KR20100000917A - Complex of antioxidant and chitosan having improved stability - Google Patents

Complex of antioxidant and chitosan having improved stability Download PDF

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KR20100000917A
KR20100000917A KR1020080060599A KR20080060599A KR20100000917A KR 20100000917 A KR20100000917 A KR 20100000917A KR 1020080060599 A KR1020080060599 A KR 1020080060599A KR 20080060599 A KR20080060599 A KR 20080060599A KR 20100000917 A KR20100000917 A KR 20100000917A
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antioxidant
acid
chitosan
reaction
chitosan complex
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KR101123366B1 (en
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김철환
조군호
신찬재
고승학
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(주)바이오제닉스
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716Glucans
    • A61K31/722Chitin, chitosan
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73Polysaccharides
    • A61K8/736Chitin; Chitosan; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00Preparations for use in therapy

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  • Animal Behavior & Ethology (AREA)
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  • Cosmetics (AREA)
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Abstract

PURPOSE: An antioxidant-chitosan complex is provided to enhance stability of the antioxidant in aqueous media and minimize denaturation of the antioxidant by temperature, light ray, oxygen, and water. CONSTITUTION: An antioxidant-chitosan complex is produced by reacting chitosan with α-lipoic acid or glutathione antioxidant and chitosan under the presence of 3-dimethyl-aminopropyl-N-ethylcarbodimide. The reaction is performed under the presence of N-hydroxysucciinimide and acid as catalyst. A method for producing the antioxidant-chitosan complex comprises: a step of reacting the antioxidant and succinic acid under the presence of 3-dimethyl-aminopropyl-N-ethyl carbodimide; and a step of reacting the 3-antioxidant-carbonyl propanoic acid and chitosan under the presence of 3-dimethyl-aminopropyl-N-ethyl carbodimide. The antioxidant is coenzyme Q10, α-tocopherol, retinol, ascorbic acid, or butylated hydroxy toluene.

Description

우수한 안정성을 갖는 항산화제와 키토산과의 복합체{Complex of antioxidant and chitosan having improved stability}Complex of antioxidant and chitosan having improved stability

본 발명은 항산화제와 키토산과의 복합체에 관한 것으로, 더욱 상세하게는 항산화제를 키토산에 직접 커플링시키거나 숙산산 등의 링커를 매개로 결합시켜 제조된 복합체(complex)에 관한 것으로, 상기 항산화제-키토산 복합체는 항산화제의 안정성을 효과적으로 증가시킬 뿐만 아니라, 항산화제의 변취 현상을 차단할 수 있어, 의약 조성물 및 화장료 조성물에 유용하게 적용될 수 있다.The present invention relates to a complex of an antioxidant and chitosan, and more particularly, to a complex prepared by directly coupling an antioxidant to chitosan or by linking a linker such as succinic acid. The zeo-chitosan complex not only effectively increases the stability of the antioxidant, but can also block the odor of the antioxidant, and thus can be usefully applied to the pharmaceutical composition and the cosmetic composition.

의약 조성물 및/또는 화장료 조성물은 다양한 항산화제를 포함한다. 상기 항산화제로는 α-리포산, 코엔자임 Q10, α-토코페롤, 레티놀, 글루타치온, 아스코르브산, 부틸화 히드록시 톨루엔(butylated hydroxy toluene), 제니스테인(genistein), 큐세틴, 프로필 갈레이트, 에피갈로카테킨 갈레이트, 갈로카테킨 갈레이트, 실리빈, 디오스메틴, 캠퍼롤, 에피카테킨, 갈란긴 등의 다양한 화합물이 알려져 있다.Pharmaceutical compositions and / or cosmetic compositions include various antioxidants. The antioxidants include α-lipoic acid, coenzyme Q10, α-tocopherol, retinol, glutathione, ascorbic acid, butylated hydroxy toluene, genistein, cucetin, propyl gallate, epigallocatechin gallate Various compounds are known, such as late, gallocatechin gallate, silybin, diosmethin, camphorol, epicatechin, galangin and the like.

예를 들어, 글루타티온 포유류와 식물조직의 호흡에 중요한 역할을 하며, 여러 신진대사 반응과정 중에 발생하는 유해한 부산물인 과산화수소를 물로 환원시켜 서 적혈구를 보호하고, 다양한 효소들의 보조인자로 작용하여 면역세포의 재생에 관여한다. 노인에 있어서, 글루타티온을 하루에 75 mg씩 섭취할 경우, 면역세포의 활동성이 크게 증가한다고 보고된 바 있다. 코엔자임 Q10은 미토콘드리아가 에너지를 만드는 것을 도와주는 보조효소로서, 항바이러스, 항균, 항암 활성을 비롯한 다양한 약리 작용이 보고된 바 있다. 또한, 토코페롤은 혈액 내 산소의 증가를 돕고 혈액의 순환을 개선하며, 동맥경화를 막아 혈관의 탄력을 유지시켜주고 혈액의 응고를 막아주므로 심혈관질환 등의 질환의 예방 및 치료 활성이 보고된 바 있다.For example, glutathione plays an important role in the respiration of mammals and plant tissues, protects red blood cells by reducing hydrogen peroxide, a harmful by-product that occurs during various metabolic reactions, into water, and acts as a cofactor for various enzymes to regenerate immune cells. To get involved. In the elderly, 75 mg of glutathione per day has been reported to significantly increase the activity of immune cells. Coenzyme Q10 is a coenzyme that helps mitochondria create energy. It has been reported to have various pharmacological actions including antiviral, antibacterial and anticancer activity. In addition, tocopherol helps increase oxygen in blood, improves blood circulation, prevents arteriosclerosis, maintains elasticity of blood vessels and prevents blood coagulation, and has been reported to prevent and treat diseases such as cardiovascular diseases. .

한편, 항산화제는 단독으로 존재할 경우, 안정성 특시 수성 매질에서의 안정성이 낮아 쉽게 변성(예를 들어, 환원)되는 문제가 있고, 항산화제에 따라서는 역한 냄새의 발생 즉, 변취 문제가 발생한다. On the other hand, when the antioxidants are present alone, there is a problem that the stability in a special aqueous medium is low, such as easily denatured (for example, reduced), depending on the antioxidants, the generation of inverse odor, that is, the problem of smell.

예를 들어, 인체의 면역 기능을 높여주고, 혈당을 저하시키며, 식욕을 억제하는 등의 다양한 약리효과를 갖는 것으로 알려져 있는 α-리포산의 경우, 쉽게 환원되어 디히드로리포산이 생성됨으로써, 역한 냄새가 발생하는 문제가 있다. 이러한 문제점을 해결하기 위하여, 리포좀을 이용하여 캡슐화하는 것이 제시된 바 있으나, 과량의 α-리포산을 캡슐화하는 것이 매우 곤란한 문제가 있다.For example, α-lipoic acid, which is known to have various pharmacological effects such as enhancing the body's immune function, lowering blood sugar, and suppressing appetite, is easily reduced to produce dihydrolipoic acid, thereby causing an adverse smell. There is a problem that occurs. In order to solve this problem, encapsulation using liposomes has been proposed, but it is very difficult to encapsulate an excess of α-lipoic acid.

또한, 대표적인 항산화제로 알려져 있는 아스코르브산의 경우, Y-락톤과 유사한 구조를 가짐으로써 공기, 특히 산소와 열, 빛 등의 외부환경에 민감하게 반응하여 쉽게 분해되는 문제점을 가지고 있다. 아스코르브산의 안정성 문제를 해결하기 위한 방안으로서, 산화방지제를 첨가하거나, 다중 유화물 중에 안정화시키는 방법, 수중 유형의 유화물에 안정화시키는 방법, 황산아연과 L-티로신을 함께 사용하 여 아스코르브산의 산화를 억제하는 방법 등이 제시된 바 있다(미국특허 제4,938,969호, 유럽특허공개 제533,667 B1호 등). 이외에도, 아스코르브산의 안정성을 향상시키기 위하여, 소듐 아스코르빌포스페이트(Sodium ascorbylphosphate), 마그네슘 아스코르빌 포스페이트(Magnesium ascorbyl phosphate), 칼슘 아스코르빌포스페이트(Calsium ascorbylphosphate), 아스코르브산 폴리펩티드(Ascorbic acid polypeptide), 에틸 아스코르빌 에테르(Ethyl ascorbyl ether), 아스코르빌 디팔미테이트(Ascorbyl dipalmitate), 아스코르빌 팔미테이트 (Ascorbyl palmitate), 아스코르빌 글루코사이드(Ascorbyl glucoside), 아스코르빌 에틸실라놀 펙티네이트(Ascorbyl ethylsilanol pectinate) 등의 유도체로 변형시킨 예가 보고된 바 있다.In addition, ascorbic acid, which is known as a representative antioxidant, has a structure similar to Y-lactone, and thus has a problem of being easily decomposed by reacting sensitively to external environments such as air, especially oxygen, heat, and light. As a solution to the problem of ascorbic acid stability, oxidation of ascorbic acid can be achieved by adding antioxidants, stabilizing in multiple emulsions, stabilizing in oil-based emulsions, and using zinc sulfate and L-tyrosine together. Inhibitors have been proposed (US Pat. No. 4,938,969, EP 553,667 B1, etc.). In addition, to improve the stability of ascorbic acid, sodium ascorbylphosphate, sodium ascorbyl phosphate, magnesium ascorbylphosphate, calcium ascorbylphosphate, and ascorbic acid polypeptide , Ethyl ascorbyl ether, ascorbyl dipalmitate, ascorbyl palmitate, ascorbyl glucoside, ascorbyl glucoside, ascorbyl ethylsilanol pectinate Examples of modifications with derivatives such as Ascorbyl ethylsilanol pectinate have been reported.

본 발명자들은 α-리포산, 글루타치온, 아스코르브산 등을 비롯한 다양한 항산화제의 안정성 특히 수성 매질에서의 안정성을 증가시킬 수 있는 방법을 개발하고자 다양한 연구를 수행하였다. 그 결과, 항산화제를 키토산과 함께 복합체(complex) 형태로 제조하였을 때, 얻어지는 항산화제-키토산 복합체가 우수한 안정성을 가질 뿐만 아니라 항산화제의 변취 문제를 근본적으로 차단할 수 있다는 것을 발견하였다. 또한, 상기 항산화제-키토산 복합체는 생체 내 환경(예를 들어, 산성 pH를 갖는 위장) 또는 피부 조직 내에서 항산화제-키토산 복합체가 분해되어 항산화제 및 키토산으로 존재할 수 있으므로, 항산화제와의 상승(synergy) 효과, 예를 들어 미백, 노화방지, 피부보호, 주름개선, 피부 보습 등의 약리효과에 있어서 상승 효과를 기대할 수 있음을 발견하였다. The inventors have conducted various studies to develop a method that can increase the stability of various antioxidants, including α-lipoic acid, glutathione, ascorbic acid and the like, especially in aqueous media. As a result, when the antioxidant was prepared in complex form with chitosan, it was found that the obtained antioxidant-chitosan complex not only has excellent stability but also can fundamentally block the problem of the deodorant of the antioxidant. In addition, since the antioxidant-chitosan complex may be present as an antioxidant and chitosan by decomposing the antioxidant-chitosan complex in a living environment (for example, a gastrointestinal acid having an acidic pH) or in skin tissue, the antioxidant-chitosan complex may be elevated. It has been found that synergistic effects can be expected in the pharmacological effects such as synergy effects, for example, whitening, anti-aging, skin protection, wrinkle improvement, and skin moisturizing.

따라서, 본 발명은 항산화제 및 키토산의 복합체를 제공하는 것을 목적으로 한다.Accordingly, the present invention aims to provide a complex of an antioxidant and chitosan.

본 발명의 일 태양에 따라, α-리포산 및 글루타치온으로 이루어진 군으로부터 선택된 항산화제와 키토산을, 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서, 반응시키는 단계를 포함하는 제조방법으로 얻어진 항산화제-키토산 복합체가 제공된다.According to an aspect of the present invention, an antioxidant selected from the group consisting of α-lipoic acid and glutathione and chitosan are obtained by a process comprising the step of reacting in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide. Antioxidant-chitosan complexes are provided.

상기 반응은 촉매로서 N-히드록시숙신이미드 및 산 존재하에서 바람직하게 수행될 수 있으며, 상기 산은 아세트산, 설폰산, 황산, 또는 인산 등을 포함한다. 또한, 상기 반응을 수행한 후, 반응 혼합물로부터 분리한 침전물을 물에 분산시키고 분자량 컷-오프 2,000 ∼ 10,000, 더욱 바람직하게는 분자량 컷-오프 약 2 000의 반투막으로 여과한 다음, 건조하는 단계를 추가로 포함할 수 있다.The reaction may preferably be carried out in the presence of N-hydroxysuccinimide and an acid as a catalyst, the acid including acetic acid, sulfonic acid, sulfuric acid, phosphoric acid and the like. Further, after performing the reaction, the precipitate separated from the reaction mixture is dispersed in water and filtered through a semipermeable membrane having a molecular weight cut-off of 2,000 to 10,000, more preferably molecular weight cut-off of about 2 000, followed by drying. It may further comprise.

본 발명의 다른 태양에 따라, (a) 코엔자임 Q10, α-토코페롤, 레티놀, 아스코르브산, 부틸화 히드록시 톨루엔(butylated hydroxy toluene), 제니스테인(genistein), 큐세틴, 프로필 갈레이트, 에피갈로카테킨 갈레이트, 갈로카테킨 갈레이트, 실리빈, 디오스메틴, 캠퍼롤, 에피카테킨, 및 갈란긴으로 이루어진 군으로부터 1종 이상 선택된 항산화제과 숙신산을 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서 반응시켜 3-항산화제-카르보닐 프로파논산을 제조하는 단계; 및 (b) 단계(a)에서 얻어진 3-항산화제-카르보닐 프로파논산과 키토산을 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서 반응시키는 단계를 포함하는 제조방법으로 얻어진 항산화제-키토산 복합체가 제공된다.According to another aspect of the invention, (a) coenzyme Q10, α-tocopherol, retinol, ascorbic acid, butylated hydroxy toluene, genistein, cucetin, propyl gallate, epigallocatechin Reaction of succinic acid with at least one antioxidant selected from the group consisting of gallate, gallocatechin gallate, silibine, diosmethine, camphorol, epicatechin, and galangin in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide To prepare 3-antioxidant-carbonyl propanoic acid; And (b) reacting the 3-antioxidant-carbonyl propanoic acid and chitosan obtained in step (a) in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide. A chitosan complex is provided.

상기 항산화제는 레티놀, 코엔자임 Q10, α-토코페롤, 또는 아스코르브산인 것인 것이 더욱 바람직다. 단계(a)의 상기 반응은 디메틸아미노피리딘, 트리에틸아민, 및 이소프로필에틸아민으로 이루어진 군으로부터 선택된 염기 존재하에서 바람직하게 수행될 수 있다. 단계(b)의 상기 반응은 촉매로서 N-히드록시숙신이미드 및 산 존재하에서 바람직하게 수행될 수 있으며, 상기 산은 아세트산, 설폰산, 황산, 또는 인산 등을 포함한다. 또한, 단계(b)의 반응을 수행한 후, 반응 혼합물로부터 분리한 침전물을 물에 분산시키고 분자량 컷-오프 2,000 ∼ 10,000, 더욱 바람직하 게는 분자량 컷-오프 약 2 000의 반투막으로 여과한 다음, 건조하는 단계를 추가로 포함할 수 있다.More preferably, the antioxidant is retinol, coenzyme Q10, α-tocopherol, or ascorbic acid. The reaction of step (a) may preferably be carried out in the presence of a base selected from the group consisting of dimethylaminopyridine, triethylamine, and isopropylethylamine. The reaction of step (b) may preferably be carried out in the presence of N-hydroxysuccinimide and an acid as a catalyst, the acid comprising acetic acid, sulfonic acid, sulfuric acid, phosphoric acid and the like. Further, after carrying out the reaction of step (b), the precipitate separated from the reaction mixture is dispersed in water and filtered through a semipermeable membrane having a molecular weight cut-off of 2,000 to 10,000, more preferably molecular weight cut-off of about 2 000. It may further comprise the step of drying.

본 발명에 따른 항산화제-키토산 복합체는 항산화제의 수성 매질에서의 안정성을 효과적으로 증가시킴으로써, 수성 조성물에 장시간 동안 보존하더라도 온도, 광선, 산소 및 물 등 환경에 의한 변성을 최소화할 수 있다. 특히, α-리포산과 같은 항산화제를 본 발명에 따라 키토산과의 복합체로 제조할 경우, 항산화제의 변성(예를 들어, 환원)으로 인한 역한 냄새의 발생 즉, 변취 문제를 근본적으로 차단할 수 있다. 또한, 키토산은 무독성, 생분해성, 생체-적합성을 갖는 물질로서, 생체 내 환경(예를 들어, 산성 pH를 갖는 위장) 또는 피부 조직 내에서 항산화제-키토산 복합체가 분해되어 항산화제 및 키토산으로 존재할 수 있으므로, 항산화제와의 상승(synergy) 효과, 예를 들어 미백, 노화방지, 피부보호, 주름개선, 피부 보습 등의 약리효과에 있어서 상승 효과를 기대할 수 있다. 따라서, 본 발명에 따른 항산화제-키토산 복합체는 의약 조성물 및 화장료 조성물에 유용하게 적용될 수 있다.The antioxidant-chitosan complex according to the present invention effectively increases the stability of the antioxidant in the aqueous medium, thereby minimizing the alteration caused by the environment such as temperature, light, oxygen and water even if stored in the aqueous composition for a long time. In particular, when an antioxidant such as α-lipoic acid is prepared in a complex with chitosan according to the present invention, it is possible to fundamentally block the occurrence of inverse odor due to degeneration (eg, reduction) of the antioxidant, that is, the problem of malodor. . In addition, chitosan is a non-toxic, biodegradable, bio-compatible material, in which the antioxidant-chitosan complexes are degraded and present as antioxidants and chitosan in vivo environment (e.g., gastrointestinal tract with acidic pH) or skin tissue. As a result, synergistic effects with antioxidants, for example, whitening, anti-aging, skin protection, anti-wrinkle, skin moisturizing effect can be expected synergistic effect. Therefore, the antioxidant-chitosan complex according to the present invention can be usefully applied to pharmaceutical compositions and cosmetic compositions.

본 발명은 α-리포산 및 글루타치온으로 이루어진 군으로부터 선택된 항산화제와 키토산을, 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서, 반응시키는 단계를 포함하는 제조방법으로 얻어진 항산화제-키토산 복합체를 제공한다.The present invention provides an antioxidant-chitosan complex obtained by a process comprising reacting an antioxidant selected from the group consisting of α-lipoic acid and glutathione with chitosan in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide. To provide.

본 발명의 항산화제-키토산 복합체 제조에 사용되는 상기 키토산은 N-아세틸 -글루코사민 단위체가 산소를 매개로 연결된 키틴(화학식 1의 구조식 참조)을 탈아세틸화시켜 얻어진 고분자(화학식 2의 구조식 참조)로서 생분해성 및 생체-적합성의 성질을 갖는다.The chitosan used in the preparation of the antioxidant-chitosan complex of the present invention is a polymer obtained by deacetylating chitin (see Structural Formula of Formula 1) in which an N-acetyl-glucosamine unit is oxygen-linked (see Structural Formula of Formula 2). Biodegradable and bio-compatible.

Figure 112008045884506-PAT00001
Figure 112008045884506-PAT00001

Figure 112008045884506-PAT00002
Figure 112008045884506-PAT00002

키토산은 상기 탈아세틸화 정도 및/또는 글루코사민 단위체의 중합도에 따라 다양한 형태로 존재할 수 있으며, 본 발명에 따른 항산화제-키토산 복합체의 제조에 사용되는 상기 키토산의 탈아세틸화 정도 및 중량평균분자량은 크게 제한되는 것이 아니다. 바람직하게는 키토산의 탈아세틸화 정도는 40 ∼ 90 %의 범위, 더욱 바람직하게는 70 ∼ 90 % 일 수 있으며, 중량평균분자량은 200 kDa ∼ 600 kDa, 더욱 바람직하게는 약 300 kDa 일 수 있다.Chitosan may exist in various forms according to the degree of deacetylation and / or the degree of polymerization of the glucosamine unit, and the degree of deacetylation and weight average molecular weight of the chitosan used in the preparation of the antioxidant-chitosan complex according to the present invention is large. It is not limited. Preferably, the degree of deacetylation of chitosan may be in the range of 40 to 90%, more preferably 70 to 90%, and the weight average molecular weight may be 200 kDa to 600 kDa, more preferably about 300 kDa.

키토산은 장내 담즙산의 흡수를 억제할 뿐만 아니라 담즙산의 농도를 떨어뜨리고 혈전을 용해시켜 동맥경화, 심장병, 뇌졸증 및 돌연사를 예방할 수 있고, 지 방을 흡착시켜 식사 후 지방의 흡수량을 저하시키며, 아울러 혈관 중의 지방질 여분을 흡착하여 체외로 배출시키므로 다이어트에도 유용한 것으로 알려져 있다. 또한, 장내의 염소를 흡수하여 체외로 배출시켜 고혈압의 발생을 예방하고, 장내 유익균의 번식을 촉진시키며 유해균의 자생을 억제하여 영양의 흡수를 증진시키며 소화기능을 개선시키는 것을 알려져 있다. 또한, 키토산은 항암효과, 면역 세포의 저항력 증가, 대장 및 혈관의 유해물질 흡착에 의한 성인병 예방 효과도 갖는 것으로 알려져 있다. Chitosan not only inhibits the absorption of bile acids in the intestine, but also lowers the concentration of bile acids and dissolves blood clots to prevent atherosclerosis, heart disease, stroke and sudden death. It is known to be useful for diet because it absorbs excess fat in the body and discharges it out of the body. In addition, it is known to absorb chlorine in the intestine and discharge it to the outside to prevent the occurrence of high blood pressure, promote the growth of enteric beneficial bacteria, inhibit the growth of harmful bacteria to promote the absorption of nutrients and improve digestive function. In addition, chitosan is known to have an anticancer effect, increase the resistance of immune cells, and prevent adult diseases by adsorption of harmful substances in the large intestine and blood vessels.

상기 항산화제와 키토산과의 반응은 커플링화제 즉, 3-디메틸-아미노프로필-N-에틸 카보디이미드를 사용하여 수행된다. 상기 항산화제는 테트라히드로퓨란, 디메틸포름아미드 등의 유기용매에 용해시켜 가할 수 있다. 상기 커플링 반응은 촉매로서 N-히드록시숙신이미드 및 산 존재하에서 바람직하게 수행될 수 있고, 상기 산은 아세트산, 설폰산, 황산, 또는 인산 등을 포함하며, 바람직하게는 아세트산을 사용할 수 있다. 또한, 상기 커플링 반응은 20 ℃ 내지 약 50 ℃ 범위, 더욱 바람직하게는 실온(약 25 ℃)에서 수행함으로써 α-리포산 등의 항산화제가 중합체를 형성하는 것을 방지할 수 있다.The reaction of the antioxidant with chitosan is carried out using a coupling agent, i.e. 3-dimethyl-aminopropyl-N-ethyl carbodiimide. The antioxidant can be added by dissolving in an organic solvent such as tetrahydrofuran, dimethylformamide and the like. The coupling reaction may be preferably carried out in the presence of N-hydroxysuccinimide and an acid as a catalyst, and the acid may include acetic acid, sulfonic acid, sulfuric acid, phosphoric acid, and the like, preferably acetic acid. In addition, the coupling reaction may be performed at a temperature of 20 ° C. to about 50 ° C., more preferably at room temperature (about 25 ° C.) to prevent antioxidants such as α-lipoic acid from forming polymers.

상기 항산화제와 키토산의 당량비는, 키토산의 탈아세틸화 정도에 따라 상이할 수 있으나, 키토산 1 당량에 대하여 항산화제 0.5 ∼ 1.5 당량, 더욱 바람직하게는 0.9 ∼ 1 당량의 범위로 사용하는 것이 미반응의 항산화제(예를 들어 α-리포산)를 남기지 않을 수 있어 정제가 용이하다.Although the equivalent ratio of the antioxidant and chitosan may vary depending on the degree of deacetylation of chitosan, it is unreacted to use 0.5 to 1.5 equivalents, more preferably 0.9 to 1 equivalents, of antioxidant per 1 equivalent of chitosan. May not leave an antioxidant (for example, α-lipoic acid), thereby facilitating purification.

상기와 같이 커플링 반응에 의해 얻어지는 항산화제-키토산 복합체는 수용성 및 지용성을 동시에 가짐으로써 자가 유화(auto-emulsifying) 성질을 가지므로, 반투막을 사용한 투석에 의해 분리하는 것이 바람직하다. 즉, 상기 커플링 반응을 수행한 후, 반응 혼합물로부터 분리한 침전물을 물에 분산시키고 분자량 컷-오프 2,000 ∼ 10,000, 더욱 바람직하게는 분자량 컷-오프 약 2 000의 반투막으로 여과하여 미반응 물질을 제거한 다음, 얻어진 여액을 건조함으로써 항산화제-키토산 복합체를 분리하는 것이 바람직하다. 상기 건조는 통상의 감압 건조, 동결건조 등에 의해 수행될 수 있으며, 동결건조에 의해 수행되는 것이 더욱 바람직하다.As described above, the antioxidant-chitosan complex obtained by the coupling reaction has auto-emulsifying properties by having water solubility and fat solubility at the same time, and therefore, separation by dialysis using a semipermeable membrane is preferable. That is, after performing the coupling reaction, the precipitate separated from the reaction mixture is dispersed in water and filtered through a semipermeable membrane having a molecular weight cut-off of 2,000 to 10,000, more preferably molecular weight cut-off of about 2 000, thereby removing the unreacted material. After removal, it is preferable to separate the antioxidant-chitosan complex by drying the obtained filtrate. The drying may be carried out by ordinary vacuum drying, lyophilization and the like, more preferably by lyophilization.

본 발명의 항산화제-키토산 복합체는 링커를 매개로 항산화제와 키토산을 반응시켜 얻어질 수 있다. 즉, 본 발명은 α-리포산, 글루타치온 이외에도, 다양한 항산화제를 양쪽에 카르복실산 모이어티를 갖는 링커, 바람직하게는 숙신산을 매개로 키토산과 연결시켜 얻어진 항산화제-키토산 복합체를 포함한다. 구체적으로, 본 발명은 (a) 항산화제과 숙신산을 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서 반응시켜 3-항산화제-카르보닐 프로파논산을 제조하는 단계; 및 (b) 단계(a)에서 얻어진 3-항산화제-카르보닐 프로파논산과 키토산을 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서 반응시키는 단계를 포함하는 제조방법으로 얻어진 항산화제-키토산 복합체를 포함한다.The antioxidant-chitosan complex of the present invention can be obtained by reacting an antioxidant with chitosan via a linker. That is, the present invention includes, in addition to α-lipoic acid and glutathione, an antioxidant-chitosan complex obtained by linking various antioxidants with chitosan via a linker having a carboxylic acid moiety on both sides, preferably succinic acid. Specifically, the present invention comprises the steps of (a) reacting the antioxidant and succinic acid in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide to prepare 3-antioxidant-carbonyl propanoic acid; And (b) reacting the 3-antioxidant-carbonyl propanoic acid and chitosan obtained in step (a) in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide. A chitosan complex.

상기 링커를 매개로한 복합체 형성에 적용될 수 있는 항산화제는 다양한 항산화제를 포함하며, 예를 들어, 코엔자임 Q10, α-토코페롤(α-tocopherol), 레티놀(retinol), 아스코르브산(ascorbic acid), 부틸화 히드록시 톨루엔(butylated hydroxy toluene), 제니스테인(genistein), 큐세틴(quecetin), 프로필 갈레이 트(propyl gallate), 에피갈로카테킨 갈레이트(epigallocatechin gallate), 갈로카테킨 갈레이트(gallocatechin gallate), 실리빈(silibin), 디오스메틴(diosmetin), 캠퍼롤(kaempferol), 에피카테킨(epicatechin), 및 갈란긴(galangin)으로 이루어진 군으로부터 1종 이상 선택될 수 있다. 더욱 바람직하게는, 상기 항산화제는 레티놀, 코엔자임 Q10, α-토코페롤, 또는 아스코르브산일 수 있다.Antioxidants that can be applied to the linker-mediated complex formation include various antioxidants, for example, coenzyme Q10, α-tocopherol, retinol, ascorbic acid, Butylated hydroxy toluene, genistein, cucetin, propyl gallate, epigallocatechin gallate, gallocatechin gallate, It may be selected from the group consisting of silbin, diosmetin, kaempferol, epicatechin, and galangin. More preferably, the antioxidant may be retinol, coenzyme Q10, α-tocopherol, or ascorbic acid.

단계(a)의 항산화제와 숙신산과의 반응은 커플링화제 즉, 3-디메틸-아미노프로필-N-에틸 카보디이미드를 사용하여 수행된다. 상기 반응은 디클로로메탄, 테트라히드로퓨란, 클로로포름, 에틸 아세테이트 등의 유기용매 중에서 수행할 수 있다. 또한, 상기 반응은 디메틸아미노피리딘, 트리에틸아민, 및 이소프로필에틸아민으로 이루어진 군으로부터 선택된 염기 존재하에서 바람직하게 수행될 수 있다. 상기 항산화제와 숙신산과의 당량비는 항산화제 1 당량에 대하여 숙신산 0.5 ∼ 0.6 당량, 더욱 바람직하게는 약 0.5 당량의 범위일 수 있다. 상기 반응으로부터 얻어지는 3-항산화제-카르보닐 프로파논산은 반응 혼합물을 감압 증류 또는 건조함으로써 분리할 수 있으며, 필요에 따라 반응 혼합물을 감압 농축한 다음, 에틸 아세테이트 등의 용매를 가한 후 염산 수용액 등으로 1회 이상 세척한 후 건조하여 분리할 수 있다. The reaction of the antioxidant of succinic acid in step (a) is carried out using a coupling agent, i.e. 3-dimethyl-aminopropyl-N-ethyl carbodiimide. The reaction can be carried out in an organic solvent such as dichloromethane, tetrahydrofuran, chloroform, ethyl acetate and the like. In addition, the reaction may be preferably carried out in the presence of a base selected from the group consisting of dimethylaminopyridine, triethylamine, and isopropylethylamine. The equivalent ratio of the antioxidant and succinic acid may be in the range of 0.5 to 0.6 equivalents, more preferably about 0.5 equivalents, based on 1 equivalent of antioxidant. The 3-antioxidant-carbonyl propanoic acid obtained from the above reaction can be separated by distillation or drying of the reaction mixture under reduced pressure. The reaction mixture is concentrated under reduced pressure, if necessary, and then a solvent such as ethyl acetate is added, followed by aqueous hydrochloric acid solution. After washing one or more times can be separated by drying.

단계 (b)의 3-항산화제-카르보닐 프로파논산과 키토산과의 반응은 커플링화제 즉, 3-디메틸-아미노프로필-N-에틸 카보디이미드를 사용하여 수행된다. 상기 커플링 반응은 촉매로서 N-히드록시숙신이미드 및 산 존재하에서 바람직하게 수행될 수 있고, 상기 산은 아세트산, 설폰산, 황산, 또는 인산 등을 포함하며, 바람직하 게는 아세트산을 사용할 수 있다. 또한, 상기 커플링 반응은 20 ℃ 내지 약 50 ℃ 범위, 더욱 바람직하게는 실온(약 25 ℃)에서 수행함으로써 3-항산화제-카르보닐 프로파논산이 중합체를 형성하는 것을 방지할 수 있다. 상기 3-항산화제-카르보닐 프로파논산과 키토산의 당량비는, 키토산의 탈아세틸화 정도에 따라 상이할 수 있으나, 키토산 1 당량에 대하여 3-항산화제-카르보닐 프로파논산 0.9 ∼ 1.5 당량, 더욱 바람직하게는 0.9 ∼ 1 당량의 범위로 사용하는 것이 미반응의 3-항산화제-카르보닐 프로파논산을 남기지 않을 수 있어 정제가 용이하다.The reaction of the 3-antioxidant-carbonyl propanoic acid with chitosan in step (b) is carried out using a coupling agent, ie 3-dimethyl-aminopropyl-N-ethyl carbodiimide. The coupling reaction may be preferably carried out in the presence of N-hydroxysuccinimide and an acid as a catalyst, the acid may include acetic acid, sulfonic acid, sulfuric acid, phosphoric acid and the like, preferably acetic acid may be used. . In addition, the coupling reaction can be performed at 20 ° C. to about 50 ° C., more preferably at room temperature (about 25 ° C.) to prevent the 3-antioxidant-carbonyl propanoic acid from forming polymers. Although the equivalent ratio of the 3-antioxidant-carbonyl propanoic acid and chitosan may vary depending on the degree of deacetylation of chitosan, the amount of 3-antioxidant-carbonyl propanoic acid is 0.9-1.5 equivalents to 1 equivalent of chitosan, More preferably, the use in the range of 0.9 to 1 equivalent may not leave unreacted 3-antioxidant-carbonyl propanoic acid, so that purification is easy.

상기와 같이 얻어진 항산화제-키토산 복합체(구체적으로는 항산화제-링커-키토산 복합체)는 수용성 및 지용성을 동시에 가짐으로써 자가 유화(auto-emulsifying) 성질을 가지므로, 반투막을 사용한 투석에 의해 분리하는 것이 바람직하다. 즉, 상기 커플링 반응을 수행한 후, 반응 혼합물로부터 분리한 침전물을 물에 분산시키고 분자량 컷-오프 2,000 ∼ 10,000, 더욱 바람직하게는 분자량 컷-오프 약 2 000의 반투막으로 여과하여 미반응 물질을 제거한 다음, 얻어진 여액을 건조함으로써 항산화제-키토산 복합체를 분리하는 것이 바람직하다. 상기 건조는 통상의 감압 건조, 동결건조 등에 의해 수행될 수 있으며, 동결건조에 의해 수행되는 것이 더욱 바람직하다.Since the antioxidant-chitosan complex (specifically, the antioxidant-linker-chitosan complex) obtained as described above has water-soluble and fat-soluble properties at the same time, it has an auto-emulsifying property, so that separation by dialysis using a semipermeable membrane is recommended. desirable. That is, after performing the coupling reaction, the precipitate separated from the reaction mixture is dispersed in water and filtered through a semipermeable membrane having a molecular weight cut-off of 2,000 to 10,000, more preferably molecular weight cut-off of about 2 000, thereby removing the unreacted material. After removal, it is preferable to separate the antioxidant-chitosan complex by drying the obtained filtrate. The drying may be carried out by ordinary vacuum drying, lyophilization and the like, more preferably by lyophilization.

이하 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이들 실시예는 본 발명을 예시하기 위한 것으로, 본 발명을 제한하는 것으로 해석되어서는 안된다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are intended to illustrate the invention and should not be construed as limiting the invention.

실시예Example 1 : α-리포산과 키토산의 복합체 합성 1: Complex synthesis of α-lipoic acid and chitosan

탈아세틸화도 90% 및 중량평균분자량 300 kDa의 키토산 5.00g(12.75 mmol), 3-디메틸-아미노프로필-N-에틸 카보디이미드 2.90g(15.30 mmol), 및 N-히드록시숙신이미드 1.76g(15.30 mmol)을 1% 아세트산 수용액 250 ml에 용해시켰다. 얻어진 용액에, α-리포산 3.16g(15.30 mmol)을 테트라히드로퓨란 30 ml에 용해시킨 용액을 가한 후, 실온에서 72시간 동안 반응시켰다. 반응 혼합물에 테트라히드로퓨란 500 ml을 가하고, 여과하여 침전물을 분리하였다. 얻어진 침전물을 물 300 ml에 완전히 용해시킨 후, Milipore dialysis tube, M.W. cut-off 2,000으로 2일 동안 반투막 여과하여 미반응물을 제거하였다. 얻어진 여액을 동결건조하여, α-리포산과 키토산의 복합체 6.14g (수율 83 %)을 얻었다.5.00 g (12.75 mmol) of chitosan at 90% deacetylation degree and 300 kDa of weight average molecular weight, 2.90 g (15.30 mmol) of 3-dimethyl-aminopropyl-N-ethyl carbodiimide, and 1.76 g of N-hydroxysuccinimide (15.30 mmol) was dissolved in 250 ml of a 1% acetic acid aqueous solution. To the obtained solution, a solution in which 3.16 g (15.30 mmol) of α-lipoic acid was dissolved in 30 ml of tetrahydrofuran was added, followed by reacting at room temperature for 72 hours. 500 ml of tetrahydrofuran was added to the reaction mixture, and the precipitate was separated by filtration. The obtained precipitate was completely dissolved in 300 ml of water, and then the Milipore dialysis tube, M.W. Unreacted material was removed by semipermeable membrane filtration for 2 days with cut-off 2,000. The obtained filtrate was lyophilized to obtain 6.14 g (yield 83%) of a complex of α-lipoic acid and chitosan.

1H NMR 400MHz ppm 2.51~2.61(α-리포산, -SCH-, -SCH2-, 3H, m) 1.55~2.18 (α-리포산, -CH2 -, 8H, m); FT-IR Cm-1 3393.13 (-OH, br) 2928.29 (-CH2-, w) 1645.82(-NHCO-, s) 1553.28(-NHCO-, s) 1 H NMR 400 MHz ppm 2.51 to 2.61 (α-lipoic acid, -SCH-, -SCH 2- , 3H, m) 1.55 to 2.18 (α-lipoic acid, -CH 2- , 8H, m); FT-IR Cm -1 3393.13 (-OH, br) 2928.29 (-CH 2- , w) 1645.82 (-NHCO-, s) 1553.28 (-NHCO-, s)

실시예Example 2 :  2 : 글루타치온과Glutathione 키토산의 복합체 합성 Complex synthesis of chitosan

α-리포산 대신 글루타치온 4.70 g(15.30 mmol)을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응을 수행하여, 글루타치온과 키토산의 복합체 5.94 g (수율 76 %)을 얻었다.The reaction was carried out in the same manner as in Example 1, except that 4.70 g (15.30 mmol) of glutathione was used instead of α-lipoic acid to obtain 5.94 g (yield 76%) of the complex of glutathione and chitosan.

1H NMR 400MHz ppm 4.09(glutathione, -NHCOCH 2 NH-, 2H, t) 3.49 (glutathione, -CH2 CH 2 CHNH2 -, 2H, t) 3.18 - 2.93(glutathione, -CHCH 2 SH, 2H, m) 2.18(gluthathione, -COCH 2 CH2-, 2H, t); FT-IR Cm-1 3392.73 (-OH, br) 2927.32 (-CH2-, w) 1682.26, 1679.64, 1644.64, 1552.15, (-NHCO-, s) 1 H NMR 400 MHz ppm 4.09 (glutathione, -NHCO CH 2 NH-, 2H, t) 3.49 (glutathione, -CH 2 CH 2 CHNH 2- , 2 H, t) 3.18-2.93 (glutathione, -CH CH 2 SH, 2H, m) 2.18 (gluthathione, -CO CH 2 CH 2- , 2H, t); FT-IR Cm -1 3392.73 (-OH, br) 2927.32 (-CH 2- , w) 1682.26, 1679.64, 1644.64, 1552.15, (-NHCO-, s)

실시예Example 3 : 3-레티놀-카르보닐  3: 3-retinol-carbonyl 프로파논산의Propanoic acid 합성 synthesis

레틴올 5.00 g(17.45 mmol)과 숙신산 2.47 g(20.95 mmol)을 디클로로메탄 70 ml에 교반하면서 가하고, 3-디메틸-아미노프로필-N-에틸 카보디이미드 40.16 g(20.95 mmol)을 30분에 걸쳐 서서히 가하였다. 반응 혼합물에 디메틸아미노피리딘 0.43 g(3.19 mmol)을 가한 후, 실온에서 9 시간 동안 교반하였다. 반응 혼합물을 감압 농축한 다음, 에틸 아세테이트 100 ml를 가하였다. 반응 혼합물을 1N 염산 수용액으로 2회 세척한 다음, 감압 농축하여 용매를 제거한 후, 진공 건조하여 고체상의 3-레틴올-카르보닐 프로파노산 5.46 g(수율 81 %)을 얻었다.5.00 g (17.45 mmol) of retinol and 2.47 g (20.95 mmol) of succinic acid were added to 70 ml of dichloromethane with stirring, and 40.16 g (20.95 mmol) of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was added over 30 minutes. Slowly added. 0.43 g (3.19 mmol) of dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature for 9 hours. The reaction mixture was concentrated under reduced pressure, and then 100 ml of ethyl acetate was added. The reaction mixture was washed twice with 1N aqueous hydrochloric acid solution, concentrated under reduced pressure to remove the solvent, and then dried in vacuo to give 5.46 g (yield 81%) of 3-retinol-carbonyl propanoic acid as a solid.

1H NMR 400MHz ppm 6.51 - 5.63(retionol, -C=CH-, 6H, s) 4.75(retinol, -OCH2-, 2H, d) 2.62 - 2.52(succinic, -CH 2 CH 2 -, 4H, m) 1.96 - 1.57(retinol ring, -CH2-, 6H, m) 1.21(retinol ring, -CH3, 6H, s) ; FT-IR Cm-1 3384.16(-OH, br) 2982.34 - 2931.97(-CH2-, w) 1714.67(-COO-, s) 1516.27(-C=CH-, m) 1 H NMR 400 MHz ppm 6.51-5.63 (retionol, -C = CH- , 6H, s) 4.75 (retinol, -OCH 2- , 2H, d) 2.62-2.52 (succinic, -CH 2 CH 2- , 4H, m ) 1.96-1.57 (retinol ring, -CH 2- , 6H, m) 1.21 (retinol ring, -CH 3 , 6H, s); FT-IR C m -1 3384.16 (-OH, br) 2982.34-2931.97 (-CH 2- , w) 1714.67 ( -CO 0-, s) 1516.27 (-C = CH-, m)

실시예 4 : 3-환원된 코엔자임 Q10-카르보닐 프로파논산의 합성Example 4 Synthesis of 3-Reduced Coenzyme Q10-Carbonyl Propanoic Acid

레틴올 대신 환원된 코엔자임 Q10 5.00 g(12.80 mmol)을 사용한 것을 제외하고는 실시예 3과 동일한 방법으로 반응을 수행하여, 3-환원된 코엔자임 Q10-카르보닐 프로파노산 6.93 g(수율 78 %)을 얻었다.Reduced instead of retinol The reaction was carried out in the same manner as in Example 3, except that 5.00 g (12.80 mmol) of coenzyme Q10 was used to obtain 6.93 g (yield 78%) of 3-reduced coenzyme Q10-carbonyl propanoic acid.

1H NMR 400MHz ppm 5.80 - 5.20(coenzyme Q10, -C=CH-, 3H, s) 3.73(coenzyme Q10, -OCH3-, 6H, s) 2.54 - 2.51(succinic, -CH2CH2-, 4H, m) 2.12 - 3.22(coenzyme Q10, -CH2-, 10H, m) 2.35(coenzyme Q10, -CH3, 3H, s) 1.73 - 1.69(coenzyme Q10, -CH3, 12H, s) ; FT-IR Cm-1 3411.27(-OH, br) 2979.36 - 2947.56(-CH2-, w) 1716.32(-COO-, s) 1516.71(-C=CH-, m) 1 H NMR 400 MHz ppm 5.80-5.20 (coenzyme Q 10 , -C = CH- , 3H, s) 3.73 (coenzyme Q 10 , -OCH 3- , 6H, s) 2.54-2.51 (succinic, -CH 2 CH 2- , 4H, m) 2.12-3.22 (coenzyme Q 10 , -CH 2- , 10H, m) 2.35 (coenzyme Q 10 , -CH 3 , 3H, s) 1.73-1.69 (coenzyme Q 10 , -CH 3 , 12H, s); FT-IR C m -1 3411.27 (-OH, br) 2979.36-2947.56 (-CH 2- , w) 1716.32 ( -CO 0-, s) 1516.71 (-C = CH-, m)

실시예Example 5 : 3-토코페롤-카르보닐  5: 3-tocopherol-carbonyl 프로파논산의Propanoic acid 합성 synthesis

레틴올 대신 α-토코페롤 5.00 g(17.46 mmol)을 사용한 것을 제외하고는 실시예 3과 동일한 방법으로 반응을 수행하여, 3-토코페롤-카르보닐 프로파노산 7.97 g(수율 86 %)을 얻었다.The reaction was carried out in the same manner as in Example 3, except that 5.00 g (17.46 mmol) of α-tocopherol was used instead of retinol to obtain 7.97 g (yield 86%) of 3-tocopherol-carbonyl propanoic acid.

1H NMR 400MHz ppm 2.63 - 2.09(tocopherol ring, -CH 2 CH 2 -, 4H, m) 2.56 - 2.48(succinic, -CH2-, 4H, m) 2.35(tocopherol, -CH3, 9H, s) 1.83(tocopherol, 1H, s) 1.65 - 1.25(tocopherol, -CH2-, 18H, m) 1.01 - 1.06(tocopherol, -CH3, 15H, s) ; FT-IR Cm-1 3413.18(-OH, br) 2978.65 - 2932.49(-CH2-, w) 1716.87(-COO-, s) 1516.83(-C=CH-, m) 1 H NMR 400 MHz ppm 2.63-2.09 (tocopherol ring, -CH 2 CH 2- , 4H, m) 2.56-2.48 (succinic, -CH 2- , 4H, m) 2.35 (tocopherol, -CH 3 , 9H, s) 1.83 (tocopherol, 1H, s) 1.65-1.25 (tocopherol, -CH 2- , 18H, m) 1.01-1.06 (tocopherol, -CH 3 , 15H, s); FT-IR C m -1 3413.18 (-OH, br) 2978.65-2932.49 (-CH 2- , w) 1716.87 ( -CO 0-, s) 1516.83 (-C = CH-, m)

실시예Example 6 : 3-아스코르브산-카르보닐  6: 3-ascorbic acid-carbonyl 프로파논산의Propanoic acid 합성 synthesis

레틴올 대신 아스코르브산 5.00 g(28.39 mmol)을 사용한 것을 제외하고는 실시예 3과 동일한 방법으로 반응을 수행하여, 3-아스코르브산-카르보닐 프로파노산 5.72 g(수율 73 %)을 얻었다.The reaction was carried out in the same manner as in Example 3, except that 5.00 g (28.39 mmol) of ascorbic acid was used instead of retinol to give 5.72 g (yield 73%) of 3-ascorbic acid-carbonyl propanoic acid.

1H NMR 400MHz ppm 4.71(ascorbic ring, -CH-, 1H, s) 3.94(ascrobic acid, -CH-, 1H, m) 3.78(ascorbic acid, -CH2-, 2H, m) 2.54 - 2.45(succinic, -CH2-, 4H, m) ; FT-IR Cm-1 3392.27(-OH, br) 2983.47 - 2987.68(-CH2-, w) 1716.87(-COO-, s) 1514.59(-C=CH-, m) 1 H NMR 400MHz ppm 4.71 (ascorbic ring, - CH-, 1H, s) 3.94 (ascrobic acid, -CH-, 1H, m) 3.78 (ascorbic acid, -CH 2 -, 2H, m) 2.54 - 2.45 (succinic , -CH 2- , 4H, m); FT-IR C m -1 3392.27 (-OH, br) 2983.47-2987.68 (-CH 2- , w) 1716.87 ( -CO 0-, s) 1514.59 (-C = CH-, m)

실시예Example 7 :  7: 레틴올과Retinol and 키토산의 복합체의 합성 Synthesis of Complexes of Chitosan

α-리포산 대신 실시예 3에서 얻어진 3-레틴올-카르보닐 프로파노산 5.91 g(15.30 mmol)을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응을 수행 하여, 레틴올과 키토산의 복합체(즉, 레틴올-링커-키토산 복합체) 8.83 g (수율 73 %)을 얻었다.The reaction was carried out in the same manner as in Example 1, except that 5.91 g (15.30 mmol) of 3-retinol-carbonyl propanoic acid obtained in Example 3 was used instead of α-lipoic acid, thereby preparing a complex of retinol and chitosan ( That is, 8.83 g (yield 73%) of retinol-linker-chitosan complex) were obtained.

1H NMR 400MHz ppm 6.49 - 5.62(retionol, -C=CH-, 6H, s) 4.69(retinol, -OCH2-, 2H, s) 2.62 - 2.52(succinic, -CH 2 CH 2 -, 4H, m) 1.89 - 1.52(retinol ring, -CH2-, 6H, m) 1.22(retinol ring, -CH3, 6H, s) ; FT-IR Cm-1 3346.34(-OH, br) 2956.85 - 2936. 75(-CH2-, w) 1718.49(-COO-, s) 1644.58(-NHCO-, s) 1553.93(-NHCO-, s) 1516.71(-C=CH-, m) 1 H NMR 400 MHz ppm 6.49-5.62 (retionol, -C = CH- , 6H, s) 4.69 (retinol, -OCH 2- , 2H, s) 2.62-2.52 (succinic, -CH 2 CH 2- , 4H, m ) 1.89-1.52 (retinol ring, -CH 2- , 6H, m) 1.22 (retinol ring, -CH 3 , 6H, s); FT-IR C m -1 3346.34 (-OH, br) 2956.85-2936. 75 (-CH 2- , w) 1718.49 ( -CO O-, s) 1644.58 (-NHCO-, s) 1553.93 (-NHCO-, s ) 1516.71 (-C = CH-, m)

실시예Example 8 : 환원된 코엔자임  8: reduced coenzyme Q10Q10 과 키토산의 복합체의 합성And synthesis of chitosan complex

α-리포산 대신 실시예 4에서 얻어진 3-코엔자임 Q10-카르보닐 프로파논산 7.48 g(15.30 mmol)을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응을 수행하여, 환원된 코엔자임 Q10과 키토산의 복합체(즉, 환원된 코엔자임 Q10-링커-키토산 복합체) 7.32 g (수율 69 %)을 얻었다.The reaction was carried out in the same manner as in Example 1, except that 7.48 g (15.30 mmol) of 3-coenzyme Q10-carbonyl propanoic acid obtained in Example 4 was used instead of α-lipoic acid to reduce the reduced coenzyme Q10 and chitosan. 7.32 g (yield 69%) of the complex (ie, the reduced coenzyme Q10-linker-chitosan complex) was obtained.

1H NMR 400MHz ppm 5.24(coenzyme Q10, -C=CH-, 3H, s) 3.50(coenzyme Q10, -OCH3, 6H, s) 2.57 - 2.53(succinic, -CH 2 CH 2 -, 4H, m) 2.12 - 2.63(coenzyme Q10, -CH2-, 10H, m) 1.92(coenzyme Q10 ring, -CH3, 3H) 1.71-1.74(coenzyme Q10, -CH3, 15H, s) ; FT-IR Cm-1 3393.48(-OH, br) 2929.46 (-CH2-, w) 1716.68(-COO-, s) 1646.75(-NHCO-, s) 1554.65(-NHCO-, s) 1517.74(-C=CH-, m) 1 H NMR 400 MHz ppm 5.24 (coenzyme Q 10 , -C = CH- , 3H, s) 3.50 (coenzyme Q 10 , -OCH 3 , 6H, s) 2.57-2.53 (succinic, -CH 2 CH 2- , 4H, m) 2.12-2.63 (coenzyme Q 10 , -CH 2- , 10H, m) 1.92 (coenzyme Q 10 ring, -CH 3 , 3H) 1.71-1.74 (coenzyme Q 10 , -CH 3 , 15H, s); FT-IR C m -1 3393.48 (-OH, br) 2929.46 (-CH 2- , w) 1716.68 ( -CO O-, s) 1646.75 (-NHCO-, s) 1554.65 (-NHCO-, s) 1517.74 (- C = CH-, m)

실시예Example 9 : 토코페롤과 키토산의 복합체의 합성 9: Synthesis of Complex of Tocopherol and Chitosan

α-리포산 대신 실시예 5에서 얻어진 3-토코페롤-카르보닐 프로파논산 5.91 g(15.30 mmol)을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응을 수행하여, 토코페롤과 키토산의 복합체(즉, 토코페롤-링커-키토산 복합체) 8.83 g (수율 73)을 얻었다.The reaction was carried out in the same manner as in Example 1, except that 5.91 g (15.30 mmol) of 3-tocopherol-carbonyl propanoic acid obtained in Example 5 was used instead of α-lipoic acid, and thus a complex of tocopherol and chitosan (ie, 8.83 g (yield 73) of tocopherol-linker-chitosan complex) were obtained.

1H NMR 400MHz ppm 2.62 - 2.06(tocopherol ring, -CH 2 CH 2 -, 4H, m) 2.52 - 2.43(succinic, -CH2-, 4H, m) 2.34(tocopherol ring, -CH3, 9H, s) 1.79(tocopherol, 1H, s) 1.63 - 1.28(tocopherol, -CH2-, 18H, m) 1.52 - 1.03(tocopherol, -CH3, 15H, s) ; FT-IR Cm-1 3362.72(-OH, br) 2994.73 - 2924. 69(-CH2-, w) 1722.71(-COO-, s) 1643.37(-NHCO-, s) 1552.81(-NHCO-, s) 1425.78(-C=C-, m) 1 H NMR 400 MHz ppm 2.62-2.06 (tocopherol ring, -CH 2 CH 2- , 4H, m) 2.52-2.43 (succinic, -CH 2- , 4H, m) 2.34 (tocopherol ring, -CH 3 , 9H, s ) 1.79 (tocopherol, 1H, s) 1.63-1.28 (tocopherol, -CH 2- , 18H, m) 1.52-1.03 (tocopherol, -CH 3 , 15H, s); FT-IR C m -1 3362.72 (-OH, br) 2994.73-2924.69 (-CH 2- , w) 1722.71 ( -CO O-, s) 1643.37 (-NHCO-, s) 1552.81 (-NHCO-, s ) 1425.78 (-C = C-, m)

실시예Example 10 : 아스코르브산과 키토산의 복합체 합성 10: complex synthesis of ascorbic acid and chitosan

α-리포산 대신 실시예 6에서 얻어진 3-아스코르브산-카르보닐 프로파논산 4.23 g(15.30 mmol)을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응을 수행하여, 아스코르브산과 키토산의 복합체(즉, 아스코르브산-링커-키토산 복합체) 6.59 g (수율 71%)을 얻었다.The reaction was carried out in the same manner as in Example 1, except that 4.23 g (15.30 mmol) of 3-ascorbic acid-carbonyl propanoic acid obtained in Example 6 was used instead of α-lipoic acid, and a complex of ascorbic acid and chitosan (ie, 6.59 g (yield 71%) of ascorbic acid-linker-chitosan complex) were obtained.

1H NMR 400MHz ppm 1H NMR 400MHz ppm 4.71(ascorbic ring, -CH -, 1H, s) 3.94(ascrobic acid, -CH-, 1H, m) 3.76(ascorbic acid, -CH2-, 2H, m) 2.49 - 2.41(succinic, -CH2-, 4H, m) ; FT-IR Cm-1 3383.64(-OH, br) 2997.81 - 2913. 54(-CH2-, w) 1722.39(-COO-, s) 1641.48(-NHCO-, s) 1548.72(-NHCO-, s) 1422.36(-C=C-, m) 1 H NMR 400MHz ppm 1 H NMR 400MHz ppm 4.71 (ascorbic ring, - CH -, 1H, s) 3.94 (ascrobic acid, -CH-, 1H, m) 3.76 (ascorbic acid, -CH 2 -, 2H, m) 2.49-2.41 (succinic, -CH 2- , 4H, m); FT-IR C m -1 3383.64 (-OH, br) 2997.81-2913. 54 (-CH 2- , w) 1722.39 ( -CO O-, s) 1641.48 (-NHCO-, s) 1548.72 (-NHCO-, s ) 1422.36 (-C = C-, m)

시험예. 성상, 화학적 안정성, 및 관능 시험Test example. Properties, chemical stability, and sensory tests

실시예 1, 2, 7, 8, 9, 및 10에서 제조한 항산화제와 키토산과의 복합체 각각 3.0 g을 증류수 1,000 ml에 완전히 용해시켜 맑은 용액을 제조하고, 40 ℃에서 30분간 교반하여, 미셀(micelle) 수용액을 제조하였다. 얻어진 수용액 10 ml을 취하여 45 ℃에서 0주, 1주, 2주, 3주, 4주 동안 보관하면서, 성상 변화, 항산화제의 잔존함량, 및 관능시험을 수행하였다. 3.0 g of each complex of the antioxidants and chitosan prepared in Examples 1, 2, 7, 8, 9, and 10 were completely dissolved in 1,000 ml of distilled water to prepare a clear solution, and stirred at 40 ° C. for 30 minutes, and micelle (micelle) aqueous solution was prepared. 10 ml of the obtained aqueous solution was taken and stored at 45 ° C. for 0 weeks, 1 week, 2 weeks, 3 weeks, and 4 weeks, whereby a change in properties, a residual content of an antioxidant, and a sensory test were performed.

상기 성상 변화는 육안으로 관찰하였다. The change in appearance was visually observed.

항산화제의 잔존함량은 항산화제-키토산 복합체로부터 수용액 중으로 용출되는 항산화제의 함량(측정함량)을 고속액체크로마토그래피로 측정하여 역산하였다. 상기 고속액체크로마토그래피 분석은 각각의 시료들을 각각 10 ml-볼륨 플라스크에 시료 0.1 g씩 취하고 클로로포름으로 10 ml로 맞춘 다음, 1 분간 볼텍싱(vortexing)하고, 10000 rpm으로 10분 동안 원심분리한 후, 고속액체크로마토그래피로 측정하였다. 상기 고속액체크로마토그래피 조건은 다음과 같다: 컬럼 - ACE 5-C18 (4.6*150mm, 5㎛), 가아드 컬럼(Guard Column) - ACE 5-C18 (2.1*12.5mm, 5㎛), 이동상 - 아세토니트릴 및 0.1% 황산 수용액의 혼합액(80:20), 검출기 파장 - UV 224 nm, 유속(Flow rate) - 1 ml/min, 주입량 - 2 ㎕.The residual content of the antioxidant was inverted by measuring the content (measurement content) of the antioxidant eluted from the antioxidant-chitosan complex into the aqueous solution by high performance liquid chromatography. In the high performance liquid chromatography, each sample was taken in a 10 ml-volume flask, each 0.1 g of the sample, adjusted to 10 ml with chloroform, vortexed for 1 minute, and centrifuged at 10000 rpm for 10 minutes. It was measured by high performance liquid chromatography. The high performance liquid chromatography conditions are as follows: column-ACE 5-C18 (4.6 * 150mm, 5㎛), Guard Column-ACE 5-C18 (2.1 * 12.5mm, 5㎛), mobile phase Mixed solution of acetonitrile and 0.1% aqueous sulfuric acid solution (80:20), detector wavelength-UV 224 nm, flow rate-1 ml / min, injection amount-2 μl.

관능시험은 다음과 같이 수행하였다: 각각의 시료를 건강한 20대 후반 여성 10인을 대상으로 취도의 강도를 측정하여 평균치를 구하였으며, 취도의 강도는 다음 표 1과 같이 설정하였다. Sensory tests were performed as follows: Each sample was measured and averaged by measuring the intensity of odor of 10 women in their late 20s, the intensity of odor was set as shown in Table 1 below.

변취 정도Bad smell 설 명Explanation 00 무취기 Odorless 1One 감지취기 Detection 22 보통취기 Normal odor 33 강한취기Strong odor 44 극심한 취기Extreme odor 55 참기 어려운 취기Unbearable odor

상기와 같이, 성상 변화, 항산화제의 잔존함량, 및 관능시험을 수행한 결과는 다음 표 2와 같다.As described above, the results of the property change, the residual content of the antioxidant, and the sensory test are shown in Table 2 below.

복합체 (실시예)Composite (Example) 보관 기간Retention period 성상변화 Change of appearance 항산화제 함량(%)Antioxidant Content (%) 관능시험 (직접관능법) Sensory test (direct sensory method) 2회 측정한 평균값 (%)Average value measured twice (%) 측정함량 (%)Measurement content (%) 잔존함량 (%)Residual content (%) 실시예 1Example 1 0주Week 0 없음none 0.00120.0012 0.790.79 99.2199.21 1.31.3 1주1 week 없음none 0.00170.0017 1.121.12 98.8898.88 1.61.6 2주2 weeks 없음none 0.00230.0023 1.511.51 98.4998.49 2.12.1 3주3 weeks 없음none 0.00320.0032 2.112.11 97.8997.89 2.72.7 4주4 Weeks 없음none 0.00580.0058 3.823.82 96.1896.18 2.62.6 실시예 2Example 2 0주Week 0 없음none 0.00220.0022 1.241.24 98.7698.76 1.31.3 1주1 week 없음none 0.00310.0031 1.751.75 98.2598.25 1.21.2 2주2 weeks 없음none 0.00370.0037 2.082.08 97.9297.92 1.71.7 3주3 weeks 없음none 0.00540.0054 3.043.04 96.9696.96 2.42.4 4주4 Weeks 없음none 0.00680.0068 3.833.83 96.1796.17 2.32.3 실시예 7Example 7 0주Week 0 없음none 0.00410.0041 2.142.14 97.8697.86 0.70.7 1주1 week 없음none 0.01120.0112 5.865.86 94.1494.14 0.60.6 2주2 weeks 없음none 0.01470.0147 7.677.67 92.3392.33 1.21.2 3주3 weeks 조금흐려짐Slightly cloudy 0.01650.0165 8.638.63 91.3791.37 2.12.1 4주4 Weeks 조금흐려짐Slightly cloudy 0.01710.0171 8.948.94 91.0691.06 2.22.2 실시예 8Example 8 0주Week 0 없음none 0.00370.0037 1.881.88 98.1298.12 0.60.6 1주1 week 없음none 0.00660.0066 3.353.35 96.6596.65 1.71.7 2주2 weeks 없음none 0.01180.0118 5.995.99 94.0194.01 1.51.5 3주3 weeks 조금흐려짐Slightly cloudy 0.01670.0167 8.498.49 91.5191.51 1.71.7 4주4 Weeks 조금흐려짐Slightly cloudy 0.01890.0189 9.609.60 90.4090.40 1.91.9 실시예 9Example 9 0주Week 0 없음none 0.00340.0034 1.961.96 98.0498.04 0.70.7 1주1 week 없음none 0.00410.0041 2.372.37 97.6397.63 0.70.7 2주2 weeks 없음none 0.00480.0048 2.772.77 97.2397.23 1.11.1 3주3 weeks 없음none 0.00570.0057 3.293.29 96.7196.71 1.31.3 4주4 Weeks 없음none 0.00630.0063 3.643.64 96.3696.36 1.61.6 실시예 10Example 10 0주Week 0 없음none 0.00310.0031 0.550.55 99.4599.45 0.80.8 1주1 week 없음none 0.00940.0094 1.661.66 98.3498.34 0.70.7 2주2 weeks 없음none 0.01330.0133 2.342.34 97.6697.66 1.41.4 3주3 weeks 옅은 노란색Pale yellow 0.01670.0167 2.942.94 97.0697.06 1.61.6 4주4 Weeks 옅은 노란색Pale yellow 0.01800.0180 3.173.17 96.8396.83 1.91.9

상기 표 2의 결과로부터, 쉽게 변색되는 항산화제들을 본 발명에 따라 키토산과의 복합체로 제조할 경우, 수성 매질 중에서 전체적으로 최소 90.4 %이상의 높은 잔존 함량을 유지함으로써 높은 안정성을 나타내며, 성상 변화도 거의 없고, 또한 변취 문제가 거의 발생하지 아니함을 알 알 수 있다.From the results of Table 2, when the antioxidants are easily discolored according to the present invention prepared with a complex with chitosan, it shows a high stability by maintaining a high residual content of at least 90.4% as a whole in an aqueous medium, there is little change in appearance In addition, it can be seen that there is little problem of malodor.

Claims (10)

α-리포산 및 글루타치온으로 이루어진 군으로부터 선택된 항산화제와 키토산을, 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서, 반응시키는 단계를 포함하는 제조방법으로 얻어진 항산화제-키토산 복합체.An antioxidant-chitosan complex obtained by the production method comprising the step of reacting chitosan with an antioxidant selected from the group consisting of α-lipoic acid and glutathione in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide. 제1항에 있어서, 상기 반응이 촉매로서 N-히드록시숙신이미드 및 산 존재하에서 수행되는 것을 특징으로 하는 항산화제-키토산 복합체.The antioxidant-chitosan complex according to claim 1, wherein the reaction is carried out in the presence of N-hydroxysuccinimide and an acid as a catalyst. 제2항에 있어서, 상기 산이 아세트산, 설폰산, 황산, 또는 인산인 것을 특징으로 하는 항산화제-키토산 복합체.The antioxidant-chitosan complex according to claim 2, wherein the acid is acetic acid, sulfonic acid, sulfuric acid, or phosphoric acid. 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 반응을 수행한 후, 반응 혼합물로부터 분리한 침전물을 물에 분산시키고 분자량 컷-오프 2,000 ∼ 10,000의 반투막으로 여과한 다음, 건조하는 단계를 추가로 포함하는 것을 특징으로 하는 항산화제-키토산 복합체.The process according to any one of claims 1 to 3, wherein after carrying out the reaction, the precipitate separated from the reaction mixture is dispersed in water, filtered through a semipermeable membrane having a molecular weight cut-off of 2,000 to 10,000, and then drying. Antioxidant-chitosan complex, further comprising. (a) 코엔자임 Q10, α-토코페롤, 레티놀, 아스코르브산, 부틸화 히드록시 톨루엔(butylated hydroxy toluene), 제니스테인(genistein), 큐세틴, 프로필 갈레이트, 에피갈로카테킨 갈레이트, 갈로카테킨 갈레이트, 실리빈, 디오스메틴, 캠퍼롤, 에피카테킨, 및 갈란긴으로 이루어진 군으로부터 1종 이상 선택된 항산화제과 숙신산을 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서 반응시켜 3-항산화제-카르보닐 프로파논산을 제조하는 단계; 및 (a) coenzyme Q10, α-tocopherol, retinol, ascorbic acid, butylated hydroxy toluene, genistein, cucetin, propyl gallate, epigallocatechin gallate, gallocatechin gallate, 3-antioxidant-carbonyl by reacting succinic acid with at least one antioxidant selected from the group consisting of silibine, diosmethine, camphorol, epicatechin, and galangin in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide Preparing propanoic acid; And (b) 단계(a)에서 얻어진 3-항산화제-카르보닐 프로파논산과 키토산을 3-디메틸-아미노프로필-N-에틸 카보디이미드 존재하에서 반응시키는 단계를 포함하는 제조방법으로 얻어진 항산화제-키토산 복합체.(b) the antioxidant obtained by the preparation method comprising the step of reacting the 3-antioxidant-carbonyl propanoic acid and chitosan obtained in step (a) in the presence of 3-dimethyl-aminopropyl-N-ethyl carbodiimide- Chitosan Complex. 제5항에 있어서, 상기 항산화제가 레티놀, 코엔자임 Q10, α-토코페롤, 또는 아스코르브산인 것을 특징으로 하는 항산화제-키토산 복합체.The antioxidant-chitosan complex according to claim 5, wherein the antioxidant is retinol, coenzyme Q10, α-tocopherol, or ascorbic acid. 제5항에 있어서, 단계(a)의 상기 반응이 디메틸아미노피리딘, 트리에틸아민, 및 이소프로필에틸아민으로 이루어진 군으로부터 선택된 염기 존재하에서 수행되는 것을 특징으로 하는 항산화제-키토산 복합체.6. The antioxidant-chitosan complex according to claim 5, wherein said reaction of step (a) is carried out in the presence of a base selected from the group consisting of dimethylaminopyridine, triethylamine, and isopropylethylamine. 제5항에 있어서, 단계(b)의 상기 반응이 촉매로서 N-히드록시숙신이미드 및 산 존재하에서 수행되는 것을 특징으로 하는 항산화제-키토산 복합체.The antioxidant-chitosan complex according to claim 5, wherein the reaction of step (b) is carried out in the presence of N-hydroxysuccinimide and an acid as a catalyst. 제8항에 있어서, 상기 산이 아세트산, 설폰산, 황산, 또는 인산인 것을 특징으로 하는 항산화제-키토산 복합체.The antioxidant-chitosan complex according to claim 8, wherein the acid is acetic acid, sulfonic acid, sulfuric acid, or phosphoric acid. 제5항 내지 제9항 중 어느 한 항에 있어서, 단계(b)의 반응을 수행한 후, 반응 혼합물로부터 분리한 침전물을 물에 분산시키고 분자량 컷-오프 2,000 ∼ 10,000의 반투막으로 여과한 다음, 건조하는 단계를 추가로 포함하는 것을 특징으로 하는 항산화제-키토산 복합체.The process according to any one of claims 5 to 9, after carrying out the reaction of step (b), the precipitate separated from the reaction mixture is dispersed in water and filtered through a semipermeable membrane having a molecular weight cut-off of 2,000 to 10,000, Antioxidant-chitosan complex, further comprising the step of drying.
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