폴리비닐 피롤리돈, 폴리우레탄, 폴리히드록시에틸 메타크릴레이트 또는 실리콘이거나, 혹은 이들의 조합일 수 있고, 이러한 친수성 고분자를 가교시키기 위한 가교제는 염화 칼슘, 황산 칼슘, 질산 칼슘, 질산 아연, 염화 아연, 황산 아연, 과황산 암모늄 또는 글루타르알데히드 등 일 수 있다. 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.
상기 기재 필름의 일면에는 상기 가교 공중합체로부터 형성된 다수의 돌기가 존재한다. 상기 돌기의 형상, 크기 및 개수는 패치의 사용 형태 및 크기 등에 따라 적절하게 제어될 수 있다. On one side of the base film, there are a number of protrusions formed from the crosslinked copolymer. The shape, size, and number of the protrusions can be appropriately controlled depending on the usage type and size of the patch.
상기 패치는 기재 필름의 일면에 형성된 돌기를 보호하기 위한 이형 필름을 추가로 포함할 수 있다. 상기 패치는 본 발명이 속한 기술분야에 알려진 다양한 탈모 방지 혹은 모발 성장 촉진 효과가 있는 첨가제를 추가로 포함할 수 있다. 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.
발명의 일 구현예에 따른 가교 공중합체는 5α-reductase의 활성 저해능과 모발 성장 촉진 효과로 인해 탈모 방지 및 모발 성장 촉진 용도로 사용할 수 있고, 기존의 히알루론산 대비 생분해성도 억제되어 오랜 시간 원하는 효과를 구현할 수 있다. 또한, 상기 가교 공중합체를 이용하면 경구 약품이나 주사를 통해 주로 이용하던 탈모 방지 제품 대신 마이크로니들과 같이 두피에 간편하게 탈부착할 수 있는 패치 형태의 탈모 방지 제품을 제공할 수 있다. The 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. It can be implemented. In addition, by using the 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.
이하 발명의 구체적인 실시예를 통해 발명의 작용, 효과를 보다 구체적으로 설명하기로 한다. 다만, 이는 발명의 예시로서 제시된 것으로 이에 의해 발명의 권리범위가 어떠한 의미로든 한정되는 것은 아니다.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.
실시예 1 내지 5: 가교 공중합체의 제조Examples 1 to 5: Preparation of crosslinked copolymers
100 mL 3구 둥근 바닥 플라스크를 세척한 후 증류수로 한번 더 세척하였다. 상기 둥근 바닥 플라스크에 증류수 60 mL와 히알루론산 나트륨(분자량: 1.8 MDa) 및 후코이단을 하기 표 1에 기재된 함량으로 투입한 후 상온에서 400 rpm으로 12 시간 이상 교반하였다. The 100 mL three-neck round bottom flask was washed and then washed once more with distilled water. 60 mL of distilled water, sodium hyaluronate (molecular weight: 1.8 MDa), and fucoidan were added in the amounts shown in Table 1 below, and then stirred at room temperature at 400 rpm for more than 12 hours.
이후 둥근 바닥 플라스크를 오일 베스 안에 넣고 가열하였다. 반응 용액의 온도가 75 ℃에 도달하면 반응 용액을 75 ℃에서 2 시간 동안 교반하였다. 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.
이후, 반응 용액이 보글거릴 수 있게 반응 용액 내로 질소를 30 분 동안 주입하였다. Afterwards, nitrogen was injected into the reaction solution for 30 minutes to allow the reaction solution to bubble.
이어서, 반응 용액의 온도를 75 ℃로 유지한 상태에서 가교 공정을 수행하였다. 상기 반응 용액에 KPS (potassium persulfate) 용액 5 mL를 투입하고 20 분 동안 교반하였다. 상기 반응 용액에 2-히드록시에틸 아크릴레이트(2-HEA) 2 mL (density: 1.106 g/mL at 25 ℃, 2.2 g)를 투입하고 약 10 내지 20 분 정도 교반 후 반응 용액이 점성을 보이면 상기 반응 용액에 폴리(에틸렌 글리콜) 디아크릴레이트(PEGDA, 수평균분자량: 700) 500 μL (density: 1.12 g/mL at 25 ℃, 560 mg)을 투입하고 3 시간 동안 교반하였다. 반응이 진행되는 동안 질소가 공급되는 니들이 반응물 내로 들어가지 않도록 반응 용액 표면 위로 니들의 위치를 조절하여 질소를 주입하였다. 상기와 같은 과정을 거쳐 히알루론산 및 후코이단의 그래프트 공중합체가 가교 결합된 공중합체를 제조하였다. 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 graft copolymers of hyaluronic acid and fucoidan were crosslinked was prepared.
히알루론산Hyaluronic acid | 후코이단Fucoidan | 히알루론산:후코이단의 중량비Weight ratio of hyaluronic acid:fucoidan | |
실시예 1Example 1 | 235.7 mg235.7mg | 12.4 mg12.4mg | 9.5:0.59.5:0.5 |
실시예 2Example 2 | 235.7 mg235.7mg | 26.2 mg26.2 mg | 9.0:1.09.0:1.0 |
실시예 3Example 3 | 235.7 mg235.7mg | 41.6 mg41.6mg | 8.5:1.58.5:1.5 |
실시예 4Example 4 | 235.7 mg235.7mg | 58.9 mg58.9mg | 8.0:2.08.0:2.0 |
실시예 5Example 5 | 235.7 mg235.7mg | 78.6 mg78.6mg | 7.5:2.57.5:2.5 |
대조예Control example | 235.7 mg235.7mg | -- | 10.0:0 10.0:0 |
시험예: 가교 공중합체의 특성 분석Test example: Characterization of cross-linked copolymers
실시예 1 내지 5에서 제조한 가교 공중합체 및 대조예의 히알루론산에 대하여 하기와 같은 방법으로 특성을 분석하고 그 결과를 표 2에 나타내었다. The properties of the crosslinked copolymers prepared in Examples 1 to 5 and the hyaluronic acid of the control example were analyzed in the following manner, and the results are shown in Table 2.
1) 세포 생존율(세포 독성) 평가1) Cell viability (cytotoxicity) evaluation
세포 생존율은 MTT 분석 방법을 통해 평가하였다. MTT 분석 방법은 미토콘드리아 탈수소 효소 작용에 의하여 노란색을 띄는 수용성 기질인 MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)가 적자색을 띄는 Formazan ((E,Z)-5-(4,5-dimethylthiazol-2-yl)-1,3-diphenylformazan)으로 환원되는 정도를 통해 세포의 대사 활동을 평가하는 방법이다. 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).
구체적으로, 계대 배양한 모유두세포(Human Follicle Dermal Papilla Cells; HFDPC)를 96-well plate에 1 X 104 cells/well로 분주하고, 37 ℃, 습도 95 %, 5 % 이산화탄소를 포함하는 배양기 내에서 24 시간 동안 배양하였다. Specifically, subcultured Human Follicle Dermal Papilla Cells (HFDPC) were dispensed at 1 Cultured for 24 hours.
한편, 실시예 1 내지 5에서 제조한 가교 공중합체 및 대조예의 히알루론산을 200 ㎍/mL의 농도로 각각 첨가한 6 개의 무혈청배지(serum free media)와 공대조군 및 음성대조군 용도로 아무 것도 첨가하지 않은 2 개의 무혈청배지를 준비하였다. Meanwhile, six serum free media were each added with the cross-linked copolymer prepared in Examples 1 to 5 and the hyaluronic acid of the control example at a concentration of 200 μg/mL, and nothing was added for use as a blank control and a negative control. Two serum-free media were prepared.
앞서 배양한 HFDPC의 배지를 상기 8 개의 배지로 교체하고 24 시간 동안 상기 세포 배양 조건에서 추가로 배양하였다. The medium of the previously cultured HFDPC was replaced with the above eight mediums and further cultured under the above cell culture conditions for 24 hours.
배양 후, 공대조군 배지를 제외한 나머지 7 개의 배지에만 MTT 용액을 첨가하고 8 개의 배지를 차광 상태에서 2 시간 동안 방치시켰다. 이후, 상등액을 제거하고, 생성된 Formazan을 DMSO로 완전히 용해시켰다. 얻어진 용액의 540 nm에서의 흡광도를 microplate reader (Biotek Synergy-HT, USA)로 측정하였다. After incubation, the MTT solution was added to only the remaining 7 media, excluding the control medium, and the 8 media were left in a darkened state 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).
상기 세포 생존율은 하기 식 1로 계산되었다. 세포 생존율 값은 세포 생존율 시험을 3 회 반복 실시한 후 그 평균값으로 규정하였다. 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.
[식 1][Equation 1]
세포 생존율(%) = (A2 - A0) / (A1 - A0) X 100Cell viability (%) = (A2 - A0) / (A1 - A0)
상기 식 1에서 A0는 공대조군의 흡광도이고, A1는 MTT 용액을 첨가한 음성대조군의 흡광도이며, A2는 세포 생존율 시험 대상을 첨가한 군의 흡광도이다. 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) 5α-reductase의 활성 저해능 평가2) Evaluation of activity inhibition ability of 5α-reductase
5α-reductase는 남성호르몬인 testosterone을 환원하여 dihydrotestosterone (DHT)으로 전환하는 효소로 탈모를 유발하는 주요 인자로 알려져 있다. 이러한 5α-reductase의 발현 정도는 실시간 중합효소연쇄반응(RT-qPCR)을 이용해 측정할 수 있다. RT-qPCR은 DNA 산물을 증폭시키는 과정에서 발생하는 형광을 측정하여 증폭 산물의 양을 실시간으로 모니터링 하여 특정 mRNA 발현을 정량분석 할 수 있는 시험법이다. 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.
구체적으로, 계대 배양한 모유두세포(HFDPC)를 60 mm dish에 5 X 105 cells/dish로 분주하고, 37 ℃, 습도 95 %, 5 % 이산화탄소를 포함하는 배양기 내에서 24 시간 동안 배양하였다. Specifically, subcultured dermal papilla cells (HFDPC) were dispensed into 60 mm dishes at 5
한편, 실시예 1 내지 5에서 제조한 가교 공중합체 및 대조예의 히알루론산을 200 ㎍/mL의 농도로 각각 첨가한 6 개의 serum free DMEM 배지와 공대조군 및 음성대조군 용도로 아무 것도 첨가하지 않은 2 개의 serum free DMEM 배지를 준비하였다. Meanwhile, six serum free DMEM media to which the cross-linked copolymer prepared in Examples 1 to 5 and the hyaluronic acid of the control example were added at a concentration of 200 μg/mL, and two media to which nothing was added for use as a blank control and a negative control. Serum free DMEM medium was prepared.
앞서 배양한 HFDPC의 배지를 상기 8 개의 배지로 교체하고, 공대조군 배지를 제외한 나머지 7 개의 배지에만 testosterone 20 nM을 첨가한 후 상기 세포 배양 조건에서 24 시간 동안 배양하였다.The medium of the previously cultured HFDPC was replaced with the above eight mediums, and 20 nM of testosterone was added only to the remaining seven mediums excluding the blank control medium, and the cells were cultured under the above cell culture conditions for 24 hours.
배양 후 RT-qPCR을 통해 각 샘플에서의 mRNA 발현량을 측정하고 하기 식 2에 대입하여 5α-reductase의 활성 저해능을 계산하였다. 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.
[식 2][Equation 2]
5α-reductase의 활성 저해능(%) = 1 - {(R2 - R0) / (R1 - R0)} X 1005α-reductase activity inhibition ability (%) = 1 - {(R2 - R0) / (R1 - R0)}
상기 식 2에서 R0는 공대조군의 mRNA 발현량이고, R1는 testosterone을 첨가한 음성대조군의 mRNA 발현량이며, R2는 5α-reductase의 활성 저해능 시험 대상을 첨가한 군의 mRNA 발현량이다. 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) 생분해성 억제 효능 평가3) Evaluation of biodegradability inhibition efficacy
시험관에 대조예의 히알루론산을 소정의 함량으로 담고 히알루론산 분해 효소(hyaluronidase) 500 U/mL을 포함한 0.2 M phosphate-buffered saline (pH 7.4)를 첨가하고 37 ℃에서 48 시간 동안 반응시켰다. A predetermined amount of hyaluronic acid from 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 reaction was performed at 37°C for 48 hours.
효소 반응을 통해 분해된 N-아세틸글루코사민(NAG)의 양을 측정하기 위하여 DMAB (p-dimethylaminobenzaldehyde) 발색 시약을 첨가한 후 37 ℃에서 30 분간 반응시켰다. 그 후 얻어진 반응물을 원심분리(3,000 rpm, 10분)하여 상등액을 취하여 585 nm에서의 흡광도를 측정하여 기준 흡광도로 규정하였다. 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.
상기와 동일한 방법으로 실시예 1 및 2의 가교 공중합체의 생분해성을 시험하되, 상기 기준 흡광도를 나타낼 때 까지의 효소 반응 시간을 기록하였다. The biodegradability of the cross-linked copolymers of Examples 1 and 2 was tested in the same manner as above, but the enzyme reaction time until the standard absorbance was recorded was recorded.
실시예가 기준 흡광도를 나타낼 때 까지의 효소 반응 시간을 대조예가 기준 흡광도를 나타낼 때 까지의 효소 반응 시간인 48 시간으로 나누어 생분해성 억제 효능 값으로 규정하였다. 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.
세포 생존율(%)Cell viability (%) |
5α-reductase의 활성 저해능(%)5α-reductase Active inhibition capacity (%) |
생분해성 억제 효능Biodegradability inhibition effect | |
실시예 1Example 1 | 114.6300114.6300 | 60.070060.0700 | 1.111.11 |
실시예 2Example 2 | 124.5300124.5300 | 64.690064.6900 | 1.181.18 |
실시예 3Example 3 | 125.0700125.0700 | 42.750042.7500 | -- |
실시예 4Example 4 | 126.9300126.9300 | 23.470023.4700 | -- |
실시예 5Example 5 | 126.5700126.5700 | 23.470023.4700 | -- |
대조예Control example | 112.8400112.8400 | 28.700028.7000 | 1One |
모발이 성장하는 성장기에는 모발의 지지대 역할을 하면서 동시에 영양분을 공급하는 모유두세포를 통해 모발이 성장하게 된다. 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.
상기 표 2를 살펴보면, 실시예 1 내지 5는 대조예 대비 모유두세포에 대하여 높은 세포 생존율을 보이는 것이 확인된다. 이로써 발명의 일 구현예에 따른 가교 공중합체를 이용하면 모유두세포의 증식을 촉진할 수 있어 모발 성장을 촉진할 수 있다는 것이 확인된다. Looking at Table 2 above, it is confirmed that Examples 1 to 5 show a high cell survival rate for dermal papilla cells compared to the control example. This confirms that using the cross-linked copolymer according to one embodiment of the invention can promote the proliferation of dermal papilla cells and thereby promote hair growth.
또한, 실시예 1 내지 5는 5α-reductase의 활성 저해능으로 탈모 방지 효과가 있다는 것이 확인되며, 생분해성 억제 효과도 함께 확인된다. In addition, it is confirmed that Examples 1 to 5 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.
특히, 실시예 1 내지 3은 우수한 세포 생존율 및 생분해성 억제능을 보이면서 높은 5α-reductase의 활성 저해능을 보였으며, 그 중에서도 실시예 1 및 2는 더 높은 5α-reductase의 활성 저해능을 보였고, 실시예 2는 모든 측면에서 가장 우수한 효과를 보이는 것이 확인된다. In particular, Examples 1 to 3 showed excellent cell viability and biodegradation inhibition ability while showing a high ability to inhibit the activity of 5α-reductase. Among them, Examples 1 and 2 showed a higher ability to inhibit the activity of 5α-reductase, and Example 2 It is confirmed that it shows the best effect in all aspects.
Claims (15)
- 히알루론산과 후코이단의 그래프트 공중합체가 3 차원적으로 가교 결합된, 가교 공중합체. A cross-linked copolymer in which a graft copolymer of hyaluronic acid and fucoidan is three-dimensionally cross-linked.
- 제 1 항에 있어서, 탈모 방지 및 모발 성장 촉진 용도로 사용되는, 가교 공중합체. The cross-linked copolymer according to claim 1, which is used for preventing hair loss and promoting hair growth.
- 제 1 항에 있어서, 상기 그래프트 공중합체는 히알루론산과 후코이단을 9.9:0.1 내지 6.0:4.0의 중량비로 포함하는, 가교 공중합체. The crosslinked copolymer according to 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.
- 제 1 항에 있어서, 상기 그래프트 공중합체는 반응성 관능기를 가지는 아크릴계 화합물과 다관능성 아크릴계 가교제를 통해 3 차원적으로 가교 결합된, 가교 공중합체. The crosslinked copolymer according to claim 1, wherein the graft copolymer is three-dimensionally crosslinked with an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent.
- 제 4 항에 있어서, 상기 아크릴계 화합물은 히드록시기, 아미노기 및 에폭시기로 이루어진 군에서 선택된 1 종 이상의 반응성 관능기를 가지는 아크릴계 화합물인, 가교 공중합체. The crosslinked copolymer according to claim 4, wherein the acrylic compound is an acrylic compound having at least one reactive functional group selected from the group consisting of a hydroxy group, an amino group, and an epoxy group.
- 제 4 항에 있어서, 상기 아크릴계 화합물은 히드록시알킬 (메트)아크릴레이트인, 가교 공중합체. The crosslinked copolymer of claim 4, wherein the acrylic compound is a hydroxyalkyl (meth)acrylate.
- 제 4 항에 있어서, 상기 아크릴계 화합물은 상기 그래프트 공중합체 100 중량부에 대하여 100 내지 1500 중량부로 사용되어 3 차원적인 가교 결합을 형성하는, 가교 공중합체.The cross-linked copolymer according to claim 4, wherein the acrylic compound is used in an amount of 100 to 1,500 parts by weight based on 100 parts by weight of the graft copolymer to form a three-dimensional cross-linked bond.
- 제 4 항에 있어서, 상기 다관능성 아크릴계 가교제는 탄소수 2 내지 10의 폴리올의 폴리(메트)아크릴레이트인, 가교 공중합체. The 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.
- 제 4 항에 있어서, 상기 다관능성 아크릴계 가교제는 상기 그래프트 공중합체 100 중량부에 대하여 50 내지 500 중량부로 사용되어 3 차원적인 가교 결합을 형성하는, 가교 공중합체.The cross-linked copolymer according to claim 4, wherein the multifunctional acrylic cross-linking 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 three-dimensional cross-link.
- 히알루론산과 후코이단을 반응시켜 그래프트 공중합체를 제조하는 단계; 및 Preparing a graft copolymer by reacting hyaluronic acid and fucoidan; and상기 그래프트 공중합체를 반응성 관능기를 가지는 아크릴계 화합물과 다관능성 아크릴계 가교제와 반응시켜 상기 그래프트 공중합체를 가교시키는 단계를 포함하는, 가교 공중합체의 제조 방법. A method for producing a crosslinked copolymer, comprising the step of crosslinking the graft copolymer by reacting the graft copolymer with an acrylic compound having a reactive functional group and a multifunctional acrylic crosslinking agent.
- 제 10 항에 있어서, 상기 그래프트 공중합체를 제조하는 단계에서는 히알루론산과 후코이단을 상온에서 8 내지 24 시간 동안 반응시킨 후, 40 내지 90 ℃에서 0.5 내지 5 시간 동안 추가 반응시키는 것을 포함하는, 가교 공중합체의 제조 방법. The method of claim 10, 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 a composite.
- 제 10 항에 있어서, 상기 가교시키는 단계에서는 상기 그래프트 공중합체에 반응성 관능기를 가지는 아크릴계 화합물을 먼저 투입하여 반응시킨 후 다관능성 아크릴계 가교제를 투입하여 가교 결합을 형성하는 것을 포함하는, 가교 공중합체의 제조 방법. The preparation of a crosslinked copolymer according to claim 10, wherein the 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.
- 기재 필름; 및 상기 기재 필름의 일면에 존재하는 다수의 돌기를 포함하며, base film; and a plurality of protrusions present on one side of the base film,상기 돌기는 제 1 항의 가교 공중합체로 형성된 것인, 패치. A patch wherein the protrusions are formed from the cross-linked copolymer of claim 1.
- 제 13 항에 있어서, 상기 기재 필름은 하이드로콜로이드 필름인, 패치. 14. The patch of claim 13, wherein the base film is a hydrocolloid film.
- 제 13 항에 있어서, 탈모 방지 및 모발 성장 촉진 용도로 사용되는, 패치. The patch according to claim 13, which is used for preventing hair loss and promoting hair growth.
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