KR20230025560A - Skin filler that is easy to predict decomposition rate and can maintain filler effect for a long time - Google Patents
Skin filler that is easy to predict decomposition rate and can maintain filler effect for a long time Download PDFInfo
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- KR20230025560A KR20230025560A KR1020210106712A KR20210106712A KR20230025560A KR 20230025560 A KR20230025560 A KR 20230025560A KR 1020210106712 A KR1020210106712 A KR 1020210106712A KR 20210106712 A KR20210106712 A KR 20210106712A KR 20230025560 A KR20230025560 A KR 20230025560A
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- Prior art keywords
- polymer
- filler
- filler composition
- decomposition rate
- skin
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- 239000000945 filler Substances 0.000 title claims abstract description 33
- 230000000694 effects Effects 0.000 title claims abstract description 17
- 238000000354 decomposition reaction Methods 0.000 title abstract description 19
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims abstract description 46
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- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- TVSPPYGAFOVROT-UHFFFAOYSA-N 2-phenoxybutanoic acid Chemical compound CCC(C(O)=O)OC1=CC=CC=C1 TVSPPYGAFOVROT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 5
- 229920000642 polymer Polymers 0.000 claims description 32
- 239000011859 microparticle Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 230000002500 effect on skin Effects 0.000 claims description 8
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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 description 3
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- 239000007864 aqueous solution Substances 0.000 claims 3
- IMLGLBWSLWRWQF-UHFFFAOYSA-N 2-phenoxyheptanoic acid Chemical compound CCCCCC(C(O)=O)OC1=CC=CC=C1 IMLGLBWSLWRWQF-UHFFFAOYSA-N 0.000 claims 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims 2
- 239000000843 powder Substances 0.000 claims 2
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims 1
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- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 abstract description 7
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 229920000747 poly(lactic acid) Polymers 0.000 description 7
- 239000004626 polylactic acid Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- MVRHCWSJCXYUGH-UHFFFAOYSA-N decanedioic acid;2-phenoxybutanoic acid Chemical compound CCC(C(O)=O)OC1=CC=CC=C1.OC(=O)CCCCCCCCC(O)=O MVRHCWSJCXYUGH-UHFFFAOYSA-N 0.000 description 4
- 238000005227 gel permeation chromatography Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 229920001427 mPEG Polymers 0.000 description 4
- -1 Carboxyphenoxy propane-sebacic acid-polyethylene Chemical group 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- OBCDVTIQASDOBK-UHFFFAOYSA-N 1-propoxycyclohexa-3,5-diene-1,3-dicarboxylic acid Chemical compound CCCOC1(C(O)=O)CC(C(O)=O)=CC=C1 OBCDVTIQASDOBK-UHFFFAOYSA-N 0.000 description 1
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
Abstract
Description
본 발명은 인체의 기능 상실, 미용 등의 목적으로 피하(皮下)나 조직에 사용하기 위한 필러로 사용할 목적으로The present invention is intended to be used as a filler for use in subcutaneous or tissue for the purpose of loss of function of the human body, beauty, etc.
카복시페녹시 프로판(carboxyphenoxy propane)-세바식산(sebacic acid)-폴리에틸렌글리콜(polyCarboxyphenoxy propane-sebacic acid-polyethylene glycol (poly
합성한synthesized
ethylene glycol)의 고분자 공중합체에 대한 것으로서, 보다 상세하게는 각 성분의 함량비율에 따라 공중합체의 생분해속도가 조절되며, 인체 내에서 우수한 생체 적합성을 가지고 있으며 치료 기능을 향상시킬 수 있는 분해속도 예측이 편리하며 장시간 필러효과를 유지할 수 있는 피부용 필러에 관한 것이다.ethylene glycol), and more specifically, the biodegradation rate of the copolymer is controlled according to the content ratio of each component, and it has excellent biocompatibility in the human body and predicts the degradation rate that can improve the therapeutic function It relates to a dermal filler that is convenient and can maintain the filler effect for a long time.
인체의 기능을 보정하거나 미용등의 목적으로 피하(皮下)나 조직에 사용하기 위한 필러는 생리적으로 인체에 무 해하며(biocompatable), 안정적이고, 인체에서 원하는 시간에 분해가능 한 것(biodegradable)이 바람직하다 할 것이다. 이들 조건에 부합되어 현재 사용가능한 필러 조성물로는 콜라겐, 젤라틴, 히알루론산(Hyaluronic acid), 덱스트란(dextran)등의 천연 고분자 물질과 폴리락틱산(poly lactic acid), 폴리글루탐산(poly glutamic acid), 폴리카프로락톤(polycaprolactone), 폴리아크릴아미드(poly acrylamide)등의 합성 고분자 물 질들이 널리 사용되고 있다. 이들 필러들 외에도 신경에 작용하는 보툴리늄 독소(상품명, Botoxⓡ)도 이들과 함 께 자주 사용되고 있다.Fillers for use in the subcutaneous tissue or subcutaneous tissue for the purpose of correcting the function of the human body or for cosmetic purposes are physiologically harmless to the human body (biocompatable), stable, and degradable at a desired time in the human body (biodegradable). would be preferable Filler compositions that meet these conditions and can be used currently include natural polymer materials such as collagen, gelatin, hyaluronic acid, and dextran, polylactic acid, and polyglutamic acid. , synthetic polymers such as polycaprolactone and polyacrylamide are widely used. In addition to these fillers, botulinum toxin (trade name, Botoxⓡ) that acts on nerves is also frequently used along with these fillers.
현재 사용되고 있는 필러들은 무해하며 안정적이나 일부에서는 두드러기 등의 알러지 반응, 두통, 감기증상, 항체로 인한 치료실패 등의 부작용 사례가 보고되고 있다. 인체에 이식하여 사용되고 있는 동물유래 고분자에서 이러한 부작용이 많이 보고되고 있는 실정이다. 특히 신경에 작용하는 보톡스의 경우에는 작게는 부자연스런 근 육움직임, 침 흘리기 등이 있으며 나아가 신경세포의 위치나 분포에 대한 정보부족에 따른 오용이나 과다사용으 로 인한 심한 통증, 안면마비와 같은 심각한 경우가 종종 발생된다. 따라서 인체 적합성과 더불어 보톡스와 같 은 신경작용물질의 부작용을 최소화하기 위해서도 부작용이 적은 필러에 대한 개발이 요구되고 있다.Currently used fillers are harmless and stable, but in some cases, side effects such as allergic reactions such as hives, headaches, cold symptoms, and treatment failure due to antibodies have been reported. Many of these side effects have been reported in animal-derived polymers that are transplanted and used in the human body. In particular, in the case of Botox that acts on nerves, there are unnatural muscle movements and drooling at the smallest level, and further, serious pain and facial paralysis due to misuse or overuse due to lack of information on the location or distribution of nerve cells. case often occurs. Therefore, in order to minimize the side effects of neuroactive substances such as Botox along with compatibility with the human body, the development of fillers with fewer side effects is required.
피부에 사용하는 필러는 고분자물질의 지속시간이 매우 중요하다. 동물이나 미생물 유래 히알루론산의 경우는 수주에서 2개월 내외의 기간에 인체에서 대사되며 이러한 특징으로 인해 환자들에게 반복시술의 불편함과 비용 의 발생이라는 심각한 단점이 있다. 따라서 부작용이 적고 분해속도를 일정하게 유지시켜 원하는 기간 동안 필 러효과를 나타낼 수 있는 물질에 대한 연구개발이 활발하게 이루어지고 있으며, 미백이나 피부노화 방지 등 피 부에 효과가 입증된 약물을 동시에 필러에 담지하여 주사제로 사용할 경우도 가능하다 할 것이다.For fillers used in the skin, the duration of polymer materials is very important. In the case of hyaluronic acid derived from animals or microorganisms, it is metabolized in the human body in a period of about several weeks to two months, and due to this feature, there are serious disadvantages of inconvenience and cost of repeated procedures to patients. Therefore, research and development on materials that can exhibit filler effects for a desired period of time by maintaining a constant decomposition rate with fewer side effects is being actively conducted, and drugs that have been proven to be effective on the skin, such as whitening or preventing skin aging, are being used as fillers at the same time. It will also be possible to use it as an injection by supporting it in the.
폴리안하이드라이드(Polyanhydride)계 고분자 중합물은 1980년대 초반 로버트 랑거(Robert Langer) 그룹에서 약 물전달용 담체로 처음으로 개발되어 미국 식품의약국의 승인을 득하여, 글리아델(Gliadelⓡ)이라는 상품명으로 뇌종양 치료용 약물전달체로 오랜 기간 동안 임상에 사용되어왔다. 현재 사용되고 있는 폴리안하이드라이드 약 물담체는 피마자유에서 추출한 세바식산(sebacic acid, SA)과 무수물(anhydride)계열의 일종인 카복시페녹시 프 로판(carboxyphenoxy propane, CPP)의 공중합체 고분자 화합물이다. 카복시페녹시 프로판-세바식산(CPP-SA) 공 중합체로 제조한 화합물은 인체에 이식된 후 비교적 장기간인 최대 232일 동안 약물 방출이 이루어지고 있음이 확인되었다. 폴리카복시 프로판(poly carboxyphenoxy propane)은 카복시페녹시 프로판(carboxyphenoxy propane)의 단량체로 분해된 후 신장에서 배출되며, 폴리세바식산(poly sebacic acid)은 세바식산으로 분해된 후 간에서 대사에 의해 흡수되는 것으로 증명되어 인체에 안전한 고분자화합물로 FDA 승인을 득하였다. 그리하 여 카복시페녹시 프로판-세바식산의 공중합체의 분해속도를 조절하기 위하여 추가로 생체 적합성 고분자이며 친 수성인 폴리에틸렌글리콜과 결합을 통하여 요구조건보다 너무 빠르게 혹은 너무 느리게 분해되는 것을 조절하고 자 한다.Polyanhydride-based high-molecular polymer was first developed as a carrier for drug delivery by the Robert Langer group in the early 1980s, and obtained approval from the US Food and Drug Administration, under the trade name Gliadelⓡ. It has been used clinically for a long time as a drug delivery system for treating brain tumors. The currently used polyanhydride drug carrier is a copolymer of sebacic acid (SA) extracted from castor oil and carboxyphenoxy propane (CPP), a type of anhydride. It was confirmed that the compound prepared from the carboxyphenoxy propane-sebacic acid (CPP-SA) copolymer released the drug for a relatively long period of up to 232 days after implantation into the human body. Poly carboxyphenoxy propane is broken down into carboxyphenoxy propane monomers and excreted from the kidneys, and poly sebacic acid is broken down into sebacic acid and absorbed by metabolism in the liver. It has been proven to be safe for the human body and has been approved by the FDA as a high molecular compound. Therefore, in order to control the decomposition rate of the copolymer of carboxyphenoxypropane-sebacic acid, it is intended to control the decomposition too fast or too slow than the requirements by combining with polyethylene glycol, which is a biocompatible polymer and hydrophilic. .
한편, 국내 특허로는 “피하 또는 피부내 삽입물”(대한민국 특허 10-0543560)에서 폴리락틱산(poly lactic acid)이 무독성이고 제약분야에서 경구 또는 비경구 경로로 모두 사용되는 고분자 미소구체라고 소개하였다. 여 기서는 폴리락틱산의 원료로 L형과 D형의 혼합형이 적당하며 동결건조 후 기계적으로 미소구체 크기로 분리하여 사용하는 것을 기술하였다. 하지만 폴리락틱산의 경우, 락틱산으로 분해되어 대사과정에서 물과 이산화탄소로 배출된다고 하나 과다한 락틱산의 배출은 인체조직에 염증등을 일으키는 원인이 되는 것으로 알려져 이 또한 개 선이 필요하다 할 것이다.On the other hand, as a domestic patent, "subcutaneous or intradermal implant" (Korean Patent No. 10-0543560) introduced polylactic acid as a polymeric microsphere that is non-toxic and used in both oral and parenteral routes in the pharmaceutical field. . Here, a mixed type of L-type and D-type is suitable as a raw material for polylactic acid, and it is described that it is mechanically separated into microspheres after freeze-drying and used. However, in the case of polylactic acid, it is decomposed into lactic acid and released as water and carbon dioxide in the metabolic process, but excessive discharge of lactic acid is known to cause inflammation in human tissues, and this also needs improvement.
본 연구자는 기존 약물전달용 담체로 사용되고 있는 폴리안하이드라이드(polyanhydride)계열 고분자 중합물이 인체에 대한 안전성(biocompatable)이 뛰어나고 인체 이식이 가능한 필러로 적당하다 생각한다. 따라서 여러 고분자 중합물들을 합성하고 기존에 사용되고 있는 폴리락틱산과 분해정도를 비교 측정하여 폴리안하이드라드계열 고분자 중합체가 필링효과를 장시간 유지할 수 있는 우수한 필러임을 주장하고자 한다.The present researcher believes that the polyanhydride-based polymer, which is used as a carrier for drug delivery, is excellent in safety (biocompatable) to the human body and suitable as a filler that can be transplanted into the human body. Therefore, we would like to claim that the polyanhydride-based polymer is an excellent filler that can maintain the peeling effect for a long time by synthesizing various high-molecular polymers and comparing and measuring the degree of decomposition with polylactic acid previously used.
따라서 본 발명은 상기 요구에 부응하기 위한 것으로, 본 발명의 목적은Therefore, the present invention is to meet the above needs, and the object of the present invention is
인체이식용 혹은 약물용 담체로 사용되고 있는 폴리안하이드라이드계 고분자인 카복시페녹시 프로판-세바식산 고분자 공중합체에 대한 것이며, 카복시페녹시 프로판과 세바식산의 함량비를 조절하여 생분해 속도 및 생체적 합성을 증진시키고 안전성(safety)이 높아진 고분자 중합체 필러조성물을 제공하는데 있다.It is about carboxyphenoxypropane-sebacic acid polymer copolymer, which is a polyanhydride-based polymer used for human implantation or as a carrier for drugs. It is to provide a high-molecular polymer filler composition with improved safety (safety).
또한 카복시페녹시 프로판-세바식산 공중합체에 폴리에틸렌글리콜을 도입하고 카복시페녹시 프로판-세바식산-폴 리에틸렌글리콜의 삼중합 공중합체를 합성하여 면역 부작용이 적고 고분자 중합체의 인체내 분해속도가 조절되 며 생체적합성이 우수한 의료용 고분자 필러를 제공하는데 다른 목적이 있다In addition, by introducing polyethylene glycol into the carboxyphenoxy propane-sebacic acid copolymer and synthesizing a tripolymer of carboxyphenoxy propane-sebacic acid-polyethylene glycol, there are few immune side effects and the degradation rate of the polymer in the body is controlled. Another purpose is to provide a medical polymer filler with excellent biocompatibility.
이와 같은 목적을 달성하기 위하여 본 발명에서는 카복시페녹시 프로판과 세바식산을 중합하여 카복시페녹시 프 로판-세바식산 고분자 공중합체를 합성하고 이를 이용하여 필러용 미소구체 (microsphere 또는 microparticle) 로 제작되며, 카복시페녹시 프로판과 세바식산의 함량 비율에 따라 분해 속도가 조절되는 미소구체를 제공하는 것을 그 기술적 특징으로 한다.In order to achieve the above object, in the present invention, carboxyphenoxy propane and sebacic acid are polymerized to synthesize a carboxyphenoxy propane-sebacic acid polymer copolymer, which is used to prepare microspheres or microparticles for filler, Its technical feature is to provide microspheres whose decomposition rate is controlled according to the content ratio of carboxyphenoxypropane and sebacic acid.
그리고 바람직하기로는 카복시페녹시 프로판-세바식산 공중합체에 폴리에틸렌글리콜을 중합하여 삼중합 공중합 체(terpolymer)를 제작하고 이를 이용하여 생분해성과 면역 반응성, 생체 적합성이 동시에 개선된 미소구체를 제공하는 데에 그 기술적 특징이 있다And preferably, a terpolymer is prepared by polymerizing polyethylene glycol with a carboxyphenoxypropane-sebacic acid copolymer, and biodegradability, immunoreactivity, and biocompatibility are improved at the same time using this terpolymer. Its technical features are
본 발명에 있어서는 정상 조직이나 피부아래에서 카복시페녹시 프로판-세바식산 공중합체가 일정기간 동안 서서 히 생분해되어 인체의 기능을 개선 또는 미용 등의 목적을 이루는 화합물을 제공하고, 폴리에틸렌글리콜을 함께 중합한 필러를 인체에 이식할 경우 생체적합성을 향상시키고 면역 반응을 경감하는 효과가 있다.In the present invention, the carboxyphenoxy propane-sebacic acid copolymer is gradually biodegraded for a certain period of time in normal tissue or under the skin to provide a compound that achieves the purpose of improving the function of the human body or cosmetic, and polymerizing polyethylene glycol together. When the filler is implanted into the human body, it has the effect of improving biocompatibility and reducing the immune response.
또한, 원하는 기간 동안 필링 효과가 유지되고 지속시간이 예측 가능한 필러를 제공하여 반복사용의 불편성 해 소하는 효과가 있다.In addition, it has the effect of resolving the inconvenience of repeated use by providing a filler in which the peeling effect is maintained for a desired period and the duration is predictable.
1. p(CPP-SA) 공중합 미소입자의 합성 1(a). CPP, SA, mPEG 전구체 준비1. Synthesis of p(CPP-SA) copolymerized microparticles 1(a). Preparation of CPP, SA, and mPEG precursors
CPP와 SA의 공중합 미소입자는 김문석등의 Bio-Medical materials and engineering 15(2005) 229-238논문을 참 고로 제조하였다.The copolymerized microparticles of CPP and SA were prepared by referring to Moon-Seok Kim et al.'s Bio-Medical materials and engineering 15 (2005) 229-238 paper.
① 카복시페녹시 프로판(1,3-Bis-carboxyphenoxy propane, CPP) 40g을 500㎖ 아세틱안하이드라이드(acetic anhydride)에 녹여 3개의 목이 달린 1000㎖둥근 플라스크에 넣는다. 플라스크는 냉각기를 장착하고 용액을 서서 히 저어주면서 질소조건아래서 1시간동안 용매를 재순환시킨다. 이때 발생한 침전물을 종이필터를 사용하여 수 득하였다. 옅은 노란색의 CPP 용액은 65℃로 감압 증발시켜 농축시킨다. 농축액은 0℃에서 재결정시키고 종이필 터로 결정을 모은 다음 진공 건조시킨다. 결정 CPP는 200㎖ ether를 사용하여 세 번 세척하고 진공 건조시켜 CPP전구체를 마련하였다.① Dissolve 40 g of carboxyphenoxypropane (1,3-Bis-carboxyphenoxy propane, CPP) in 500 ml acetic anhydride and put it in a 1000 ml round flask with three necks. The flask was equipped with a condenser and the solvent was recycled for 1 hour under nitrogen conditions while slowly stirring the solution. The precipitate generated at this time was obtained using a paper filter. The pale yellow CPP solution was concentrated by evaporation under reduced pressure at 65°C. The concentrated solution is recrystallized at 0℃, and the crystals are collected with a paper filter and vacuum dried. The crystalline CPP was washed three times using 200 ml of ether and vacuum dried to prepare a CPP precursor.
② 세바식산(sebacic acid, SA) 40g을 세 개의 목이 달린 1000㎖ 둥근 플라스크에 넣고 500㎖ 아세틱안하이드라이드(acetic anhydride)에 녹인다. CPP와 마찬가지로 질소조건에서 1시간동안 저어주며 용매를 재순환시킨다. 미 반응된 용매는 녹는점이 낮은 SA의 특성을 고려하여 50℃로 감압 증류하여 제거하였다. 반응물은 톨루엔 200 ㎖에 녹여 재결정하고 미 반응된 용매를 제거하기위하여 petroleum ether와 ethyl ether(v/v=50/50) 200㎖에 넣고 충분시간동안 저어준다. 불순물이 제거된 SA 전구체 결정은 데시케이터내에서 진공 건조시켜 준비하였다. ③ 모노메톡실 폴리에틸렌글리콜(Monomethoxyl poly ethylene glycol, Molecular weight 2000, mPEG) 10g을② Put 40 g of sebacic acid (SA) in a 1000 ml round flask with three necks and dissolve in 500 ml acetic anhydride. Like CPP, it is stirred for 1 hour under nitrogen conditions and the solvent is recycled. The unreacted solvent was removed by distillation under reduced pressure at 50 °C in consideration of the characteristics of SA having a low melting point. The reactants were dissolved in 200 ml of toluene, recrystallized, and added to 200 ml of petroleum ether and ethyl ether (v/v=50/50) to remove unreacted solvents and stirred for a sufficient time. SA precursor crystals from which impurities were removed were prepared by vacuum drying in a desiccator. ③ 10 g of Monomethoxyl poly ethylene glycol (Molecular weight 2000, mPEG)
0.56㎖의 트리에틸아민(triethylamine)과 함께 50㎖ 디클로로메탄(dichloromethane, DCM)에 녹인다. 다른 플라 스크에는 0.9g 무수숙신산(succinic anhydride)을 디옥산(1,4-dioxane) 50㎖에 녹인 후 0.244g의 디메틸아미노 피리딘(4-dimethylaminopyridine)을 첨가한다. 두 용액을 완전히 혼합하고 질소조건하에서 24시간동안 상온에서 반응시킨다. 반응이 완료되면 로터리증발기를 이용하여 용매를 완전제거하고 최종생성물을 15㎖ 테트라하이드로 퓨란(tetrahydrofuran, THF)에 녹인다. 최종생성물이 포함된 용액은 24시간동안 증류수(deionized water)로 투 석하고 동결건조하여 준비하였다.Dissolve in 50 ml of dichloromethane (DCM) with 0.56 ml of triethylamine. In another flask, 0.9 g of succinic anhydride is dissolved in 50 ml of dioxane (1,4-dioxane), and then 0.244 g of 4-dimethylaminopyridine is added. The two solutions were thoroughly mixed and reacted at room temperature for 24 hours under nitrogen conditions. When the reaction is complete, the solvent is completely removed using a rotary evaporator, and the final product is dissolved in 15 ml of tetrahydrofuran (THF). A solution containing the final product was prepared by dialysis with deionized water for 24 hours and lyophilization.
1(b). CPP와 SA 공중합 고분자 반응1(b). CPP and SA copolymerization reaction
1(a).에서 얻은 CPP와 SA의 전구체를 정해진 비율에 맞추어 시험관에 질소분위기하에서 고분자반응을 실시하였 다. 시험관 내부는 진공펌프를 사용하여 진공상태를 유지하며 매 30분마다 15초간 질소가스를 흘려보내며 반응 을 실시하였다. 반응시험관은 180℃로 유지되는 오일 남비에 담근 후 2시간동안 자체조립(self assembly)반응법 으로 공중합 반응을 실시하였다. 최종 공중합체 반응물은 DCM에 녹인 후 petroleum ether를 부어 침전시켰다. 공중합체 화합물은 무수 에테르(ether)로 여러 차례 세척한 후 진공 건조시켜 -20℃에 보관하였다.The polymer reaction was carried out in a test tube under a nitrogen atmosphere by adjusting the CPP and SA precursors obtained in 1(a). The inside of the test tube was maintained in a vacuum state using a vacuum pump, and the reaction was carried out by flowing nitrogen gas for 15 seconds every 30 minutes. The reaction test tube was immersed in an oil pot maintained at 180 ° C., and then the copolymerization reaction was carried out by self assembly reaction method for 2 hours. The final copolymer reactant was dissolved in DCM and precipitated by pouring petroleum ether. The copolymer compound was washed several times with anhydrous ether, dried under vacuum, and stored at -20°C.
1(c). p(CPP-SA) 공중합 미세입자(microparticles) 제조1(c). Preparation of p(CPP-SA) copolymer microparticles
1(b).에서 얻은 p(CPP-SA)공중합체를 THF 10㎖에 녹인 후 물을 넣어 미세입자(microparticles)를 제조하였다. 둥근 플라스크에서 THF에 녹인 공중합체를 빠르게 저어주며 실린지 펌프를 이용하여 10㎖/h 속도로 물 (deionized water, 5㎖)을 주입한다. 이후 상온에서 5시간이상 서서히 교반시키며 THF를 증발시키고, 최종적으 로 THF를 완전히 제거하여 미세입자를 제조하였다.After dissolving the p(CPP-SA) copolymer obtained in 1(b) in 10 ml of THF, water was added to prepare microparticles. While rapidly stirring the copolymer dissolved in THF in a round flask, deionized water (5 ml) is injected at a rate of 10 ml/h using a syringe pump. Thereafter, THF was evaporated while slowly stirring at room temperature for 5 hours or more, and finally, THF was completely removed to prepare microparticles.
1(d). p(mPEG-CPP-SA) 고분자 중합체 합성1(d). Synthesis of p(mPEG-CPP-SA) polymer polymer
mPEG-CPP-SA 고분자 중합체는 위(CPP-SA)조성비에 10% 중량비의 폴리에틸렌글리콜을 첨가하여 삼중합 고분자 (terpolymer)를 제조하였다. 삼중합 고분자 중합체는 melt-condensation polymerization기법으로 합성하였다. 먼저 정해진 함량에 따라 계량한 3개 성분의 전구체를 둥근 플라스크에 넣는다. 플라스크내에서 재료가 완전히 녹은 후 고진공을 전개하며 180℃ 오일남비에서 2시간동안 중합반응을 실시한다. 반응이 완료된 합성물은 상온 에서 서서히 냉각시킨다. 최종생성물은 반응물을 DCM에 녹인 후 에테르를 사용하여 추출하고 진공 건조시킨후 -20℃에 보관하였다.mPEG-CPP-SA polymer The polymer was prepared as a terpolymer by adding 10% weight ratio of polyethylene glycol to the above (CPP-SA) composition ratio. The triple polymer polymer was synthesized by melt-condensation polymerization technique. First, the precursors of the three components weighed according to the predetermined content are put into a round flask. After the material is completely melted in the flask, a high vacuum is developed and polymerization is carried out in an oil pot at 180 ° C for 2 hours. The reaction-completed compound is slowly cooled at room temperature. After dissolving the reactants in DCM, the final product was extracted using ether, dried under vacuum, and stored at -20°C.
1(e). p(mPEG-LLA) 고분자 중합체 합성1(e). p(mPEG-LLA) polymer synthesis
엘 라틱산에 폴리에틸렌글리콜을 10% 중량비를 포함시킨 p(mPEG-LLA) 공중합체를 제조하였다. 엘 라틱산(L- lactic acid, LLA)은 개환 중합반응(ring opening polymerization)방법으로 mPEG의 하이드록실그룹을 연결하였 다. 미리 정해진 양의 LLA와 모노메톡실 폴리에틸렌글리콜(Monomethoxyl PEG, MW 2000, mPEG)을 라운드 플라스 크에 넣고 100℃에서 녹인다. 플라스크 내부를 진공상태로 유지하며 0.5wt%(0.06g) 주석촉매(stannous 2- ethylhexanoate)를 첨가하고 180℃에서 6시간동안 고분자화 반응을 실시한다. 합성된 결과물을 메틸렌클로라이 드(methylene chloride)에 녹이고 디에틸에테르(diethylether)를 사용하여 침전시킨다. 생성된 침전물을 여과하 여 40℃ 진공오븐 내에서 3일간 건조하여 준비하였다.A p(mPEG-LLA) copolymer was prepared by including 10% weight ratio of polyethylene glycol to elastomeric acid. L-lactic acid (LLA) linked the hydroxyl group of mPEG by ring opening polymerization. A predetermined amount of LLA and monomethoxyl polyethylene glycol (Monomethoxyl PEG, MW 2000, mPEG) were put into a round flask and melted at 100°C. While maintaining the inside of the flask in a vacuum state, 0.5 wt% (0.06 g) of a tin catalyst (stannous 2-ethylhexanoate) was added, and polymerization was carried out at 180°C for 6 hours. The synthesized product is dissolved in methylene chloride and precipitated using diethylether. The resulting precipitate was filtered and dried in a vacuum oven at 40 °C for 3 days.
2. 고분자 중합체 미소입자의 분해도 측정2. Measurement of the degree of degradation of polymer microparticles
2(a). p(CPP-SA) 미세입자의 분해속도 측정2(a). Decomposition rate measurement of p(CPP-SA) microparticles
1(c).에서 제조된 함량비가 다른 p(CPP-SA) 미세입자 200㎎씩을 pH 7.4의 인산완충용액(phosphate buffer) 10 ㎖에 넣고 37℃에서 100rpm으로 저어주면서 미세입자의 분해속도를 측정하였다. 정해진 시간 간격에 맞추어 시 료를 100㎕채취하여 GPC장치(Gel permeation chromatography, Agilent PL-GPC 50)에서 Agilent PLgel 3㎛과 PLgel 5㎛ 컬럼을 사용하여 굴절계 검출기(Refractive Index detector)로 분자량을 분석하였다. 이때 전개용매 로는 THF를 사용하였고 유속은 1㎖/min이다.200 mg of p(CPP-SA) microparticles with different content ratios prepared in 1(c) were put into 10 ml of phosphate buffer at pH 7.4 and stirred at 37°C at 100 rpm to measure the decomposition rate of the microparticles did 100 μl of the sample was collected at a set time interval, and the molecular weight was analyzed with a refractometer detector using Agilent PLgel 3 μm and PLgel 5 μm columns in a GPC device (Gel permeation chromatography, Agilent PL-GPC 50). . At this time, THF was used as the developing solvent and the flow rate was 1 ml/min.
시간경과에 따른 공중합 고분자물의 분해비율을 도 1.에 나타내었다. p(CPP-SA) 공중합 고분자는 SA 중량비의 증가에 따라 분해비율이 증가하였다. 이는 CPP보다 SA가 친수성이 조금 더 강하여 SA비율이 증가함에 따라 분해 속도가 빠르게 진행되는 것으로 추측되었다. 분해결과를 보면 CPP가 50% 중량비 이상에서는 분해속도가 시간에 비례함을 보였는데 이 그림의 결과를 외삽하면 최대 분해시간 예측을 가능케 하였다.The decomposition rate of the copolymerized polymer over time is shown in Figure 1. The decomposition rate of the p(CPP-SA) copolymer increased as the SA weight ratio increased. It was speculated that the hydrophilicity of SA was slightly stronger than that of CPP, so that the decomposition rate proceeded faster as the SA ratio increased. The disintegration results showed that the decomposition rate was proportional to time when the CPP was above 50% by weight, and extrapolation of the results in this figure made it possible to predict the maximum decomposition time.
2(b). p(mPEG-CPP-SA)와 p(mPEG-LLA) 분해도 비교2(b). Comparison of p(mPEG-CPP-SA) and p(mPEG-LLA) resolution
폴리에틸렌글리콜이 10중량% 포함된 1(d).와 1(e).의 고분자 중합체를 위 2(a)의 실험과 같이 pH 7.4 인산완충 용액 10㎖에 각각 200㎎씩 분산시켜 이들의 분해정도를 GPC를 이용하여 측정하였다. 도 2.에 나타난바와 같이 폴리에틸렌글리콜을 도입하면 폴리에틸렌글리콜 도입 이전보다 분해가 빠르게 진행됨을 알 수 있었다.200 mg each of the polymers of 1(d) and 1(e) containing 10% by weight of polyethylene glycol were dispersed in 10 ml of pH 7.4 phosphate buffer solution as in the experiment of 2 (a) above, and the degree of their decomposition was measured using GPC. As shown in FIG. 2, it was found that when polyethylene glycol was introduced, decomposition proceeded faster than before polyethylene glycol was introduced.
또한 폴리락틱산 공중합물인 p(mPEG-LLA)는 실험 시작 후 10일정도 경과 동안에는 선형적으로 분해되다 14일 이 후에는 분해속도가 빠르게 진행되었다. 반면 p(mPEG-CPP-SA) 중합체는 CPP의 함량이 75%이상에서는 일정시간 경 과(14일)후에는 p(mPEG-LLA)보다 오히려 낮은 분해비율을 보였으며 분해속도 또한 선형적으로 증가함을 보였다. 따라서 CPP가 SA보다 일정수준 높은 함량비의 p(mPEG-CPP-SA) 공중합체는 p(mPEG-LLA)보다 공중합체가 장시간 유지될 수 있음을 알 수 있었다. 이들 결과는 p(mPEG-LLA) 중합체는 초기에는 물에 의한 분해가 천천히 진행되 다 일정시간이 경과하면 전체 결합이 한꺼번에 붕괴되는 bulk erosion의 경향을 보이나 p(mPEG-CPP-SA)공중합체 는 표면붕괴(surface erosion)반응 경향을 보이는 것으로 추측된다.In addition, p(mPEG-LLA), a polylactic acid copolymer, was linearly degraded for about 10 days after the start of the experiment, and the degradation rate progressed rapidly after 14 days. On the other hand, the p(mPEG-CPP-SA) polymer showed a lower degradation rate than p(mPEG-LLA) after a certain period of time (14 days) when the CPP content was 75% or more, and the degradation rate also increased linearly. showed Therefore, it was found that the p(mPEG-CPP-SA) copolymer with a certain level of CPP content ratio higher than SA could be maintained for a longer period of time than p(mPEG-LLA). These results show that the p(mPEG-LLA) polymer is initially slowly decomposed by water, and after a certain period of time, all bonds are collapsed at once, showing a tendency to bulk erosion, but the p(mPEG-CPP-SA) copolymer It is presumed to show a tendency of surface erosion reaction.
이 결과는 폴리안하이드라이드계열 공중합체를 제조할 때 각 성분의 함량비를 조정하면 기존의 폴리락틱산에 비 하여 분해속도가 느리고 지속기간을 연장시킬 수 있는 고분자 필러를 제조할 수 있을 것으로 생각된다.This result suggests that when preparing polyanhydride-based copolymers, adjusting the content ratio of each component can produce a polymer filler with a slower decomposition rate and longer duration than conventional polylactic acid. do.
Claims (8)
상기 무수물(anhydride)계열 화합물은 고분자 중합체의 전체 중량 대비 20∼90중량%이고, 상기 세바식산 (sebacic acie, SA)은 10∼60중량%이며, 상기 폴리에틸렌글리콜(poly ethylene glycol, PEG)은 0.1∼30중량%인 것을 특징으로 하는 피부용 필러 조성물According to claim 1,
The anhydride-based compound is 20 to 90% by weight based on the total weight of the polymer, the sebacic acid (SA) is 10 to 60% by weight, and the polyethylene glycol (PEG) is 0.1 Dermal filler composition, characterized in that ~ 30% by weight
상기 무수물계열 화합물은 카복시페녹시 메탄(Carboxyphenoxy methane, CPM) 또는 카복시페녹시 프로판 (Carboxyphenoxy propane, CPP) 또는 카복시페녹시 헥산(Carboxyphenoxy hexane, CPH)인 것을 특징으로 하는 피부용 필러 조성물According to claim 1,
The anhydride-based compound is carboxyphenoxy methane (CPM), carboxyphenoxy propane (CPP), or carboxyphenoxy hexane (CPH), characterized in that the dermal filler composition
상기 고분자 중합체의 미소구체의 직경은 0.1㎛ ~ 100㎛의 미소입자인 것을 특징으로 하는 피부용 필러 조성물According to claim 1,
The dermal filler composition, characterized in that the diameter of the microspheres of the polymer is a microparticle of 0.1 μm to 100 μm
상기 고분자 중합체를 분산시킨 주사액에 리도카인(lidocaine), 프로카인(procaine), 크실로카인(xylocaine)등 의 국소마취제를 더 포함한 것을 특징으로 하는 피부용 필러 조성물According to claim 1,
Dermal filler composition characterized by further comprising a local anesthetic such as lidocaine, procaine, and xylocaine in the injection solution in which the polymer is dispersed
상기 고분자 중합체 수용액에 히알루론산(Hyaluronic acid) 및 보툴리늄 톡신(Botlinum toxin, Botoxⓡ)을 더 포함한 것을 특징으로 하는 피부용 필러 조성물According to claim 1,
Dermal filler composition characterized by further comprising hyaluronic acid and botulinum toxin (Botoxⓡ) in the aqueous polymer solution
상기 고분자 중합체 분말을 분산한 수용액은 인산완충생리식염수(phosphate buffered saline)인 것을 특징으로 하는 피부용 필러조성물.According to claim 1,
A filler composition for skin, characterized in that the aqueous solution in which the polymer powder is dispersed is phosphate buffered saline.
상기 고분자 중합체의 수용액에 상처치료, 미백, 피부 노화방지 등 피부에 효과를 기대하는 단백질이나 호르몬 혹은 약물이 더 포함되는 것을 특징으로 하는 피부용 필러 조성물According to claim 1,
Dermal filler composition characterized in that the aqueous solution of the polymer further contains proteins, hormones or drugs expected to have effects on the skin such as wound healing, whitening, and anti-aging of the skin
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| KR1020210106712A KR20230025560A (en) | 2021-08-12 | 2021-08-12 | Skin filler that is easy to predict decomposition rate and can maintain filler effect for a long time |
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| Application Number | Priority Date | Filing Date | Title |
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| KR1020210106712A KR20230025560A (en) | 2021-08-12 | 2021-08-12 | Skin filler that is easy to predict decomposition rate and can maintain filler effect for a long time |
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| KR20230025560A true KR20230025560A (en) | 2023-02-22 |
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| KR1020210106712A KR20230025560A (en) | 2021-08-12 | 2021-08-12 | Skin filler that is easy to predict decomposition rate and can maintain filler effect for a long time |
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| KR (1) | KR20230025560A (en) |
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