KR102485144B1 - Dermal filler composition containing hyaluronic acid and method for manufacturing the same - Google Patents
Dermal filler composition containing hyaluronic acid and method for manufacturing the same Download PDFInfo
- Publication number
- KR102485144B1 KR102485144B1 KR1020220032917A KR20220032917A KR102485144B1 KR 102485144 B1 KR102485144 B1 KR 102485144B1 KR 1020220032917 A KR1020220032917 A KR 1020220032917A KR 20220032917 A KR20220032917 A KR 20220032917A KR 102485144 B1 KR102485144 B1 KR 102485144B1
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- KR
- South Korea
- Prior art keywords
- hyaluronic acid
- crosslinked
- acid
- citric acid
- crosslinked hyaluronic
- Prior art date
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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 title claims abstract description 218
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 210
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 210
- 239000000945 filler Substances 0.000 title claims abstract description 85
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- 230000002500 effect on skin Effects 0.000 title claims description 15
- 238000000034 method Methods 0.000 title description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 114
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
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- 238000002156 mixing Methods 0.000 claims description 11
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- 229930003268 Vitamin C Natural products 0.000 claims description 10
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 claims description 10
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- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 claims description 2
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- 235000010469 Glycine max Nutrition 0.000 description 4
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- WUADCCWRTIWANL-UHFFFAOYSA-N biochanin A Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O WUADCCWRTIWANL-UHFFFAOYSA-N 0.000 description 2
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- ADFCQWZHKCXPAJ-GFCCVEGCSA-N equol Chemical compound C1=CC(O)=CC=C1[C@@H]1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-GFCCVEGCSA-N 0.000 description 2
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- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 description 2
- 235000006539 genistein Nutrition 0.000 description 2
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 2
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- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 2
- -1 hyaluronic acid salt Chemical class 0.000 description 2
- ADFCQWZHKCXPAJ-UHFFFAOYSA-N indofine Natural products C1=CC(O)=CC=C1C1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-UHFFFAOYSA-N 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
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- 241000287828 Gallus gallus Species 0.000 description 1
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- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
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Images
Classifications
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- 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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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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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
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
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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
- 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
- A61L2300/23—Carbohydrates
- A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
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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
- 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
- A61L2300/428—Vitamins, e.g. tocopherol, riboflavin
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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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
Abstract
Description
본 발명은 피부에 주입되어 피부의 주름 개선 및 모양 형성에 기여하는 피부 필러 조성물 및 그 제조방법에 관한 것으로, 하나의 실시 형태에 따라서 필러의 유효성분으로서 히알루론산을 포함하되, 이에 더하여 구연산에 의해 가교된 구연산-가교 히알루론산을 포함하여, 필러 특성이 개선된 히알루론산 함유 피부 필러 조성물 및 그 제조방법에 관한 것이다. The present invention relates to a dermal filler composition that is injected into the skin and contributes to wrinkle improvement and shape formation of the skin and a manufacturing method thereof. According to one embodiment, the active ingredient of the filler includes hyaluronic acid, It relates to a hyaluronic acid-containing dermal filler composition having improved filler properties, including crosslinked citric acid-crosslinked hyaluronic acid, and a manufacturing method thereof.
얼굴이나 신체 등의 외모에 대한 관심이 증가함에 따라 피부 상태를 개선하고 외모의 부족한 부분을 보완하고자 하는 피부 미용 시술이 늘어나고 있다. 특히, 피부 주름이나 그 밖의 피부 외관 상태를 개선하는 것을 목적으로 하는 피부 미용 시술에 대한 관심이 높아지고 있다. As interest in the appearance of the face or body increases, skin cosmetic procedures to improve skin conditions and compensate for the lack of appearance are increasing. In particular, interest in skin cosmetic procedures aimed at improving skin wrinkles or other skin appearance conditions is increasing.
대표적으로는 생체 적합성의 필러 조성물을 피부에 국소적으로 주입하여 주름을 개선하고 모양을 형성하는 방법이다. 필러 조성물은 주사기를 통해 인체의 볼, 입술, 가슴 및 엉덩이 등의 특정 부위에 주입되어 연부 조직을 확장시키고 피부의 잔주름 및 깊은 주름을 감소(완화)시켜 주름을 개선하고 피부의 윤곽을 교정한다. Representatively, it is a method of improving wrinkles and forming shapes by locally injecting a biocompatible filler composition into the skin. The filler composition is injected through a syringe into specific areas of the body such as cheeks, lips, breasts, and buttocks to expand soft tissue and reduce (relieve) fine and deep wrinkles of the skin to improve wrinkles and correct skin contours.
일반적으로, 필러 조성물은 필러 유효성분으로서 히알루론산(HA ; Hyaluronic acid)이 사용되었다. 히알루론산(HA)은 N-아세틸-D-글루코사민과 D-글루쿠론산으로 이루어진 반복 단위가 선형으로 연결되어 있는 생체 고분자 물질로서, 이는 안구의 유리액, 관절의 활액 및 닭벼슬 등에 많이 존재한다. 이러한 히알루론산(HA)은 피부의 주름 개선 및 모양 형성에 기여하고 생체 적합성을 가짐으로 인해 피부 필러(dermal filler)로서 유용하다. In general, filler compositions use hyaluronic acid (HA) as an active filler component. Hyaluronic acid (HA) is a biopolymer material in which repeating units composed of N-acetyl-D-glucosamine and D-glucuronic acid are linearly connected, and it is present in abundance in the vitreous humor of the eyeball, synovial fluid of joints, and chicken combs. . Such hyaluronic acid (HA) is useful as a dermal filler because it contributes to wrinkle improvement and shape formation of the skin and has biocompatibility.
그러나 히알루론산 그 자체는 인체 내에서 수 시간에 불과한 짧은 반감기를 나타내어 체내 지속성이 낮다. 이에, 히알루론산의 가교 결합을 통해 반감기(체내 지속성)를 증대시키고 있으며, 주로 1,4-부탄디올 디글리시딜에테르(BDDE) 등의 가교제를 사용하여 가교 결합시킨 가교 히알루론산을 사용하고 있다. 가교 히알루론산은 비가교의 선형 히알루론산보다 생체 내 지속성이 높다. 예를 들어, 한국 등록특허 제10-2334794호 및 한국 공개특허 제10-2017-0117368호 등에는 위와 관련한 기술이 제시되어 있다. However, hyaluronic acid itself exhibits a short half-life of only several hours in the human body, so the persistence in the body is low. Accordingly, the half-life (persistence in the body) is increased through cross-linking of hyaluronic acid, and cross-linked hyaluronic acid cross-linked using a cross-linking agent such as 1,4-butanediol diglycidyl ether (BDDE) is mainly used. Cross-linked hyaluronic acid has higher persistence in vivo than non-cross-linked linear hyaluronic acid. For example, Korean Patent Registration No. 10-2334794 and Korean Patent Publication No. 10-2017-0117368 suggest technologies related to the above.
일반적으로, 필러 조성물은 적절한 점도와 기계적 강도(탄성도 등)가 요구되고 있다. 그러나 종래의 가교 히알루론산을 주성분으로 하는 필러 조성물은 점도가 높고 탄성도가 낮다. 이에 따라, 피부에 주입될 경우, 주입된 부위에서 이탈할 가능성은 낮으나, 주입된 형태(모양)를 오래 유지하지 못하고 형태 유지 기간이 짧은 문제점이 있다. In general, filler compositions are required to have appropriate viscosity and mechanical strength (elasticity, etc.). However, conventional filler compositions containing crosslinked hyaluronic acid as a main component have high viscosity and low elasticity. Accordingly, when injected into the skin, the possibility of leaving the injected site is low, but there is a problem in that the injected shape (shape) cannot be maintained for a long time and the shape maintenance period is short.
이에, 본 발명은 적절한 점도와 기계적 강도(탄성도 등)를 가짐으로 인해, 피부의 주입된 부위에서 이탈할 가능성이 낮으면서도 주입된 형태를 오래 유지할 수 있는 히알루론산 함유 피부 필러 조성물 및 그 제조방법을 제공하는 데에 목적이 있다. Therefore, the present invention is a hyaluronic acid-containing dermal filler composition that can maintain the injected form for a long time while having a low possibility of leaving the injected area of the skin due to having appropriate viscosity and mechanical strength (elasticity, etc.) and a method for manufacturing the same It aims to provide
상기 목적을 달성하기 위하여 본 발명은, In order to achieve the above object, the present invention,
피부에 주입되어 피부의 주름 개선 및 모양 형성에 기여하는 피부 필러 조성물로서, A dermal filler composition that is injected into the skin to contribute to wrinkle improvement and shape formation of the skin,
히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산; 및 at least one non-crosslinked hyaluronic acid selected from hyaluronic acid and hyaluronic acid salts; and
히알루론산 및 히알루론산염으로부터 선택된 하나 이상이 가교제에 의해 가교 결합된 가교 히알루론산을 포함하는 히알루론산 함유 피부 필러 조성물을 제공한다. Provided is a hyaluronic acid-containing dermal filler composition comprising cross-linked hyaluronic acid cross-linked by at least one selected from hyaluronic acid and a salt thereof by a cross-linking agent.
본 발명의 바람직한 실시형태에 따라서, 상기 가교 히알루론산은, 상기 히알루론산 및 히알루론산염으로부터 선택된 하나 이상이 구연산에 의해 가교 결합된 구연산-가교 히알루론산을 포함한다. 아울러, 본 발명의 다른 실시형태에 따라서, 피부 필러 조성물은 이소플라본(Isoflavone) 및 비타민 C 등을 더 포함할 수 있다. According to a preferred embodiment of the present invention, the crosslinked hyaluronic acid includes citric acid-crosslinked hyaluronic acid in which at least one selected from the above hyaluronic acid and a salt thereof is crosslinked with citric acid. In addition, according to another embodiment of the present invention, the dermal filler composition may further include isoflavone and vitamin C.
또한, 본 발명은, In addition, the present invention,
피부에 주입되어 피부의 주름 개선 및 모양 형성에 기여하는 피부 필러 조성물의 제조방법으로서, A method for producing a dermal filler composition that is injected into the skin to contribute to wrinkle improvement and shape formation of the skin,
히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산을 준비하는 제1단계; A first step of preparing at least one non-crosslinked hyaluronic acid selected from hyaluronic acid and hyaluronic acid salts;
히알루론산 및 히알루론산염으로부터 선택된 하나 이상과 가교제를 반응시켜 히알루론산 및 히알루론산염으로부터 선택된 하나 이상이 가교제에 의해 가교 결합된 가교 히알루론산을 생성하는 제2단계; 및 A second step of reacting at least one selected from hyaluronic acid and salts with a cross-linking agent to produce cross-linked hyaluronic acid in which at least one selected from hyaluronic acid and salts is cross-linked by the cross-linking agent; and
상기 비가교 히알루론산과 가교 히알루론산을 혼합하는 제3단계를 포함하는 피부 필러 조성물의 제조방법을 제공한다. It provides a method for preparing a dermal filler composition comprising a third step of mixing the non-crosslinked hyaluronic acid and the crosslinked hyaluronic acid.
이때, 상기 제2단계에서는, 상기 가교제로서 구연산을 사용하되, 상기 히알루론산 및 히알루론산염으로부터 선택된 하나 이상과 상기 구연산을 1 : 0.5 ~ 2.0의 중량비로 포함하는 반응물을 차아인산염(hypophosphite)의 존재 하에서 80℃ ~ 95℃의 온도에서 2시간 ~ 4시간 동안 에스테르화 가교 반응시켜 구연산-가교 히알루론산을 생성한다. At this time, in the second step, citric acid is used as the crosslinking agent, but a reactant containing at least one selected from hyaluronic acid and hyaluronic acid and the citric acid in a weight ratio of 1: 0.5 to 2.0 is present in hypophosphite. Under the temperature of 80 ℃ ~ 95 ℃ esterification cross-linking reaction for 2 hours to 4 hours to produce a citric acid-crosslinked hyaluronic acid.
또한, 상기 제3단계에서는, 상기 비가교 히알루론산과 가교 히알루론산을 1 : 1.2 ~ 4.0의 중량비로 혼합할 수 있다. In addition, in the third step, the uncrosslinked hyaluronic acid and the crosslinked hyaluronic acid may be mixed in a weight ratio of 1:1.2 to 4.0.
본 발명에 따르면, 적어도 필러 특성이 개선되는 효과를 갖는다. 구체적으로, 본 발명에 따르면, 필러 특성에 유리한 적절한 점도와 기계적 강도(탄성도 등)를 가짐으로 인해, 피부의 주입된 부위에서 이탈할 가능성이 낮고, 이와 동시에 주입된 형태를 오래 유지(체내 지속성)할 수 있는 효과를 갖는다. According to the present invention, it has an effect of improving at least filler characteristics. Specifically, according to the present invention, due to having an appropriate viscosity and mechanical strength (elasticity, etc.) that are advantageous to the characteristics of the filler, there is a low possibility of departing from the injected site of the skin, and at the same time, the injected form is maintained for a long time (persistence in the body) ) has the effect of
또한, 본 발명에 따르면, 이소플라본 및 비타민 C를 더 포함하여 피부 미백, 노화 방지 및 주름 개선 등의 효과를 갖는다. In addition, according to the present invention, isoflavone and vitamin C are further included to have effects such as skin whitening, anti-aging, and wrinkle improvement.
도 1은 본 발명의 실시예에 따라 제조된 구연산-가교 히알루론산의 SEM 사진이다. 1 is a SEM picture of citric acid-crosslinked hyaluronic acid prepared according to an embodiment of the present invention.
본 발명에서 사용되는 용어 "및/또는"은 전후에 나열한 구성요소들 중에서 적어도 하나 이상을 포함하는 의미로 사용된다. 본 발명에서 사용되는 용어 "하나 이상"은 하나 또는 둘 이상의 복수를 의미한다. The term "and/or" used in the present invention is used to mean including at least one or more of the elements listed before and after. As used herein, the term "one or more" means one or a plurality of two or more.
본 발명은, 적어도 필러 특성이 개선된 히알루론산 함유 피부 필러 조성물을 제공한다. 본 발명에 따른 히알루론산 함유 피부 필러 조성물(이하, 「필러 조성물」로 약칭한다.)은 필러의 유효성분으로서, 히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산(제1필러)과; 히알루론산 및 히알루론산염으로부터 선택된 하나 이상이 가교제에 의해 가교 결합된 가교 히알루론산(제2필러)을 포함한다. The present invention provides a hyaluronic acid-containing dermal filler composition having at least improved filler properties. The hyaluronic acid-containing dermal filler composition (hereinafter, abbreviated as "filler composition") according to the present invention includes at least one non-crosslinked hyaluronic acid (first filler) selected from hyaluronic acid and hyaluronic acid salts as an active ingredient of the filler; It includes cross-linked hyaluronic acid (second filler) cross-linked by at least one selected from hyaluronic acid and salts of hyaluronic acid by a cross-linking agent.
본 발명의 바람직한 실시형태에 따라서, 상기 가교 히알루론산(제2필러)은 구연산(가교제)에 의해 가교 결합된 구연산-가교 히알루론산을 포함한다. 이때, 본 발명의 실시형태에 따라서, 상기 구연산-가교 히알루론산은 히알루론산 및 히알루론산염으로부터 선택된 하나 이상과 구연산을 1 : 0.5 ~ 2.0의 중량비로 포함하는 반응물이 차아인산염(hypophosphite)의 존재 하에서 80℃ ~ 95℃의 온도에서 2시간 ~ 4시간 동안 에스테르화 가교 반응되어 생성된 것이 사용된다. 본 발명에 따른 필러 조성물은 필러의 유효성분으로서, 비가교 히알루론산과 가교 히알루론산(구연산-가교 히알루론산)을 포함하되, 이에 더하여 선택적인 부가 성분으로서 이소플라본(Isoflavone) 및/또는 비타민 C(Vitamin C) 등을 더 포함할 수 있다. According to a preferred embodiment of the present invention, the crosslinked hyaluronic acid (second filler) comprises citric acid-crosslinked hyaluronic acid crosslinked by citric acid (crosslinking agent). At this time, according to an embodiment of the present invention, the citric acid-crosslinked hyaluronic acid is a reactant comprising at least one selected from hyaluronic acid and hyaluronic acid and citric acid in a weight ratio of 1: 0.5 to 2.0 in the presence of hypophosphite. A product obtained by esterification and crosslinking reaction at a temperature of 80° C. to 95° C. for 2 hours to 4 hours is used. The filler composition according to the present invention includes non-crosslinked hyaluronic acid and crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) as active ingredients of the filler, in addition to isoflavone and / or vitamin C ( Vitamin C) and the like may be further included.
본 발명에 따르면, 제1필러로서의 비가교 히알루론산(가교되지 않은 선형의 히알루론산)과 제2필러로서의 가교 히알루론산(구연산에 의해 가교된 구연산-가교 히알루론산)을 포함하여, 적어도 필러 특성이 개선된다. 구체적으로, 본 발명에 따르면, 비가교 히알루론산과 가교 히알루론산(구연선-가교 히알루론산)의 혼합으로 적절한 점도와 기계적 강도(탄성도 등)를 가짐으로 인해, 피부의 주입된 부위에서 이탈할 가능성이 낮고, 이와 동시에 주입된 형태를 오래 유지(체내 지속성)할 수 있다. According to the present invention, including non-crosslinked hyaluronic acid (non-crosslinked linear hyaluronic acid) as a first filler and crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid crosslinked by citric acid) as a second filler, at least the filler properties are Improved. Specifically, according to the present invention, the mixture of non-crosslinked hyaluronic acid and crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) has appropriate viscosity and mechanical strength (elasticity, etc.) The possibility is low, and at the same time, the injected form can be maintained for a long time (persistence in the body).
또한, 본 발명은, 상기 본 발명에 따른 필러 조성물을 제조하기 위한 제조방법으로서, 히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산을 준비하는 제1단계; 히알루론산 및 히알루론산염으로부터 선택된 하나 이상과 가교제를 가교 결합(가교 반응)시킨 가교 히알루론산을 생성(합성)하는 제2단계; 및 상기 비가교 히알루론산과 가교 히알루론산을 혼합하는 제3단계를 포함하는 필러 조성물의 제조방법을 제공한다. 이하, 본 발명의 실시형태에 따른 필러 조성물의 제조방법을 설명하면서 본 발명에 따른 필러 조성물의 실시형태를 함께 설명하면 다음과 같다. In addition, the present invention, as a manufacturing method for preparing the filler composition according to the present invention, a first step of preparing at least one non-crosslinked hyaluronic acid selected from hyaluronic acid and hyaluronic acid salts; A second step of generating (synthesizing) cross-linked hyaluronic acid obtained by cross-linking (cross-linking reaction) at least one selected from hyaluronic acid and a salt thereof with a cross-linking agent; and a third step of mixing the non-crosslinked hyaluronic acid with the crosslinked hyaluronic acid. Hereinafter, an embodiment of the filler composition according to the present invention will be described together while explaining a manufacturing method of the filler composition according to an embodiment of the present invention.
[제1단계] 비가교 히알루론산의 준비 [Step 1] Preparation of non-crosslinked hyaluronic acid
본 발명에서, 상기 비가교 히알루론산은 가교 결합되지 않은 선형의 히알루론산계 생체 고분자로서, 이는 통상과 같다. 구체적으로, 상기 비가교 히알루론산은 N-아세틸-D-글루코사민과 D-글루쿠론산으로 이루어진 반복 단위가 선형으로 연결된 히알루론산(HA) 및/또는 히알루론산염으로부터 선택된다. 상기 히알루론산염은, 예를 들어 히알루론산나트륨 등을 들 수 있다. In the present invention, the non-crosslinked hyaluronic acid is a linear hyaluronic acid-based biopolymer that is not crosslinked, as usual. Specifically, the non-crosslinked hyaluronic acid is selected from hyaluronic acid (HA) and/or hyaluronic acid salts in which repeating units composed of N-acetyl-D-glucosamine and D-glucuronic acid are linearly linked. As for the said hyaluronate, sodium hyaluronate etc. are mentioned, for example.
상기 비가교 히알루론산은, 예를 들어 통상과 같이 0.1 x 106 내지 4.0 x 106 Da(달턴), 또는 0.5 x 106 내지 4.0 x 106 Da, 또는 1.0 x 106 내지 3.8 x 106 Da, 또는 2.5 x 106 내지 3.8 x 106 Da, 또는 2.5 x 106 내지 3.5 x 106 Da의 평균 분자량을 가지는 것을 사용할 수 있다. 본 제1단계에서는 적어도 위와 같은 비가교 히알루론산을 포함하는 비가교 히알루론산 용액을 준비한다. 이때, 상기 비가교 히알루론산 용액은 비가교 히알루론산(히알루론산(HA) 및/또는 히알루론산염)의 분산을 위한 물(증류수, 정제수 및 식염수 등) 및/또는 완충액 등을 포함할 수 있다. The non-crosslinked hyaluronic acid is, for example, 0.1 x 10 6 to 4.0 x 10 6 Da (daltons), or 0.5 x 10 6 to 4.0 x 10 6 Da, or 1.0 x 10 6 to 3.8 x 10 6 Da as usual. , or 2.5 x 10 6 to 3.8 x 10 6 Da, or 2.5 x 10 6 to 3.5 x 10 6 Da may be used. In this first step, a non-crosslinked hyaluronic acid solution containing at least the above non-crosslinked hyaluronic acid is prepared. In this case, the non-crosslinked hyaluronic acid solution may include water (distilled water, purified water, saline, etc.) and/or a buffer solution for dispersing the non-crosslinked hyaluronic acid (hyaluronic acid (HA) and/or hyaluronic acid salt).
[제2단계] 가교 히알루론산의 생성(합성) [Step 2] Creation of cross-linked hyaluronic acid (synthesis)
비가교 히알루론산과 가교제를 반응시켜, 상기 비가교 히알루론산이 가교제에 의해 가교 결합된 가교 히알루론산을 생성(합성)한다. 상기 가교 히알루론산의 생성(합성)을 위한 비가교 히알루론산은 가교되지 않은 선형의 히알루론산계 생체 고분자로서, 이는 상기한 바와 같다. 즉, 상기 가교 히알루론산의 생성(합성)을 위한 비가교 히알루론산은, 예를 들어 0.1 x 106 내지 4.0 x 106 Da(달턴), 또는 0.5 x 106 내지 4.0 x 106 Da, 또는 1.0 x 106 내지 3.8 x 106 Da, 또는 2.5 x 106 내지 3.8 x 106 Da, 또는 2.5 x 106 내지 3.5 x 106 Da의 평균 분자량을 가지는 히알루론산 및/또는 히알루론산염으로부터 선택된다. By reacting non-crosslinked hyaluronic acid with a crosslinking agent, crosslinked hyaluronic acid in which the noncrosslinked hyaluronic acid is crosslinked by the crosslinking agent is produced (synthesized). The non-crosslinked hyaluronic acid for the generation (synthesis) of the crosslinked hyaluronic acid is a linear hyaluronic acid-based biopolymer that is not crosslinked, as described above. That is, the non-crosslinked hyaluronic acid for the generation (synthesis) of the crosslinked hyaluronic acid is, for example, 0.1 x 10 6 to 4.0 x 10 6 Da (dalton), or 0.5 x 10 6 to 4.0 x 10 6 Da, or 1.0 hyaluronic acid and/or its salts having an average molecular weight of from x 10 6 to 3.8 x 10 6 Da, or from 2.5 x 10 6 to 3.8 x 10 6 Da, or from 2.5 x 10 6 to 3.5 x 10 6 Da.
본 발명의 바람직한 실시형태에 따라서, 상기 가교 히알루론산의 생성(합성)을 위한 가교제는 구연산(citric acid)으로부터 선택된다. 즉, 본 발명에서, 상기 가교 히알루론산은, 비가교 히알루론산(가교되지 않은 히알루론산 및/또는 히알루론산염)이 구연산에 의해 가교 결합된 구연산-가교 히알루론산을 포함한다. 본 발명에 따르면, 상기 구연산-가교 히알루론산은 기존의 다른 가교물(예를 들어, 1,4-부탄디올 디글리시딜에테르(BDDE) 등의 가교제를 사용하여 가교 결합된 가교 히알루론산)에 비해 필러 특성(탄성도 등)에 유리하고, 이는 또한 가교제로서 식품 등급의 구연산이 사용되어 피부 자극(독성)이나 부작용이 없다. According to a preferred embodiment of the present invention, the cross-linking agent for the generation (synthesis) of the cross-linked hyaluronic acid is selected from citric acid. That is, in the present invention, the crosslinked hyaluronic acid includes citric acid-crosslinked hyaluronic acid in which non-crosslinked hyaluronic acid (non-crosslinked hyaluronic acid and/or a salt thereof) is crosslinked with citric acid. According to the present invention, the citric acid-crosslinked hyaluronic acid is compared to other conventional crosslinked products (eg, crosslinked hyaluronic acid crosslinked using a crosslinking agent such as 1,4-butanediol diglycidyl ether (BDDE)). It is advantageous for filler properties (elasticity, etc.), and it also has no skin irritation (toxicity) or side effects because food grade citric acid is used as a crosslinking agent.
상기 구연산-가교 히알루론산을 생성(합성)함에 있어서는 비가교 히알루론산(가교되지 않은 히알루론산 및/또는 히알루론산염)과 구연산을 1 : 0.5 ~ 2.0의 중량비로 포함하는 반응물을 차아인산염(hypophosphite)의 존재 하에서 80℃ ~ 95℃의 온도에서 2시간 ~ 4시간 동안 에스테르화 가교 반응시켜 생성(합성)하는 것이 바람직하다. 구체적인 실시형태에 따라서, 반응기에 비가교 히알루론산(가교되지 않은 히알루론산 및/또는 히알루론산염)과 구연산 수용액을 넣고, 여기에 차아인산염(hypophosphite)을 더 첨가한 다음, 반응기의 온도를 80℃ ~ 95℃로 유지시켜 2시간 ~ 4시간 동안 교반을 진행하면서 반응시킨다. In the production (synthesis) of the citric acid-crosslinked hyaluronic acid, a reaction product containing non-crosslinked hyaluronic acid (non-crosslinked hyaluronic acid and/or acid salt) and citric acid in a weight ratio of 1:0.5 to 2.0 is hypophosphite. It is preferable to produce (synthesize) by esterification crosslinking reaction at a temperature of 80 ° C. to 95 ° C. for 2 hours to 4 hours in the presence of. According to a specific embodiment, non-crosslinked hyaluronic acid (non-crosslinked hyaluronic acid and/or acid salt) and an aqueous solution of citric acid are put in a reactor, hypophosphite is further added thereto, and the temperature of the reactor is set to 80°C. It is maintained at ~ 95 ° C and reacted while stirring for 2 hours to 4 hours.
상기 구연산-가교 히알루론산을 생성(합성)함에 있어서, 상기 비가교 히알루론산(가교되지 않은 히알루론산 및/또는 히알루론산염)과 구연산의 중량비(혼합 비율), 반응 온도 및 반응 시간은 구연산-가교 히알루론산의 제조효율, 반응성, 액성(pH) 및 필러 특성 등에 영향을 끼치는 중요한 기술적 인자로 작용한다. 먼저, 비가교 히알루론산과 구연산의 중량비(혼합 비율)에 있어서, 구연산이 0.5 중량비 미만으로 사용되는 경우 구연산-가교 히알루론산의 제조효율(생성량)이 저하되며, 구연산이 2.0 중량비를 초과하여 사용되는 경우 미반응된 구연산의 잔류량이 많아지고 pH가 낮아진다. 그리고 상기 반응 온도가 80℃ 미만인 경우 반응성이 떨어져 비가교 히알루론산과 구연산의 가교 결합이 잘 진행되지 않으며, 상기 반응 온도가 95℃를 초과하는 경우 과도한 반응으로 점도가 너무 증가될 수 있다. 이때, 점도가 너무 증가된 경우 필러 특성이 떨어지고, 유연성 저하로 주사기에 의한 피부 주입 시 압출이 어려워질 수 있다. 아울러, 상기 반응 시간은 2시간 ~ 4시간 정도가 바람직하며, 반응 시간이 2시간 미만인 경우 반응물의 사용량에 비해 구연산-가교 히알루론산의 제조효율(생성량)이 낮아질 수 있고, 4시간을 초과하는 경우 점도가 크게 증가될 수 있다. In producing (synthesizing) the citric acid-crosslinked hyaluronic acid, the weight ratio (mixing ratio) of the non-crosslinked hyaluronic acid (non-crosslinked hyaluronic acid and/or acid salt) and citric acid, reaction temperature and reaction time are determined by citric acid-crosslinked hyaluronic acid. It acts as an important technical factor affecting the production efficiency, reactivity, liquid (pH) and filler characteristics of hyaluronic acid. First, in the weight ratio (mixing ratio) of non-crosslinked hyaluronic acid and citric acid, when citric acid is used in a weight ratio of less than 0.5, the production efficiency (production amount) of citric acid-crosslinked hyaluronic acid decreases, and citric acid is used in a weight ratio exceeding 2.0. In this case, the residual amount of unreacted citric acid increases and the pH decreases. In addition, when the reaction temperature is less than 80 ° C., the cross-linking of non-crosslinked hyaluronic acid and citric acid does not proceed well due to low reactivity, and when the reaction temperature exceeds 95 ° C., the viscosity may be excessively increased due to excessive reaction. At this time, if the viscosity is too high, the characteristics of the filler are deteriorated, and extrusion may be difficult when injected into the skin by a syringe due to a decrease in flexibility. In addition, the reaction time is preferably about 2 hours to 4 hours, and if the reaction time is less than 2 hours, the production efficiency (production amount) of citric acid-crosslinked hyaluronic acid may be lowered compared to the amount of reactant used, and if it exceeds 4 hours Viscosity can be greatly increased.
따라서, 상기 구연산-가교 히알루론산을 생성(합성)함에 있어서는 구연산-가교 히알루론산의 제조효율, 반응성, 액성(pH) 및 필러 특성 등을 고려하여, 위와 같은 조건에서 반응시키는 것이 바람직하며, 보다 바람직하게는 비가교 히알루론산과 구연산을 1 : 1.2 ~ 1.5의 중량비로 혼합하고, 약 80℃ ~ 90℃의 항온 조건에서 2시간 ~ 3시간 동안 교반을 진행하면서 반응시키는 것이 좋다. Therefore, in producing (synthesizing) the citric acid-crosslinked hyaluronic acid, it is preferable to react under the above conditions in consideration of the production efficiency, reactivity, liquid (pH) and filler characteristics of the citric acid-crosslinked hyaluronic acid, and more preferably Preferably, uncrosslinked hyaluronic acid and citric acid are mixed in a weight ratio of 1: 1.2 to 1.5, and reacted while stirring for 2 to 3 hours at a constant temperature of about 80 ° C to 90 ° C.
또한, 상기 차아인산염(hypophosphite)은 비가교 히알루론산과 구연산의 가교 결합을 위한 반응 개시제 및/또는 반응 촉매로서 작용한다. 상기 차아인산염(hypophosphite)은, 예를 들어 차아인산나트륨(Sodium hypophosphite)(NaPO2H2) 및 이의 1수화물(Sodium hypophosphite monohydrate) 등을 사용할 수 있다. 상기 구연산-가교 히알루론산의 생성(합성) 시에 차아인산염이 첨가되지 않은 경우, 구연산-가교 히알루론산의 생성이 어렵거나 반응속도가 현저히 낮아질 수 있다. 특별히 한정하는 것은 아니지만, 상기 차아인산염은 구연산 100중량부에 대하여 0.5 ~ 10중량부로 사용될 수 있다. In addition, the hypophosphite acts as a reaction initiator and/or reaction catalyst for cross-linking of uncross-linked hyaluronic acid and citric acid. As the hypophosphite, for example, sodium hypophosphite (NaPO 2 H 2 ) and its monohydrate (Sodium hypophosphite monohydrate) may be used. When hypophosphite is not added during the production (synthesis) of the citric acid-crosslinked hyaluronic acid, production of the citric acid-crosslinked hyaluronic acid may be difficult or the reaction rate may be remarkably low. Although not particularly limited, the hypophosphite may be used in an amount of 0.5 to 10 parts by weight based on 100 parts by weight of citric acid.
하기 [화학식]은 상기 구연산-가교 히알루론산의 생성 과정(반응식)을 예시한 것으로서, 이는 선형 히알루론산(HA)과 구연산의 가교 반응을 보인 것이다. 하기 [화학식]에서, n은 예를 들어 50 ~ 5,000의 정수일 수 있으며, 구체적인 예를 들어 200 ~ 3,000의 정수일 수 있다. 하기 [화학식]에 보인 바와 같이, 상기 구연산-가교 히알루론산은 히알루론산의 OH과 구연산의 COOH에 의한 에스테르 결합을 갖는다. The following [Formula] illustrates the production process (reaction formula) of the citric acid-crosslinked hyaluronic acid, which shows a crosslinking reaction between linear hyaluronic acid (HA) and citric acid. In the following [Formula], n may be, for example, an integer of 50 to 5,000, and may be an integer of 200 to 3,000, for example. As shown in [Formula] below, the citric acid-crosslinked hyaluronic acid has an ester bond by OH of hyaluronic acid and COOH of citric acid.
[화학식] [chemical formula]
본 제2단계에서는 적어도 위와 같은 가교 히알루론산(구연산-가교 히알루론산)을 포함하는 가교 히알루론산 용액을 제조한다. 이때, 상기 가교 히알루론산 용액은 겔(gel) 상태의 가교 히알루론산(구연산-가교 히알루론산겔)을 포함하되, 물(증류수, 정제수 및 식염수 등) 및/또는 완충액 등을 더 포함할 수 있다. 또한, 본 제2단계에서는 상기 겔(gel) 상태의 가교 히알루론산(구연산-가교 히알루론산겔)을 생성(합성)한 후, 통상과 같이 겔의 절단/분쇄, 중화 및/또는 정제 등의 공정을 진행하여 미립자의 마이크로겔을 수득하고, 이를 멸균/살균 처리하여 본 발명에 따른 필러 조성물의 유효성분으로 사용할 수 있다. In this second step, a crosslinked hyaluronic acid solution containing at least the above crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) is prepared. At this time, the cross-linked hyaluronic acid solution includes cross-linked hyaluronic acid in a gel state (citric acid-cross-linked hyaluronic acid gel), but may further include water (distilled water, purified water, saline, etc.) and/or a buffer solution. In addition, in this second step, after generating (synthesizing) the crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid gel) in the gel state, the gel is cut/crushed, neutralized and/or purified, etc. to obtain a microgel of microparticles, which can be sterilized/sterilized and used as an active ingredient of the filler composition according to the present invention.
[제3단계] 혼합 [Step 3] Mixing
다음으로, 상기 제1단계에서 준비된 제1필러로서의 비가교 히알루론산과 상기 제2단계에서 생성된 제2필러로서의 가교 히알루론산(구연산-가교 히알루론산)을 혼합한다. 이때, 상기 비가교 히알루론산과 가교 히알루론산(구연산-가교 히알루론산)을 혼합함에 있어서는, 적어도 필러 특성을 고려하여 상기 비가교 히알루론산과 가교 히알루론산(구연산-가교 히알루론산)을 1 : 1.2 ~ 4.0의 중량비로 혼합하는 것이 바람직하다. 상기 비가교 히알루론산과 가교 히알루론산(구연산-가교 히알루론산)의 중량비(혼합 비율)에 있어서, 상기 가교 히알루론산(구연산-가교 히알루론산)이 1.2 중량비 미만인 경우, 예를 들어 탄성도 등의 강도가 낮아 주입된 부위에서 이탈할 가능성이 높고 체내 지속성이 낮아질 수 있다. 또한, 상기 가교 히알루론산(구연산-가교 히알루론산)이 4.0 중량비를 초과하는 경우, 예를 들어 유연성 등의 저하로 주사기를 통한 피부 주입 시 주사기의 압출이 어려워질 수 있다. 이러한 점을 고려할 때, 상기 비가교 히알루론산과 가교 히알루론산(구연산-가교 히알루론산)을 1 : 1.8 ~ 3.2의 중량비로 혼합하는 것이 더욱 바람직하다. Next, the uncrosslinked hyaluronic acid prepared in the first step as the first filler and the crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) as the second filler produced in the second step are mixed. At this time, in mixing the non-crosslinked hyaluronic acid and the crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid), the ratio of the non-crosslinked hyaluronic acid and crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) is 1: 1.2 to 1: 1.2 in consideration of at least the filler properties. Mixing in a weight ratio of 4.0 is preferred. In the weight ratio (mixing ratio) of the non-crosslinked hyaluronic acid and crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid), when the crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) is less than 1.2 weight ratio, for example, strength such as elasticity It is highly likely to escape from the injected site and may have low persistence in the body. In addition, when the weight ratio of the cross-linked hyaluronic acid (citric acid-cross-linked hyaluronic acid) exceeds 4.0, extrusion of the syringe may be difficult when injected into the skin through a syringe due to a decrease in flexibility. Considering this point, it is more preferable to mix the uncrosslinked hyaluronic acid and the crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) in a weight ratio of 1:1.8 to 3.2.
본 제3단계에서는 본 발명의 필러 조성물 전체 중량 기준으로, 특별히 한정하는 것은 아니지만 상기 비가교 히알루론산은 0.5 ~ 15중량%로 포함되도록 하고, 상기 가교 히알루론산(구연산-가교 히알루론산)은 0.8 ~ 35중량%로 포함되도록 혼합할 수 있다. 각 성분의 함량은 필러 조성물의 피부 적용 부위, 사용방법 및/또는 보관방법 등을 고려하여 적절히 조절될 수 있다. 그리고 나머지 잔량은 첨가제, 물(증류수, 정제수 및 식염수 등) 및 완충액 등이 차지할 수 있다. In the third step, based on the total weight of the filler composition of the present invention, although not particularly limited, the non-crosslinked hyaluronic acid is included in an amount of 0.5 to 15% by weight, and the crosslinked hyaluronic acid (citric acid-crosslinked hyaluronic acid) is 0.8 to 15% by weight. It can be mixed so that it is included in 35% by weight. The content of each component may be appropriately adjusted in consideration of the skin application site of the filler composition, method of use and / or storage method. And the remaining amount may be occupied by additives, water (distilled water, purified water and saline solution, etc.) and buffer solution.
또한, 본 발명의 실시형태에 따라서, 본 제3단계에서는 이소플라본(Isoflavone) 및/또는 비타민 C(Vitamin C) 등을 더 혼합할 수 있다. 이때, 상기 이소플라본과 비타민 C는 필러 조성물 전체 중량 기준으로 각각 0.1 ~ 5중량%로 포함하도록 혼합할 수 있다. In addition, according to an embodiment of the present invention, in the third step, isoflavone and/or vitamin C may be further mixed. In this case, the isoflavones and vitamin C may be mixed to include 0.1 to 5% by weight, respectively, based on the total weight of the filler composition.
상기 이소플라본(isoflavone)은 주로 콩(대두)에 함유된 식물성 에스트로겐(phytoestrogen) 화합물이다. 상기 이소플라본은 본 발명의 필러 조성물에 포함되어, 예를 들어 피부 미백, 노화 방지 및 주름 개선 등을 도모할 수 있다. 상기 이소플라본은 콩(대두)에 함유된 것으로서 제니스테인(genistein), 다이드제인(daidzein), 글리시테인(glycitein), 포르모노네틴(formononetin), 비오카닌 A(biochanin A) 및 에쿠올(equol) 등으로부터 선택된 1종 이상을 사용할 수 있다. The isoflavone is a phytoestrogen compound mainly contained in soybeans (soybeans). The isoflavones may be included in the filler composition of the present invention to, for example, promote skin whitening, anti-aging, and wrinkle improvement. The isoflavones contained in soybeans (soybeans) include genistein, daidzein, glycitein, formononetin, biochanin A, and equol ( equol) and the like may be used.
상기 비타민 C는 면역 기능 향상, 콜라겐의 생성 촉진, 피부 미백, 노화 방지 및 주름 개선 등을 위해 사용된다. 상기 비타민 C는 L-아스코르브산(L-ascorbic acid), 아스코르브산 폴리펩타이드(Ascorbic acid polypeptide), 에틸아스코르빌 에테르(Ethyl ascorbyl ether), 아스코르빌 디팔미테이트(Ascorbyl dipalmitate), 아스코르빌 팔미테이트(Ascorbyl palmitate) 및 아스코르빌 글루코사이드(Ascorbyl glucoside) 등으로부터 선택된 1종 이상을 사용할 수 있다. The vitamin C is used for improving immune function, promoting collagen production, skin whitening, anti-aging, and wrinkle improvement. The vitamin C is L-ascorbic acid, ascorbic acid polypeptide, ethyl ascorbyl ether, ascorbyl dipalmitate, ascorbyl At least one selected from palmitate (Ascorbyl palmitate) and ascorbyl glucoside (Ascorbyl glucoside) may be used.
또한, 본 제3단계에서는 당 업계에서 통상적으로 사용되는 마취제, 완충액, 식염수 및/또는 첨가제 등을 더 혼합하여 필러 조성물을 제조할 수 있다. 상기 마취제는 국소 마취제로서, 예를 들어 리도카인(lidocaine), 암부카인(ambucaine), 아몰라논(amolanone), 아밀로카인(amylocaine), 베녹시네이트(benoxinate) 및/또는 벤조카인(benzocaine) 등으로부터 선택될 수 있으며, 이는 필러 조성물 전체 중량 기준으로 0.01 ~ 2중량%로 포함하도록 혼합할 수 있다. 상기 완충액은, 예를 들어 구연산, 인산일수소나트륨, 인산이수소나트륨, 아세트산, 디에틸바비투르산 및/또는 아세트산 나트륨 등으로부터 선택된 하나 이상을 포함하는 용액을 사용할 수 있으며, 이는 필러 조성물 전체 중량 기준으로 2 ~ 30중량%로 포함하도록 혼합할 수 있다. 상기 첨가제는 글리세린, 아미노산, 산화방지제 및/또는 미네랄 등을 예로 들 수 있으며, 이들은 각각 필러 조성물 전체 중량 기준으로 0.01 ~ 5중량%로 포함하도록 혼합할 수 있다. In addition, in this third step, a filler composition may be prepared by further mixing an anesthetic, buffer, saline, and/or additives commonly used in the art. The anesthetic is a local anesthetic, for example lidocaine, ambucaine, amolanone, amylocaine, benoxinate and/or benzocaine, etc. It may be selected from, which may be mixed to include 0.01 to 2% by weight based on the total weight of the filler composition. The buffer solution may be, for example, a solution containing at least one selected from citric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, acetic acid, diethylbarbituric acid and/or sodium acetate, which is based on the total weight of the filler composition. It can be mixed to include 2 to 30% by weight on a basis. Examples of the additives include glycerin, amino acids, antioxidants, and/or minerals, which may be mixed to include 0.01 to 5% by weight based on the total weight of the filler composition.
이하, 본 발명의 제조예, 실시예 및 비교예를 예시한다. 하기의 제조예 및 실시예는 본 발명의 이해를 돕기 위해 예시적으로 제공되는 것일 뿐, 이에 의해 본 발명의 기술적 범위가 한정되는 것은 아니다. 또한, 하기의 비교예는 종래 기술을 의미하는 것은 아니며, 이는 단지 실시예와의 비교를 위해 제공된다. Hereinafter, production examples, examples and comparative examples of the present invention are illustrated. The following manufacturing examples and examples are provided as examples to aid understanding of the present invention, and the technical scope of the present invention is not limited thereby. In addition, the following comparative examples do not imply the prior art, and are provided only for comparison with the examples.
[제조예] 구연산-가교 히알루론산의 합성 [Production Example] Synthesis of citric acid-crosslinked hyaluronic acid
< 제조예 1 > <Preparation Example 1>
인산염 완충액에 평균 분자량 약 2.8 x 106 Da의 히알루론산(HA)이 용해된 히알루론산 용액(히알루론산(HA)의 농도 약 13.5wt%)을 준비하였다. 또한, 가교제로서 식품 첨가물 등급의 무수 구연산을 준비하였다. 이때, 무수 구연산에 히알루론산을 직접 첨가하게 되면 에스테르 결합이 일어나지 않으므로, 먼저 반응기에 무수 구연산과 물(증류수)을 넣고 혼합 교반하여 구연산을 물에 녹였다. 이후, 반응기의 구연산 수용액에 상기 히알루론산 용액을 넣은 다음, 소량의 차아인산나트륨 수화물(Sodium hypophosphite monohydrate)을 첨가하였다. 히알루론산(HA)과 구연산은 약 1 : 1.4의 중량비로 사용되었다. A hyaluronic acid solution (HA concentration of about 13.5 wt%) in which hyaluronic acid (HA) having an average molecular weight of about 2.8 x 10 6 Da was dissolved in a phosphate buffer was prepared. In addition, anhydrous citric acid of food additive grade was prepared as a crosslinking agent. At this time, when hyaluronic acid is directly added to anhydrous citric acid, an ester bond does not occur. First, anhydrous citric acid and water (distilled water) were put in a reactor and mixed and stirred to dissolve citric acid in water. Thereafter, the hyaluronic acid solution was added to the citric acid aqueous solution in the reactor, and then a small amount of sodium hypophosphite monohydrate was added. Hyaluronic acid (HA) and citric acid were used in a weight ratio of about 1:1.4.
질소기류 하에서 반응기의 온도를 약 84±1℃의 항온으로 유지하고 약 2시간 30분 동안 교반하여 가교화 반응(에스테르화 반응)을 진행하였다. 가교 반응이 진행되는 동안 점도의 증가로 교반이 제대로 이루어지지 않아 초기보다 마그네틱 바(magnetic bar)의 rpm 속도를 높여주며 반응을 진행하였다. 반응 종료 후 겔 상태의 구연산-가교 히알루론산이 생성됨을 확인하였다. 다음으로, 통상과 같은 방법으로 중화와 정제를 진행하여, 구연산-가교 히알루론산을 포함하는 필러 용액을 제조하였다. 첨부된 도 1은 본 제조예에 따라 제조된 구연산-가교 히알루론산 필러 용액의 탈수 및 건조 후 SEM 사진이다. A crosslinking reaction (esterification reaction) was performed by maintaining the temperature of the reactor at a constant temperature of about 84±1° C. under a nitrogen stream and stirring for about 2 hours and 30 minutes. During the crosslinking reaction, stirring was not performed properly due to an increase in viscosity, so the reaction was performed by increasing the rpm speed of the magnetic bar compared to the initial stage. After completion of the reaction, it was confirmed that citric acid-crosslinked hyaluronic acid in a gel state was produced. Next, neutralization and purification were performed in the same manner as usual to prepare a filler solution containing citric acid-crosslinked hyaluronic acid. 1 is a SEM picture after dehydration and drying of the citric acid-crosslinked hyaluronic acid filler solution prepared according to this preparation example.
< 제조예 2 및 3 > <Preparation Examples 2 and 3>
상기 제조예 1과 대비하여, 각 제조예에 따라 히알루론산(HA)과 구연산의 중량비, 반응 온도 및 반응 시간을 달리하여 각 제조예에 따른 겔 제형의 구연산-가교 히알루론산을 포함하는 필러 용액을 제조하였다. 각 제조예에 따른 구연산-가교 히알루론산의 생성 조건을 하기 [표 1]에 나타내었다. Compared to Preparation Example 1, the filler solution containing the citric acid-crosslinked hyaluronic acid of the gel formulation according to each Preparation Example was prepared by varying the weight ratio, reaction temperature and reaction time of hyaluronic acid (HA) and citric acid according to each Preparation Example. manufactured. The production conditions of citric acid-crosslinked hyaluronic acid according to each preparation example are shown in [Table 1] below.
[시험예] [Test Example]
상기 각 제조예에 따른 구연산-가교 히알루론산 필러 용액에 대하여, 통상과 같은 방법으로 레오미터(Rheometer)를 이용하여 1 Hz 주파수에서 탄성 모듈러스(G')와 점도를 측정하였다. 그 결과를 하기 [표 1]에 나타내었다. For the citric acid-crosslinked hyaluronic acid filler solutions according to each preparation example, elastic modulus (G') and viscosity were measured at a frequency of 1 Hz using a rheometer in the same manner as usual. The results are shown in [Table 1] below.
Conditions for producing citric acid-crosslinked hyaluronic acid
Property evaluation result
중량비 Hyaluronic acid: of citric acid
weight ratio
(G')modulus of elasticity
(G')
Preparation Example 1
Preparation Example 2
Preparation Example 3
상기 [표 1]에 보인 바와 같이, 구연산-가교 히알루론산 필러 용액은 반응에 사용된 히알루론산과 구연산의 중량비(혼합 비율), 반응 온도 및 반응 시간 등의 생성 조건에 따라 물성(탄성 모듈러스(G') 및 점도)이 달라짐을 알 수 있었다. 먼저, 제조예 1과 같은 탄성 모듈러스(G') 및 점도는 필러 특성에 적합한 수치를 나타낸다. 반면에, 반응 온도가 높고 반응 시간이 긴 경우(제조예 2)에는 점도가 과도하게 높아짐을 알 수 있었다. 또한, 반응 온도가 낮은 경우(제조예 3), 가교 반응이 제대로 진행되지 않아 탄성 모듈러스(G')가 매우 낮고, 점도의 경우에도 매우 낮게 평가됨을 알 수 있었다. As shown in [Table 1], the citric acid-crosslinked hyaluronic acid filler solution has physical properties (elastic modulus (G ') and viscosity) were found to be different. First, elastic modulus (G ') and viscosity as in Preparation Example 1 represent values suitable for filler properties. On the other hand, it was found that the viscosity was excessively increased when the reaction temperature was high and the reaction time was long (Preparation Example 2). In addition, when the reaction temperature was low (Preparation Example 3), it was found that the crosslinking reaction did not proceed properly, so that the elastic modulus (G') was very low and the viscosity was also evaluated very low.
[실시예 1] [Example 1]
질소기류 하에서 교반기가 달린 밀폐 용기에 제1필러로서 히알루론산 용액(히알루론산(HA)의 농도 약 13.5wt%)을 넣고, 여기에 제2필러로서 상기 제조예 1에 따라 제조된 구연산-가교 히알루론산 필러 용액을 투입하였다. 이때, 제1필러로서의 히알루론산 용액(비가교 히알루론산)과 제2필러로서의 구연산-가교 히알루론산 필러 용액은 약 1 : 2의 중량비로 사용되었다. 이후, 제니스테인을 주성분으로 하는 이소플라본 용액(독일 BASF사 제품), L-아스코르브산(비타민 C 제품) 및 리도카인을 첨가하고 약 32℃에서 혼합하였다. 이어서, 멸균 처리한 후 기포를 제거하여 본 실시예에 따른 필러 조성물을 제조하였다. A hyaluronic acid solution (having a hyaluronic acid (HA) concentration of about 13.5 wt%) was placed as a first filler in an airtight container equipped with a stirrer under a nitrogen stream, and the citric acid-crosslinked hyaluronic acid prepared according to Preparation Example 1 was used as a second filler therein. The Lonic acid filler solution was added. At this time, the hyaluronic acid solution (non-crosslinked hyaluronic acid) as the first filler and the citric acid-crosslinked hyaluronic acid filler solution as the second filler were used in a weight ratio of about 1:2. Thereafter, an isoflavone solution containing genistein as a main component (product of BASF, Germany), L-ascorbic acid (vitamin C product), and lidocaine were added and mixed at about 32°C. Then, after sterilization, air bubbles were removed to prepare a filler composition according to this embodiment.
[비교예 1] [Comparative Example 1]
상기 실시예 1과 대비하여, 제2필러(구연산-가교 히알루론산 필러 용액)를 혼합하지 않은 것을 본 비교예에 따른 시편으로 사용하였다. In contrast to Example 1, a sample in which the second filler (citric acid-crosslinked hyaluronic acid filler solution) was not mixed was used as a specimen according to this comparative example.
[비교예 2] [Comparative Example 2]
상기 실시예 1과 대비하여, 제1필러(히알루론산 용액)를 혼합하지 않고, 제2필러로는 제조예 2에 따라 제조된 구연산-가교 히알루론산 필러 용액을 사용한 것을 본 비교예에 따른 시편으로 사용하였다. In contrast to Example 1, the first filler (hyaluronic acid solution) was not mixed, and the citric acid-crosslinked hyaluronic acid filler solution prepared according to Preparation Example 2 was used as the second filler as a specimen according to this comparative example. used
상기 각 실시예 및 비교예에 따른 필러 조성물에 대하여, 상기와 동일한 방법으로 탄성 모듈러스(G')와 점도를 측정하였다. 또한, 각 필러 조성물을 주사기에 충전한 후, 압출력을 평가하였다. 이때, 압출력은 주사기를 손으로 눌렀을 때, 필러 조성물의 압출 정도(힘이 드는 정도)로 평가하였다. 그 결과를 하기 [표 2]에 나타내었다. With respect to the filler composition according to each of the Examples and Comparative Examples, elastic modulus (G ') and viscosity were measured in the same manner as described above. In addition, after each filler composition was filled into a syringe, the extrusion force was evaluated. At this time, the extrusion force was evaluated by the degree of extrusion (force) of the filler composition when the syringe was pressed by hand. The results are shown in [Table 2] below.
(G')modulus of elasticity
(G')
압출력by syringe
extrusion force
(제조예 1)Example 1
(Production Example 1)
Comparative Example 1
(제조예 2)Comparative Example 2
(Production Example 2)
상기 [표 2]에 보인 바와 같이, 실시예 1에 따른 필러 조성물은 선형의 비가교 히알루론산(제1필러)과 구연산-가교 히알루론산(제2필러)의 혼합을 포함하여, 필러 특성에 유리한 물성을 가지면서 적절한 유연성을 가져 주사기에 의한 압출이 적절함을 알 수 있었다. As shown in [Table 2], the filler composition according to Example 1 includes a mixture of linear non-crosslinked hyaluronic acid (first filler) and citric acid-crosslinked hyaluronic acid (second filler), which is advantageous in filler properties. It was found that extrusion by a syringe was appropriate because it had appropriate flexibility while having physical properties.
Claims (6)
(1) 히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산을 준비하는 제1단계;
(2) 히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산과 가교제를 반응시켜, 히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산이 가교제에 의해 가교 결합된 가교 히알루론산을 생성하는 제2단계; 및
(3) 상기 제1단계에서 준비된 비가교 히알루론산과 상기 제2단계에서 생성된 가교 히알루론산을 혼합하는 제3단계를 포함하고,
상기 제2단계에서는, 상기 가교제로서 구연산을 사용하되, 상기 히알루론산 및 히알루론산염으로부터 선택된 하나 이상의 비가교 히알루론산과 상기 구연산을 1 : 0.5 ~ 2.0의 중량비로 포함하는 반응물을 차아인산염(hypophosphite)의 존재 하에서 80℃ ~ 95℃의 온도에서 2시간 ~ 4시간 동안 에스테르화 가교 반응시켜 구연산-가교 히알루론산 겔을 생성하며,
상기 제3단계에서는, 상기 제1단계에서 준비된 비가교 히알루론산과 상기 제2단계에서 생성된 구연산-가교 히알루론산 겔을 1 : 1.2 ~ 4.0의 중량비로 혼합하는 것을 특징으로 하는 피부 필러 조성물의 제조방법.
A method for producing a dermal filler composition that is injected into the skin through a syringe to contribute to wrinkle improvement and shape formation of the skin,
(1) a first step of preparing at least one non-crosslinked hyaluronic acid selected from hyaluronic acid and hyaluronic acid salts;
(2) Reacting at least one non-crosslinked hyaluronic acid selected from hyaluronic acid and salts with a crosslinking agent to produce crosslinked hyaluronic acid in which at least one noncrosslinked hyaluronic acid selected from hyaluronic acid and salts is crosslinked by a crosslinking agent Step 2; and
(3) a third step of mixing the uncrosslinked hyaluronic acid prepared in the first step and the crosslinked hyaluronic acid produced in the second step;
In the second step, citric acid is used as the crosslinking agent, but hypophosphite is a reactant containing at least one non-crosslinked hyaluronic acid selected from hyaluronic acid and hyaluronate salts and the citric acid in a weight ratio of 1:0.5 to 2.0. Esterification cross-linking reaction at a temperature of 80 ℃ ~ 95 ℃ in the presence of 2 hours ~ 4 hours to produce a citric acid-crosslinked hyaluronic acid gel,
In the third step, preparation of a dermal filler composition characterized in that the uncrosslinked hyaluronic acid prepared in the first step and the citric acid-crosslinked hyaluronic acid gel produced in the second step are mixed in a weight ratio of 1: 1.2 to 4.0. Way.
상기 제2단계에서는, 반응기에 구연산과 물을 넣고 혼합하여 구연산 수용액을 얻은 후, 상기 반응기의 구연산 수용액에 비가교 히알루론산 용액을 넣고, 여기에 상기 구연산 100중량에 대하여 차아인산염(hypophosphite) 0.5 ~ 10중량부를 더 첨가한 다음, 상기 반응기의 온도를 80℃ ~ 95℃로 유지하고 2시간 ~ 4시간 동안 교반을 진행하면서 에스테르화 가교 반응시켜, 상기 비가교 히알루론산과 구연산이 에스테르 결합을 가지는 구연산-가교 히알루론산 겔을 생성하며,
상기 제3단계에서는, 이소플라본 및 비타민 C를 더 혼합하는 것을 특징으로 하는 피부 필러 조성물의 제조방법.
According to claim 1,
In the second step, after mixing citric acid and water in a reactor to obtain an aqueous solution of citric acid, a solution of uncrosslinked hyaluronic acid is added to the aqueous solution of citric acid in the reactor, and 0.5 to 0.5 to hypophosphite based on 100 weight of the citric acid is added thereto. After adding 10 parts by weight, an esterification cross-linking reaction was performed while maintaining the temperature of the reactor at 80 ° C. to 95 ° C. and stirring for 2 to 4 hours, so that the uncrosslinked hyaluronic acid and citric acid had an ester bond. - creates a cross-linked hyaluronic acid gel,
In the third step, isoflavone and vitamin C are further mixed, characterized in that the manufacturing method of the dermal filler composition.
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| KR102649054B1 (en) * | 2023-04-20 | 2024-03-19 | 주식회사 큐에이치바이오 | Dermal filler composition containing hyaluronic acid cross-linked by epichlorohydrin and biocompatible micro particles, and method for preparing the same |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010032398A (en) * | 1997-11-25 | 2001-04-16 | 로날드 디. 맥크레이 | Absorbent Foam |
| KR20130139305A (en) * | 2010-11-08 | 2013-12-20 | 알러간 인더스트리 에스에이에스 | Hyaluronic acid based formulations |
| KR20170117368A (en) | 2014-11-13 | 2017-10-23 | 메르츠 파마 게엠베하 운트 코. 카가아 | Dermal filler based on crosslinked hyaluronic acid and carboxymethyl cellulose lubricant |
| KR101879065B1 (en) * | 2016-12-12 | 2018-07-17 | 구태훈 | Filler for soft tissue having particles of bead type and, manufacturing methods for the same |
| KR20190070343A (en) * | 2016-10-13 | 2019-06-20 | 알레간 인코포레이티드 | Coacervate hyaluronan hydrogel for dermal filler application |
| US20190269597A1 (en) * | 2016-11-11 | 2019-09-05 | Anteis S.A. | Hyaluronic acid dermal fillers crosslinked with citric acid, method for making same and uses thereof |
| KR102051467B1 (en) * | 2019-06-12 | 2019-12-03 | 박상준 | Skin filler composition and method for manufacturing the same |
| KR102334794B1 (en) | 2018-12-20 | 2021-12-03 | 주식회사 엘지화학 | Filler with superior filler properties comprising hyaluronic acid hydrogel |
-
2022
- 2022-03-16 KR KR1020220032917A patent/KR102485144B1/en active IP Right Grant
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010032398A (en) * | 1997-11-25 | 2001-04-16 | 로날드 디. 맥크레이 | Absorbent Foam |
| KR20130139305A (en) * | 2010-11-08 | 2013-12-20 | 알러간 인더스트리 에스에이에스 | Hyaluronic acid based formulations |
| KR20170117368A (en) | 2014-11-13 | 2017-10-23 | 메르츠 파마 게엠베하 운트 코. 카가아 | Dermal filler based on crosslinked hyaluronic acid and carboxymethyl cellulose lubricant |
| KR20190070343A (en) * | 2016-10-13 | 2019-06-20 | 알레간 인코포레이티드 | Coacervate hyaluronan hydrogel for dermal filler application |
| US20190269597A1 (en) * | 2016-11-11 | 2019-09-05 | Anteis S.A. | Hyaluronic acid dermal fillers crosslinked with citric acid, method for making same and uses thereof |
| KR101879065B1 (en) * | 2016-12-12 | 2018-07-17 | 구태훈 | Filler for soft tissue having particles of bead type and, manufacturing methods for the same |
| KR102334794B1 (en) | 2018-12-20 | 2021-12-03 | 주식회사 엘지화학 | Filler with superior filler properties comprising hyaluronic acid hydrogel |
| KR102051467B1 (en) * | 2019-06-12 | 2019-12-03 | 박상준 | Skin filler composition and method for manufacturing the same |
Non-Patent Citations (1)
| Title |
|---|
| 성은진 et al., "주름 치료의 한의학적 고찰." 한방안이비인후피부과학회지 (2008), 제21권 제3호, pp. 184-199* * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102649054B1 (en) * | 2023-04-20 | 2024-03-19 | 주식회사 큐에이치바이오 | Dermal filler composition containing hyaluronic acid cross-linked by epichlorohydrin and biocompatible micro particles, and method for preparing the same |
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