KR101491728B1 - Conjugate of vitamin C with vitamin B3 and antioxidant comprising the same - Google Patents

Conjugate of vitamin C with vitamin B3 and antioxidant comprising the same Download PDF

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KR101491728B1
KR101491728B1 KR20120146422A KR20120146422A KR101491728B1 KR 101491728 B1 KR101491728 B1 KR 101491728B1 KR 20120146422 A KR20120146422 A KR 20120146422A KR 20120146422 A KR20120146422 A KR 20120146422A KR 101491728 B1 KR101491728 B1 KR 101491728B1
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vitamin
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polyethylene glycol
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정봉열
황재택
방성식
유민지
정인화
김택중
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Abstract

본 발명은 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트 및 그를 포함하는 항산화제에 관한 것이다. 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 유기용매에 대한 용해도가 개선되고, 안정하며, 독성이 없고, 체내에서 가수분해되어 활성 비타민 C와 비타민 B3를 방출할 수 있으므로, 노화방지용 화장료 조성물, 약제학적 조성물, 건강기능식품 등에 효과적으로 사용될 수 있다.The present invention relates to a vitamin C-polyethylene glycol-vitamin B3 conjugate and an antioxidant containing the same. The vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention has improved solubility in an organic solvent, is stable, has no toxicity, can be hydrolyzed in the body to release active vitamin C and vitamin B3, Cosmetic compositions, pharmaceutical compositions, health functional foods, and the like.

Description

비타민 C와 비타민 B3의 컨쥬게이트 및 그를 포함하는 항산화제 {Conjugate of vitamin C with vitamin B3 and antioxidant comprising the same}Conjugates of vitamin C with vitamin B3 and antioxidants containing same Conjugate of vitamin C with vitamin B3 and antioxidant comprising the same

본 발명은 비타민 C와 비타민 B3의 컨쥬게이트 및 그를 포함하는 항산화제에 관한 것으로, 더욱 상세하게는 유기용매에 대한 용해도가 개선되고, 안정하며, 독성이 없고, 우수한 항산화력을 나타내는 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트 및 그를 포함하는 항산화제에 관한 것이다. The present invention relates to a conjugate of vitamin C and vitamin B3 and an antioxidant containing the same, and more particularly to a vitamin C-polyethylene which exhibits improved solubility in an organic solvent, is stable, has no toxicity, Glycol-vitamin B3 conjugates and antioxidants containing same.

하기 화학식 2의 비타민 C는 L-아스코르빈산이라고도 하며, 항산화 작용을 가진 수용성 생리활성 물질로서 괴혈병 치료 등을 위한 의약품으로 사용되고 있다.Vitamin C of the following formula (2) is also referred to as L-ascorbic acid, and is a water-soluble physiologically active substance having an antioxidative action and is used as a medicament for the treatment of scurvy.

[화학식 2](2)

Figure 112012104289203-pat00001
Figure 112012104289203-pat00001

또한, 비타민 C는 멜라닌 색소의 축적 억제, 콜라겐 생합성 증가, 섬유 아세포의 생장촉진, 자외선 차단 등의 다양한 생리활성 작용으로, 기미나 주근깨 등을 감소시켜 주고, 주름개선 효과, 피부미백 효과 등이 있어 화장품 분야에서 여러 형태로 화장품 첨가제로 이용되고 있다.In addition, vitamin C has various physiological activities such as inhibition of accumulation of melanin pigment, increase of collagen biosynthesis, stimulation of fibroblast growth, and ultraviolet ray blocking, thereby reducing spots and freckles, and improving wrinkles and skin whitening It is used as a cosmetic additive in various forms in the field of cosmetics.

아울러, 비타민 C는 식품의 갈변을 방지하고, 향을 보존하고, 신선도를 유지하는 등의 목적으로 식품 첨가제로도 사용되고 있다.In addition, vitamin C is used as a food additive for the purpose of preventing browning of food, preserving fragrance, and maintaining freshness.

그런데, 비타민 C는 중성 수용액에는 완전하게 용해되지만, 유기용매, 예를 들어 글리세린, 프로필렌글리콜 등에는 잘 녹지 않아 피부로 운반하는데 매우 제한적이다. 즉, 비타민 C는 친수성이 높아 피부로의 분배가 낮으므로 경피 흡수가 어려운 문제점이 있다. 또한, 비타민 C는 열이나 빛에 약하여 안정성에 문제가 있다. However, although vitamin C is completely dissolved in a neutral aqueous solution, it is insoluble in an organic solvent such as glycerin, propylene glycol and the like and is very limited to be transported to the skin. Namely, since vitamin C has high hydrophilicity and distribution to the skin is low, there is a problem that it is difficult to absorb percutaneous absorption. In addition, vitamin C is weak against heat or light, and has a problem in stability.

따라서, 순수 비타민 C의 문제점을 극복하기 위해 다양한 비타민 C 유도체가 개발되어 왔다. 예를 들어 인산화된 아스코르빈산이나 인산화된 아스코르빈산의 금속염, 아스코르빌-6-팔미테이트와 같은 지방산이 결합된 형태의 아스코르빈산, 펩타이드가 결합된 아스코르빈산 등이 알려져 있다[참조: 대한민국 특허공개 제2004-0094302호]. Therefore, various vitamin C derivatives have been developed to overcome the problem of pure vitamin C. For example, there are known metal salts of phosphorylated ascorbic acid or phosphorylated ascorbic acid, ascorbic acid in the form of fatty acids such as ascorbyl-6-palmitate, ascorbic acid bound with peptides, etc. : Korean Patent Publication No. 2004-0094302].

그러나 종래의 비타민 C 유도체는 그 활성이 순수 비타민 C 보다 떨어지는 등의 문제가 있어, 순수 비타민 C의 활성을 유지하면서 경피흡수성과 안정성을 높일 수 있는 기술의 개발이 요구되어 왔다.
However, conventional vitamin C derivatives have a problem that their activity is lower than that of pure vitamin C, and development of a technique capable of increasing transdermal absorption and stability while maintaining the activity of pure vitamin C has been required.

한편, 비타민 B3로도 알려진 니아신은 하기 화학식 3의 니코틴산의 일반명이다. On the other hand, niacin, also known as vitamin B3, is a generic name for nicotinic acid of the formula (3).

[화학식 3](3)

Figure 112012104289203-pat00002
Figure 112012104289203-pat00002

니아신의 생리학적 활성 형태는 니아신아미드이며, 이 또한 비타민 B3 화합물군의 하나이다. 상기 비타민 B3 화합물은 통상적으로 니아신 결핍증 및 펠레그라병을 치료하기 위해 사용되었다. The physiologically active form of niacin is niacinamide, which is also one of the group of vitamin B3 compounds. The vitamin B3 compound was conventionally used to treat niacin deficiency and Pelagra ' s disease.

또한, 비타민 B3 화합물은 스킨 케어 활성물질 분야에서도 용도가 있음이 밝혀졌다. 미국 특허 제4,096,240호에는 니아신아미드의 피부 미백용 용도가 개시되어 있다. 또한, 국제공개 WO 97/39733호에는 비타민 B3 화합물이 피부 노화로 인한 주름 등 피부 상태를 조절하는데 사용될 수 있음이 개시되어 있다. It has also been found that the vitamin B3 compound has applications in the field of skin care active ingredients. U.S. Pat. No. 4,096,240 discloses a use for skin whitening of niacinamide. International Publication WO 97/39733 also discloses that a vitamin B3 compound can be used to control skin conditions such as wrinkles caused by skin aging.

그러나, 피부에 국소적으로 도포할 경우, 도포된 비타민 B3 화합물의 약 2 내지 4%만이 실제로 피부로 투과하는 것으로 알려져 있다. 또한, 대부분의 비타민 B3 화합물들이 극성 용매에 용해되기 때문에, 주로 친지성 물질로 구성되는 화장료 조성물을 제조할 때, 안정성이 문제될 수 있는 것으로 보고되어 있다.However, when topically applied to the skin, it is known that only about 2-4% of the applied vitamin B3 compound actually penetrates the skin. In addition, since most of the vitamin B3 compounds are dissolved in a polar solvent, it has been reported that stability may be a problem when a cosmetic composition composed mainly of lipophilic substances is prepared.

본 발명자들은 상기한 비타민 C의 문제점인 화학적 불안정성과 유기용매에 대한 난용성 문제를 개선하고, 비타민 B3의 문제점인 열악한 피부 투과력 및 안정성 문제를 개선하기 위해 예의 연구 검토한 결과, 본 발명에 따른 하기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트가 유기용매에 대한 용해도가 개선되고, 안정하며, 독성감소 효과를 가짐을 발견하고 본 발명을 완성하게 되었다. The inventors of the present invention have conducted intensive studies to improve the chemical instability and the poor solubility problem of organic solvents, and to solve the problem of poor permeability and stability of the skin, which is a problem of vitamin B3. Polyethylene glycol-vitamin B3 conjugate of formula (1) has improved solubility in organic solvents, is stable, and has a toxicity reduction effect, thus completing the present invention.

따라서, 본 발명의 목적은 유기용매에 대한 용해도가 개선되고, 안정하며, 독성이 없고, 우수한 항산화력을 나타내는 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트를 제공하는 것이다.Accordingly, an object of the present invention is to provide a vitamin C-polyethylene glycol-vitamin B3 conjugate which has improved solubility in organic solvents, is stable, has no toxicity, and exhibits excellent antioxidant ability.

본 발명의 다른 목적은 상기 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트를 포함하는 항산화제를 제공하는 것이다.Another object of the present invention is to provide an antioxidant comprising said vitamin C-polyethylene glycol-vitamin B3 conjugate.

본 발명은 하기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트에 관한 것이다.The present invention relates to vitamin C-polyethylene glycol-vitamin B3 conjugates of formula (1).

[화학식 1] [Chemical Formula 1]

Figure 112012104289203-pat00003
Figure 112012104289203-pat00003

상기 식에서,In this formula,

X1 및 X2는 각각 독립적으로 NH, O 또는 S이고, X 1 and X 2 are each independently NH, O or S,

n은 1 내지 700의 정수, 바람직하게는 4 내지 200의 정수이며,n is an integer of 1 to 700, preferably an integer of 4 to 200,

m은 0 또는 1이고,m is 0 or 1,

Y는

Figure 112012104289203-pat00004
또는
Figure 112012104289203-pat00005
이며,Y is
Figure 112012104289203-pat00004
or
Figure 112012104289203-pat00005
Lt;

R1은 수소 또는 C1-C6의 알킬기이다.
R 1 is hydrogen or a C 1 -C 6 alkyl group.

본 명세서에서 사용되는 C1-C6의 알킬기는 탄소수 1 내지 6개로 구성된 직쇄형 또는 분지형 탄화수소를 의미하며, 예를 들어 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, s-부틸, t-부틸, n-펜틸, n-헥실 등이 포함되나 이에 한정되는 것은 아니다.
As used herein, the C 1 -C 6 alkyl group means a linear or branched hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, Butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

일 태양으로, 본 발명의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 하기 화학식 1-1의 화합물이다.In one embodiment, the vitamin C-polyethylene glycol-vitamin B3 conjugate of the present invention is a compound of the following formula 1-1.

[화학식 1-1][Formula 1-1]

Figure 112012104289203-pat00006
Figure 112012104289203-pat00006

상기 식에서,In this formula,

X1 및 X2는 각각 독립적으로 NH, O 또는 S, 바람직하게는 O이고, X 1 and X 2 are each independently NH, O or S, preferably O,

n은 1 내지 700의 정수, 바람직하게는 4 내지 200의 정수이며,n is an integer of 1 to 700, preferably an integer of 4 to 200,

R1은 수소 또는 C1-C6의 알킬기, 바람직하게는 에틸기이다.
R 1 is hydrogen or a C 1 -C 6 alkyl group, preferably an ethyl group.

다른 태양으로, 본 발명의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 하기 화학식 1-2의 화합물이다.In another embodiment, the vitamin C-polyethylene glycol-vitamin B3 conjugate of the present invention is a compound of formula 1-2.

[화학식 1-2][Formula 1-2]

Figure 112012104289203-pat00007
Figure 112012104289203-pat00007

상기 식에서,In this formula,

X1은 NH, O 또는 S, 바람직하게는 O이고, X 1 is NH, O or S, preferably O,

n은 1 내지 700의 정수, 바람직하게는 4 내지 200의 정수이다.
n is an integer of 1 to 700, preferably an integer of 4 to 200. [

본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 예를 들어 하기 반응식 1 및 반응식 2에 나타낸 방법에 따라 제조될 수 있다. 하기 반응식에 기재된 방법은 본 발명에서 대표적으로 사용된 방법을 예시한 것일 뿐 단위조작의 순서, 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다. The vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention can be prepared, for example, according to the following reaction scheme 1 and scheme 2. The method described in the following reaction formulas exemplifies the method typically used in the present invention, and the order of the unit operation, the reaction reagent, the reaction conditions, and the like may be changed as required.

[반응식 1] [Reaction Scheme 1]

Figure 112012104289203-pat00008
Figure 112012104289203-pat00008

상기 식에서,In this formula,

X1, X2, n 및 R1은 화학식 1에서 정의한 바와 같다.
X 1 , X 2 , n and R 1 are as defined in formula (1).

상기 반응식 1에 따르면, 상기 화학식 3의 화합물과 상기 화학식 4의 화합물을 축합 반응시켜 상기 화학식 5의 화합물을 수득한 다음, 상기 화학식 5의 화합물과 상기 화학식 6의 화합물을 반응시켜 상기 화학식 7의 화합물을 수득한 후, 상기 화학식 7의 화합물과 상기 화학식 8의 화합물을 축합 반응시켜 상기 화학식 9의 화합물을 수득한 다음, 탈보호화 반응시켜 상기 화학식 1-1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트를 제조한다.
According to Reaction Scheme 1, the compound of Formula 3 and the compound of Formula 4 are condensed to obtain the compound of Formula 5, and then the compound of Formula 5 and the compound of Formula 6 are reacted to produce the compound of Formula 7 , The compound of formula (7) and the compound of formula (8) are condensed to obtain the compound of formula (9), followed by deprotection reaction to obtain a vitamin C-polyethylene glycol-vitamin B3 conjugate .

[반응식 2][Reaction Scheme 2]

Figure 112012104289203-pat00009
Figure 112012104289203-pat00009

상기 식에서,In this formula,

X1 및 n은 화학식 1에서 정의한 바와 같고,X 1 and n are as defined in formula (1)

R2는 메틸기 또는 톨릴기, 바람직하게는 p-톨릴기이다.
R 2 is a methyl group or a tolyl group, preferably a p-tolyl group.

상기 반응식 2에 따르면, 상기 화학식 3의 화합물과 상기 화학식 4-1의 화합물을 축합 반응시켜 상기 화학식 5-1의 화합물을 수득한 다음, 상기 화학식 5-1의 화합물과 상기 화학식 10의 화합물을 반응시켜 상기 화학식 11의 화합물을 수득한 후, 상기 화학식 11의 화합물과 상기 화학식 8-1의 화합물을 반응시켜 상기 화학식 12의 화합물을 수득한 다음, 탈보호화 반응시켜 상기 화학식 1-2의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트를 제조한다.
According to Reaction Scheme 2, the compound of Formula 3 and the compound of Formula 4-1 are subjected to a condensation reaction to obtain the compound of Formula 5-1, and then the compound of Formula 5-1 and the compound of Formula 10 are reacted To obtain a compound of Formula 11, and then reacting the compound of Formula 11 with the compound of Formula 8-1 to obtain a compound of Formula 12, followed by deprotection to obtain a vitamin C- A polyethylene glycol-vitamin B3 conjugate is prepared.

상기 축합 반응은 용매 중에서 축합제 및 유기아민 촉매의 존재 하에 수행하는 것이 바람직하다. The condensation reaction is preferably carried out in the presence of a condensing agent and an organic amine catalyst in a solvent.

상기 축합제로는 N,N,N',N'-테트라메틸-(벤조트리아졸-1-일)-우로니움테트라플루오로보레이트(TBTU), N-(3-디메틸아미노프로필)-N'-에틸-카보디이미드(EDC), N,N'-디이소프로필카보디이미드(DIC) 또는 N,N‘-디사이클로헥실카보디이미드(DCC)을 사용할 수 있으나, 이에 한정되는 것은 아니다. 또한, 축합반응을 촉진시키는 유기아민 촉매로는 디이소프로필에틸아민(DIPEA) 또는 4-디메틸아미노피리딘(DMAP)을 사용할 수 있으나, 이에 한정되는 것은 아니다. 용매로는 무수 유기용매, 예를 들어 디클로로메탄, 벤젠, 톨루엔, 테트라하이드로푸란 및 디에틸에테르 중에서 선택된 1종 이상을 사용할 수 있으나, 이에 한정되는 것은 아니다. 축합 반응은 냉각 내지 가온된 상태에서 진행될 수 있다.
Examples of the condensing agent include N, N, N ', N'-tetramethyl- (benzotriazol-1-yl) -uronium tetrafluoroborate (TBTU) But are not limited to, ethyl-carbodiimide (EDC), N, N'-diisopropylcarbodiimide (DIC) or N, N'-dicyclohexylcarbodiimide (DCC). Diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP) may be used as the organic amine catalyst for promoting the condensation reaction, but the present invention is not limited thereto. As the solvent, at least one selected from anhydrous organic solvents such as dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether may be used, but the present invention is not limited thereto. The condensation reaction can proceed in a cooled or warmed state.

상기 반응식 1에서, 화학식 3의 화합물은 화학식 4의 화합물을 기준으로 1 내지 3 당량 사용하는 것이 바람직하고, 화학식 6의 화합물은 화학식 5의 화합물을 기준으로 2 내지 10 당량 사용하는 것이 바람직하다. 또한, 화학식 8의 화합물은 화학식 7의 화합물을 기준으로 1 내지 2 당량 사용하는 것이 바람직하다. In Scheme 1, the compound of Formula 3 is preferably used in an amount of 1 to 3 equivalents based on the compound of Formula 4, and the compound of Formula 6 is preferably used in an amount of 2 to 10 equivalents based on the compound of Formula 5. The compound of formula (8) is preferably used in an amount of 1 to 2 equivalents based on the compound of formula (7).

화학식 9의 화합물의 탈보호화 반응은 트리플루오로아세트산(TFA), 염산, 황산 및 아세트산과 같은 산 존재 하에 수행할 수 있으며, 용매로는 테트라하이드로푸란, 디클로로메탄 및 메탄올 중에서 선택된 1종 이상을 사용할 수 있으나, 이에 한정되는 것은 아니다.
The deprotection reaction of the compound of formula (9) can be carried out in the presence of an acid such as trifluoroacetic acid (TFA), hydrochloric acid, sulfuric acid and acetic acid, and at least one selected from tetrahydrofuran, dichloromethane and methanol But is not limited thereto.

상기 반응식 2에서, 화학식 3의 화합물은 화학식 4-1의 화합물을 기준으로 1 내지 3 당량 사용하는 것이 바람직하고, 화학식 10의 화합물은 화학식 5-1의 화합물을 기준으로 2 내지 10 당량 사용하는 것이 바람직하다. 또한, 화학식 8-1의 화합물은 화학식 11의 화합물을 기준으로 1 내지 3 당량 사용하는 것이 바람직하다. In Scheme 2, the compound of Formula 3 is preferably used in an amount of 1 to 3 equivalents based on the compound of Formula 4-1, and the compound of Formula 10 is used in an amount of 2 to 10 equivalents based on the compound of Formula 5-1 desirable. The compound of formula (8-1) is preferably used in an amount of 1 to 3 equivalents based on the compound of formula (11).

화학식 12의 화합물의 탈보호화 반응은 트리플루오로아세트산(TFA), 염산, 황산 및 아세트산과 같은 산 존재 하에 수행할 수 있으며, 용매로는 테트라하이드로푸란, 디클로로메탄 및 메탄올 중에서 선택된 1종 이상을 사용할 수 있으나, 이에 한정되는 것은 아니다.
The deprotecting reaction of the compound of formula (12) can be carried out in the presence of an acid such as trifluoroacetic acid (TFA), hydrochloric acid, sulfuric acid and acetic acid, and at least one selected from tetrahydrofuran, dichloromethane and methanol But is not limited thereto.

X1 및 X2가 O인 화학식 4의 화합물(PEG)는 공지의 수용성 고분자로서 상업적으로 입수하거나 공지된 방법[참고문헌: Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol. 3, pages 138-161]에 따라 에틸렌 글리콜을 개환 중합반응시켜 제조할 수 있다. The compound (PEG) represented by the formula (4) wherein X 1 and X 2 are O can be obtained as a known water-soluble polymer by a commercially available method or a known method (see Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol. 3, pages 138-161].

X1 및 X2가 NH인 화학식 4의 화합물(말단에 아민기를 가지는 PEG 유도체)는 상업적으로 입수하거나 공지된 방법[참고문헌: Makromol. Chem., 1981, vol. 182, pages 1379-1384 등]에 따라 PEG로부터 제조할 수 있다.The compound of formula (4) wherein X 1 and X 2 are NH (PEG derivative having an amine group at the terminal) is commercially available or can be obtained by a known method [References: Makromol. Chem., 1981 , vol. 182, pages 1379-1384, etc.).

X1 및 X2가 S인 화학식 4의 화합물(말단에 티올기를 가지는 PEG 유도체)는 상업적으로 입수하거나 공지된 방법[참고문헌: Bioconjugate chemistry, 1993, Vol. 4, pages 314-318]에 따라 PEG로부터 제조할 수 있다.
The compound of formula (4) wherein X 1 and X 2 are S (PEG derivative having a thiol group at the terminal) can be obtained commercially or can be prepared by a known method (refer to Bioconjugate chemistry, 1993 , Vol. 4, pages 314-318].

본 발명에 따른 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 자유라디칼 소거 효과 실험에서 니코틴산(Nicotinic acid)과 유사한 항산화력을 나타내었으며, 세포활성도 평가 실험에서 독성감소 효과를 나타내었다.The vitamin C-polyethylene glycol-vitamin B3 conjugate of Formula 1 according to the present invention showed antioxidant activity similar to that of nicotinic acid in the free radical scavenging effect test, and exhibited toxicity reduction effect in the cell activity evaluation experiment.

따라서, 본 발명에 따른 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 우수한 항산화제로서 사용될 수 있다.
Accordingly, the vitamin C-polyethylene glycol-vitamin B3 conjugate of Formula 1 according to the present invention can be used as an excellent antioxidant.

일 태양으로, 본 발명에 따른 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 노화방지용 화장료 조성물에 사용될 수 있다. In one aspect, the vitamin C-polyethylene glycol-vitamin B3 conjugate of Formula 1 according to the present invention can be used in an anti-aging cosmetic composition.

본 발명에 따른 화장료 조성물은 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트를 유효성분으로서 약 0.1 내지 10 중량%, 바람직하게는 0.5 내지 2 중량%로 포함한다. 유효성분의 함량은 그의 사용 목적에 따라 적절하게 결정될 수 있다.The cosmetic composition according to the present invention contains about 0.1 to 10% by weight, preferably 0.5 to 2% by weight, of the vitamin C-polyethylene glycol-vitamin B3 conjugate of Formula 1 as an active ingredient. The content of the active ingredient can be appropriately determined depending on the purpose of use thereof.

본 발명의 화장료 조성물은 유효성분으로서 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트 이외에 화장료 조성물에 통상적으로 사용되는 성분들, 예를 들어 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함한다.The cosmetic composition of the present invention may further contain, as an active ingredient, components commonly used in cosmetic compositions, such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and the like, in addition to the vitamin C- polyethylene glycol- Customary adjuvants such as perfumes, and carriers.

본 발명의 화장료 조성물은 당업계에서 통상적으로 사용되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 파우더, 스프레이 등으로 제형화될 수 있다. The cosmetic composition of the present invention may be prepared in any form conventionally used in the art and may be formulated into, for example, solutions, suspensions, emulsions, pastes, gels, creams, powders, sprays and the like.

본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크, 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream or gel, an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicon, bentonite, silica, talc, .

본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트, 폴리아미드 파우더 등이 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder and the like may be used as a carrier component. In particular, Propane / butane or dimethyl ether.

본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제, 예를 들어 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방산 에스테르, 폴리에틸렌 글리콜, 소르비탄의 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a solution or an emulsion, a solvent, a solubilizer or an emulsifier such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 3-butyl glycol oil, glycerol fatty acid ester, polyethylene glycol, fatty acid esters of sorbitan, and the like.

본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 또는 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가, 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester or polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar, tracant and the like may be used.

본 발명의 화장료 조성물은 스킨, 로션, 크림, 에센스, 팩, 파운데이션, 색조화장품, 선크림, 투웨이케이크, 페이스파우더, 콤팩트, 메이크업베이스, 스킨커버, 아이쉐도우, 립스틱, 립글로스, 립픽스, 아이브로우 펜슬 등의 화장품에 적용될 수 있다.
The cosmetic composition of the present invention can be used as a cosmetic composition for skin, lotion, cream, essence, pack, foundation, color cosmetic, sunscreen, two way cake, face powder, compact, And the like.

다른 태양으로, 본 발명에 따른 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 노화방지용 약제학적 조성물에 사용될 수 있다.In another aspect, the vitamin C-polyethylene glycol-vitamin B3 conjugate of Formula 1 according to the present invention may be used in an anti-aging pharmaceutical composition.

본 발명에 따른 약제학적 조성물은 경구적으로(예를 들면, 복용 또는 흡입) 또는 비경구적으로(예를 들면, 주사, 경피흡수, 직장투여) 투여될 수 있으며, 주사는 예를 들면, 정맥주사, 피하주사, 근육내주사 또는 복강내주사일 수 있다. 본 발명에 따른 약제학적 조성물은 투여 경로에 따라, 정제, 캡슐제, 과립제, 파인 서브틸래(fine subtilae), 분제, 설하 정제, 좌약, 연고, 주사제, 유탁액제, 현탁액제, 시럽제, 분무제 등으로 제형화될 수 있다. 상기 여러 가지 형태의 본 발명에 따른 약제학적 조성물은 각 제형에 통상적으로 사용되는 약제학적으로 허용되는 담체(carrier)를 사용하여 공지기술에 의해 제조될 수 있다. 약제학적으로 허용되는 담체의 예는 부형제, 결합제, 붕해제(disintegrating agent), 윤활제, 방부제, 항산화제, 등장제(isotonic agent), 완충제, 피막제, 감미제, 용해제, 기제(base), 분산제, 습윤제, 현탁화제, 안정제, 착색제 등을 포함한다. The pharmaceutical composition according to the present invention may be administered orally (e.g., by taking or inhalation) or parenterally (for example, by injection, percutaneous absorption, rectal administration), and the injection may be, for example, , Subcutaneous injection, intramuscular injection or intraperitoneal injection. The pharmaceutical composition according to the present invention may be formulated into tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, Can be formulated. The various forms of the pharmaceutical composition according to the present invention can be prepared by a known technique using a pharmaceutically acceptable carrier commonly used in each formulation. Examples of pharmaceutically acceptable carriers are excipients such as excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, encapsulating agents, sweeteners, solubilizers, bases, , Suspending agents, stabilizers, coloring agents and the like.

본 발명에 따른 약제학적 조성물은 약제의 형태에 따라 다르지만, 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트를 약 0.1 내지 10 중량%, 바람직하게는 0.5 내지 2 중량%로 포함한다. The pharmaceutical composition according to the present invention contains about 0.1 to 10% by weight, preferably 0.5 to 2% by weight, of the vitamin C-polyethylene glycol-vitamin B3 conjugate of Formula 1, though it varies depending on the form of the drug.

본 발명의 약제학적 조성물의 구체적인 투여량은 치료되는 사람을 포함한 포유동물의 종류, 체중, 성별, 질환의 정도, 의사의 판단 등에 따라 다를 수 있다. 바람직하게는, 경구투여의 경우에는 하루에 체중 1 kg 당 활성성분 10 내지 200 mg이 투여된다. 상기 총 일일 투여량은 질환의 정도, 의사의 판단 등에 따라 한번에 또는 수회로 나누어 투여될 수 있다.
The specific dosage of the pharmaceutical composition of the present invention may vary depending on the kind of mammal including the person to be treated, body weight, sex, degree of disease, judgment of a doctor, and the like. Preferably, in the case of oral administration, 10 to 200 mg of active ingredient per kg of body weight per day is administered. The total daily dose may be administered once or several times depending on the severity of the disease, the judgment of the physician, and the like.

또 다른 태양으로, 본 발명에 따른 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 노화방지용 건강기능식품에 사용될 수 있다.In another embodiment, the vitamin C-polyethylene glycol-vitamin B3 conjugate of Formula 1 according to the present invention may be used in an anti-aging health functional food.

본 발명에 따른 건강기능식품의 종류에는 특별한 제한이 없으며, 산제, 과립제, 정제, 캡슐제, 현탁액제, 에멀젼, 시럽제 등의 경구형 제제 형태이거나, 캔디, 과자, 껌, 아이스크림, 면류, 빵, 음료 등 일반적인 식품에 첨가될 수 있다. The health functional food according to the present invention is not particularly limited and may be in the form of an oral preparation such as a powder, a granule, a tablet, a capsule, a suspension, an emulsion or a syrup, a candy, a cake, May be added to general foods such as beverages.

본 발명의 건강기능식품은 형태에 따라 통상적인 방법으로 충진제, 증량제, 결합제, 습윤제, 붕해제, 감미제, 방향제, 보존제, 계면활성제, 윤활제, 부형제 등 식품학적으로 허용되는 담체를 적절히 사용하여 제조될 수 있다. The health functional food of the present invention may be prepared by suitably using a food acceptable carrier such as a filler, an extender, a binder, a wetting agent, a disintegrant, a sweetener, a fragrance, a preservative, a surfactant, a lubricant, .

상기 건강기능식품의 제조에 있어서 상기 화학식 1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트의 함량은 건강기능식품의 형태에 따라 다르지만, 약 0.1 내지 10 중량%, 바람직하게는 0.5 내지 2 중량%의 농도이다.The content of the vitamin C-polyethylene glycol-vitamin B3 conjugate of formula 1 in the preparation of the health functional food varies depending on the form of the health functional food, but is about 0.1 to 10% by weight, preferably 0.5 to 2% by weight Concentration.

본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 유기용매에 대한 용해도가 개선되고, 안정하며, 독성감소 효과를 가진다. The vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention has improved solubility in organic solvents, is stable, and has toxicity reduction effect.

아울러, 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 생체 내 pH 조건에서 가수분해되어 활성 비타민 C와 비타민 B3를 방출할 수 있으므로, 항산화, 주름개선, 미백 등 비타민 C와 비타민 B3의 생리활성을 나타낼 수 있다.In addition, the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention is capable of hydrolyzing at pH in vivo to release active vitamin C and vitamin B3, and thus can inhibit the production of vitamin C and vitamin B3 And can exhibit physiological activity.

따라서, 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 우수한 비타민 C와 비타민 B3의 공급원으로서, 노화방지용 화장료 조성물, 약제학적 조성물, 건강기능식품 등에 효과적으로 사용될 수 있다.Therefore, the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention is a good source of vitamin C and vitamin B3, and can be effectively used for cosmetic compositions for preventing aging, pharmaceutical compositions, health functional foods and the like.

도 1은 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트(Vit.B3-PEG-EtVit.C)의 자유라디칼 잔존율을 아스코르빈산 및 니코틴산과 비교한 그래프이다.
도 2는 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트(Vit.B3-PEG-EtVit.C)의 세포활성도(cell viability)를 아스코르빈산 및 니코틴산과 비교한 그래프이다.
도 3은 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트(Vit.B3-PEG-EtVit.C)의 완충용액 및 인간 혈청 중 가수분해율을 나타낸 그래프이다.BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph comparing free radical survival rates of vitamin C-polyethylene glycol-vitamin B3 conjugate (Vit.B3-PEG-EtVit.C) according to the present invention with ascorbic acid and nicotinic acid.
FIG. 2 is a graph comparing the cell viability of vitamin C-polyethylene glycol-vitamin B3 conjugate (Vit.B3-PEG-EtVit.C) according to the present invention with ascorbic acid and nicotinic acid.
FIG. 3 is a graph showing the buffer solution and the hydrolysis rate in human serum of a vitamin C-polyethylene glycol-vitamin B3 conjugate (Vit.B3-PEG-EtVit.C) according to the present invention.

이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are for illustrative purpose only and that the scope of the present invention is not limited to these embodiments.

제조예 1: 3-에틸-5,6-이소프로필리덴 아스코르빈산(RPreparation Example 1: Preparation of 3-ethyl-5,6-isopropylidene ascorbic acid (R 1One 이 에틸기인 화학식 8의 화합물)의 제조Compound of formula 8, which is the ethyl group)

에틸 아스코르빈산 10.1 g에 아세톤 50 ml를 넣고 교반한 후, 0 ℃에서 아세틸클로라이드 0.85 g(0.011 mol)을 천천히 가한 다음, 실온에서 3 시간 동안 교반하였다. 반응 용매를 제거하고, 에틸아세테이트와 n-헥산(1:3)으로 실리카겔 컬럼 크로마토그래피하여 8.66 g의 백색 고형의 표제 화합물을 수득하였다.To 10.1 g of ethyl ascorbic acid was added 50 ml of acetone and the mixture was stirred. Then, 0.85 g (0.011 mol) of acetyl chloride was added slowly at 0 ° C and the mixture was stirred at room temperature for 3 hours. The reaction solvent was removed and the residue was subjected to silica gel column chromatography with ethyl acetate and n-hexane (1: 3) to obtain 8.66 g of white solid title compound.

1H NMR 400 MHz(CDCl3) δ 6.40(bs, 1H), 4.58-4.53(m, 3H), 4.27(q, 1H), 4.15(t, 1H), 4.03(t, 1H), 1.38(dd, 6H), 1.36(s, 3H)
 1 H NMR 400 MHz (CDCl 3 ) δ 6.40 (bs, 1H), 4.58-4.53 (m, 3H), 4.27 (q, 1H), 4.15 (t, 1H), 4.03 (t, 1H), 1.38 (dd , ≪ / RTI > 6H), 1.36 (s, 3H)

제조예 2: 5,6-이소프로필리덴 아스코르빈산(화학식 8-1의 화합물)의 제조Production Example 2: Preparation of 5,6-isopropylidene ascorbic acid (compound of Formula 8-1)

아스코르빈산 15.0 g에 아세톤 75 ml를 넣고 교반한 후, 0 ℃에서 아세틸클로라이드 1.33 g(0.017 mol)을 천천히 가한 다음, 실온에서 3 시간 동안 교반하였다. 반응 용매를 제거하고, 에틸아세테이트와 n-헥산(1:3)으로 실리카겔 컬럼 크로마토그래피하여 11.3 g의 백색 고형의 표제 화합물을 수득하였다.To 15.0 g of ascorbic acid was added 75 ml of acetone and the mixture was stirred. Then, 1.33 g (0.017 mol) of acetyl chloride was added slowly at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction solvent was removed and the resultant was subjected to silica gel column chromatography with ethyl acetate and n-hexane (1: 3) to obtain 11.3 g of white solid title compound.

1H NMR 400 MHz(CDCl3) δ 4.71(s, 1H), 4.27(dt, 1H), 4.10(t, 1H), 3.88(dd, 1H)
 1 H NMR 400 MHz (CDCl 3 )? 4.71 (s, IH), 4.27 (dt, IH), 4.10

실시예 1: Vit.B3-PEG-EtVit.C(XExample 1: Vit.B3-PEG-EtVit.C (X 1One 및 X And X 22 가 산소이고, n은 4이며, RIs oxygen, n is 4, R 1One 은 에틸기인 화학식 1-1의 화합물)의 제조Lt; / RTI > is an ethyl group)

실시예 1-1: Vit.B3-PEG-숙신산(XExample 1-1: Vit.B3-PEG-succinic acid (X 1One 및 X And X 22 가 산소이고, n은 4인 화학식 7의 화합물)의 제조Lt; / RTI > is oxygen and n is 4)

폴리에틸렌글리콜(PEG200) 8.49 g(0.044 mol)을 디클로로메탄 100 ml에 용해한 용액에 4-디메틸아미노피리딘 5.9 g(0.048 mol)과 니코틴산 5.4 g(0.044 mol)을 가하고, N-(3-디메틸아미노프로필)-N'-에틸-카보디이미드 10.1 g(0.053 mol)을 가한 후 실온에서 5시간 동안 교반하였다. 반응 용액을 포화 염화암모늄 수용액으로 세척하고, 유기층을 무수 황산마그네슘으로 처리한 후 여과하여 감압 농축하였다.5.9 g (0.048 mol) of 4-dimethylaminopyridine and 5.4 g (0.044 mol) of nicotinic acid were added to a solution of 8.49 g (0.044 mol) of polyethylene glycol (PEG200) dissolved in 100 ml of dichloromethane, N- (3- ) -N'-ethyl-carbodiimide (10.1 g, 0.053 mol) was added thereto, followed by stirring at room temperature for 5 hours. The reaction solution was washed with a saturated ammonium chloride aqueous solution, and the organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

생성된 혼합물을 디클로로메탄 70 ml에 용해한 용액에 트리에틸아민 5.07 g(0.05 mol)과 4-디메틸아미노피리딘 2.45 g(0.02 mol)을 가하였다. 반응 용액에 숙신산무수물 5.02 g(0.05 mol)을 가하고, 반응 용액을 1.0 N 염산 수용액과 포화 염화암모늄 수용액으로 순차적으로 세척한 다음, 유기층을 무수 황산마그네슘으로 처리한 후 여과하여 감압 농축하였다. 생성된 혼합물을 메탄올과 디클로로메탄(1:15)으로 실리카겔 컬럼 크로마토그래피하여 5.74 g의 표제 화합물을 수득하였다. 5.07 g (0.05 mol) of triethylamine and 2.45 g (0.02 mol) of 4-dimethylaminopyridine were added to a solution of the resulting mixture in 70 ml of dichloromethane. 5.02 g (0.05 mol) of succinic anhydride was added to the reaction solution, and the reaction solution was washed sequentially with 1.0 N hydrochloric acid aqueous solution and saturated ammonium chloride aqueous solution. The organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography with methanol and dichloromethane (1: 15) to obtain 5.74 g of the title compound.

1H NMR 400 MHz (CDCl3) δ 9.25(s, 1H), 8.79(d, 1H), 8.32(dd, 1H), 7.43(dt, 1H), 4.52(dt, 2H), 3.86(t, 2H), 3.85-3.64(PEG, 12H), 2.84(t, 2H), 2.74(t, 2H)
 1 H NMR 400 MHz (CDCl 3 ) δ 9.25 (s, 1H), 8.79 (d, 1H), 8.32 (dd, 1H), 7.43 (dt, 1H), 4.52 (dt, 2H), 3.86 (t, 2H ), 3.85-3.64 (PEG, 12H), 2.84 (t, 2H), 2.74 (t, 2H)

실시예 1-2: Vit.B3-PEG-(3-에틸-5,6-이소프로필리덴)Vit.C(XExample 1-2: Vit.B3-PEG- (3-ethyl-5,6-isopropylidene) Vit.C (X 1One 및 X And X 22 가 산소이고, n은 4 이며, RIs oxygen, n is 4, R 1One 은 에틸기인 화학식 9의 화합물)의 제조Lt; RTI ID = 0.0 > (9) < / RTI >

실시예 1-1에서 수득한 Vit.B3-PEG-숙신산 5 g(0.0147 mol)과 4-디메틸아미노피리딘 1.84 g(0.015 mol)을 디클로로메탄 100 ml에 용해하고, 제조예 1에서 수득한 3-에틸-5,6-이소프로필리덴 아스코르빈산 3.45 g(0.0147 mol)을 가한 다음, N-(3-디메틸아미노프로필)-N'-에틸-카보디이미드 3.6 g(0.019 mol)을 가하고 12시간 동안 교반하였다. 반응 용액을 1.0 N 염산 수용액과 포화 탄산수소나트륨 수용액으로 순차적으로 세척하고, 유기층을 무수 황산마그네슘으로 처리한 후 여과하여 감압 농축하였다. 생성된 혼합물을 메탄올과 디클로로메탄(1:15)으로 실리카겔 컬럼 크로마토그래피하여 3.47 g의 표제 화합물을 수득하였다.5 g (0.0147 mol) of Vit.B3-PEG-succinic acid obtained in Example 1-1 and 1.84 g (0.015 mol) of 4-dimethylaminopyridine obtained in Example 1-1 were dissolved in 100 ml of dichloromethane. To a solution of 3- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide (3.6 g, 0.019 mol) was added thereto, and the mixture was stirred for 12 hours Lt; / RTI > The reaction solution was washed sequentially with 1.0 N hydrochloric acid aqueous solution and saturated aqueous sodium hydrogencarbonate solution, and the organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography with methanol and dichloromethane (1:15) to obtain 3.47 g of the title compound.

1H NMR 400 MHz (CDCl3) δ 9.25(s, 1H), 8.79(d, 1H), 8.32(dd, 1H), 7.43(dt, 1H), 4.83(d, 1H), 4.52(dt, 2H), 4.39(t, 2H), 4.23(t, 2H), 4.02(t, 1H), 3.86-3.64(PEG & CHb, 15H), 2.84(t, 2H), 2.74(t, 2H), 1.38(s, 3H), 1.37(t, 3H), 1.35(s, 3H)
 1 H NMR 400 MHz (CDCl 3 ) δ 9.25 (s, 1H), 8.79 (d, 1H), 8.32 (dd, 1H), 7.43 (dt, 1H), 4.83 (d, 1H), 4.52 (dt, 2H ), 4.39 (t, 2H) , 4.23 (t, 2H), 4.02 (t, 1H), 3.86-3.64 (PEG & CH b, 15H), 2.84 (t, 2H), 2.74 (t, 2H), 1.38 (s, 3H), 1.37 (t, 3H), 1.35 (s, 3H)

실시예 1-3: Vit.B3-PEG-EtVit.C(XExample 1-3: Vit.B3-PEG-EtVit.C (X 1One 및 X And X 22 가 산소이고, n은 4 이며, RIs oxygen, n is 4, R 1One 은 에틸기인 화학식 1-1의 화합물)의 제조Lt; / RTI > is an ethyl group)

실시예 1-2에서 수득한 Vit.B3-PEG-(3-에틸-5,6-이소프로필리덴)Vit.C 1.0 g(1.60 mmol)을 테트라히드라퓨란 20 ml에 용해한 용액에 염산 1.7 ml(16.0 mmol)를 가하고 1 시간 정도 교반하였다. 반응 용매를 감압하여 제거하고, 잔류물을 디클로로메탄에 용해시켜 포화 탄산수소나트륨 수용액으로 세척한 다음, 유기층을 무수 황산마그네슘으로 처리하고 여과한 후 감압 농축하여 0.72 g의 표제 화합물을 수득하였다.To a solution of Vit.B3-PEG- (3-ethyl-5,6-isopropylidene) Vit.C obtained in Example 1-2 (1.0 g, 1.60 mmol) in 20 ml of tetrahydrofuran was added 1.7 ml 16.0 mmol) was added thereto, followed by stirring for about 1 hour. The reaction solvent was removed under reduced pressure, the residue was dissolved in dichloromethane and washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 0.72 g of the title compound.

1H NMR 400 MHz (CDCl3) δ 9.23(s, 1H), 8.78(d, 1H), 8.34(dd, 1H), 7.43(dt, 1H), 4.83(d, 1H), 4.52(dt, 2H), 4.39(t, 2H), 4.23(t, 2H), 4.02(t, 1H), 3.86-3.64(PEG & CHb, 15H), 2.84(t, 2H), 2.74(t, 2H), 1.37(t, 3H)
 1 H NMR 400 MHz (CDCl 3 ) δ 9.23 (s, 1H), 8.78 (d, 1H), 8.34 (dd, 1H), 7.43 (dt, 1H), 4.83 (d, 1H), 4.52 (dt, 2H ), 4.39 (t, 2H) , 4.23 (t, 2H), 4.02 (t, 1H), 3.86-3.64 (PEG & CH b, 15H), 2.84 (t, 2H), 2.74 (t, 2H), 1.37 (t, 3 H)

실시예 2: Vit.B3-PEG-Vit.C(XExample 2: Vit.B3-PEG-Vit.C (X 1One 이 산소이고, n은 4인 화학식 1-2의 화합물)의 제조Is oxygen, and n is 4)

실시예 2-1: Vit.B3-PEG-OMs(XExample 2-1: Vit.B3-PEG-OMs (X 1One 이 산소이고, n은 4이며, RIs oxygen, n is 4, R 22 는 메틸기인 화학식 11의 화합물)의 제조Lt; / RTI > is a methyl group)

폴리에틸렌글리콜(PEG200) 11.4 g(58.8 mmol)을 디클로로메탄 100 ml에 용해한 용액에 4-디메틸아미노피리딘 8.6 g(70.5 mmol)과 니코틴산 7.23 g(58.8 mmol)을 가하고, N-(3-디메틸아미노프로필)-N'-에틸-카보디이미드 16.9 g(88.1 mmol)을 천천히 가한 후 실온에서 2시간 동안 교반하였다. 반응 용액을 1.0 N 염산 수용액으로 세척하고, 유기층을 무수 황산마그네슘으로 처리한 후 여과하여 감압 농축하였다. Dimethylaminopyridine (8.6 g, 70.5 mmol) and nicotinic acid (7.23 g, 58.8 mmol) were added to a solution of 11.4 g (58.8 mmol) of polyethylene glycol (PEG200) in 100 ml of dichloromethane and N- (3- ) -N'-ethyl-carbodiimide (16.9 g, 88.1 mmol) was slowly added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was washed with 1.0 N hydrochloric acid aqueous solution, and the organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

혼합물을 디클로로메탄 150 ml에 용해하고, 트리에틸아민 8.2 ml(58.8 mmol)을 가한 다음, 메실클로라이드 9.1 ml(0.118 mol)을 가하고 12 시간 동안 교반하였다. 반응 용액을 포화 염화암모늄 수용액으로 세척하고, 유기층을 무수 황산마그네슘으로 처리한 후 여과하여 감압 농축하였다. 생성된 혼합물을 메탄올과 디클로로메탄(1:12)으로 실리카겔 컬럼 크로마토그래피하여 9.1 g의 정제된 표제 화합물을 수득하였다.The mixture was dissolved in dichloromethane (150 ml), and then 8.2 ml (58.8 mmol) of triethylamine was added. 9.1 ml (0.118 mol) of mesyl chloride was added and stirred for 12 hours. The reaction solution was washed with a saturated ammonium chloride aqueous solution, and the organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography with methanol and dichloromethane (1: 12) to obtain 9.1 g of the purified title compound.

1H NMR 400 MHz(CDCl3) δ 9.25(s, 1H), 8.79(d, 1H), 8.32(dt, 1H), 7.41(dd, 1H), 4.51(dt, 2H), 3.86(dt, 2H), 3.76-3.59(PEG & Ms, 15H)
 1 H NMR 400 MHz (CDCl 3 ) δ 9.25 (s, 1H), 8.79 (d, 1H), 8.32 (dt, 1H), 7.41 (dd, 1H), 4.51 (dt, 2H), 3.86 (dt, 2H ), 3.76-3.59 (PEG & Ms, 15H)

실시예 2-2: Vit.B3-PEG-(5,6-이소프로필리덴)Vit.C(XExample 2-2: Vit.B3-PEG- (5,6-isopropylidene) Vit.C (X 1One 이 산소이고, n은 4인 화학식 12의 화합물)의 제조Lt; / RTI > is oxygen and n is 4)

실시예 2-1에서 수득한 Vit.B3-PEG-OMs 5.0 g(13.2 mmol)을 테트라하이드로퓨란 50 ml에 용해한 용액에 제조예 2에서 수득한 5,6-이소프로필리덴 아스코르빈산 2.86 g(13.2 mmol)을 디메틸설폭사이드 50 ml에 용해한 용액을 가하고, 50 ℃로 가온하여 10분 정도 교반하였다. 그런 다음, 반응 용액에 탄산칼륨 1.83 g(13.2 mmol)을 가하고, 60 ℃로 가온하여 3 시간 동안 교반하였다. 반응 용액을 감압하여 테트라하이드로퓨란을 제거하고 디클로로메탄 150 ml를 가한 다음, 포화 염화암모늄 수용액 100 ml로 세척하였다. 유기층을 무수 황산마그네슘으로 처리한 후 여과하여 감압 농축하였다. 생성된 혼합물을 에틸아세테이트와 헥산(3:1)로 실리카겔 컬럼 크로마토그래피하여 5.4 g의 표제화합물을 수득하였다.To a solution of 5.0 g (13.2 mmol) of Vit.B3-PEG-OMs obtained in Example 2-1 in 50 ml of tetrahydrofuran was added 2.86 g of 5,6-isopropylidene ascorbic acid obtained in Preparation Example 2 13.2 mmol) in 50 ml of dimethylsulfoxide was added, and the mixture was heated to 50 DEG C and stirred for about 10 minutes. Then, 1.83 g (13.2 mmol) of potassium carbonate was added to the reaction solution, which was then heated to 60 DEG C and stirred for 3 hours. The reaction solution was reduced in pressure to remove tetrahydrofuran, 150 ml of dichloromethane was added, and the mixture was washed with 100 ml of a saturated aqueous solution of ammonium chloride. The organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography with ethyl acetate and hexane (3: 1) to obtain 5.4 g of the title compound.

1H NMR 400 MHz(CDCl3) δ 9.24(d, 1H), 8.78(dd, 1H), 8.32(d, 1H), 7.41(dd, 1H), 4.65(d, 1H), 4.52(dt, 2H), 4.43(q, 1H), 4.15(dd, 1H), 4.08(dd, 1H), 3.85(dt, 2H), 3.72-3.64(PEG, 12H), 1.40(s, 3H), 1.36(s, 3H)
 1 H NMR 400 MHz (CDCl 3 )? 9.24 (d, 1 H), 8.78 (dd, 1 H), 8.32 3H), 1.36 (s, 3H), 4.43 (s, 3H), 4.43 (d, 3H)

실시예 2-3: Vit.B3-PEG-Vit.C(XExample 2-3: Vit.B3-PEG-Vit.C (X 1One 이 산소이고, n은 4인 화학식 1-2의 화합물)의 제조Is oxygen, and n is 4)

실시예 2-2에서 수득한 Vit.B3-PEG-(5,6-이소프로필리덴)Vit.C 3 g을 디클로로메탄 32 ml에 용해한 용액에 트리플루오로아세트산 8 ml를 가하고, 실온에서 30분 동안 교반하였다. 반응 용매를 감압하여 제거하고, 잔류물을 디클로로메탄에 용해시켜 물로 세척한 다음, 유기층을 무수 황산마그네슘으로 처리하고 여과한 후, 감압 농축하여 2.3 g의 표제 화합물을 수득하였다.8 ml of trifluoroacetic acid was added to a solution of 3 g of Vit.B3-PEG- (5,6-isopropylidene) Vit.C obtained in Example 2-2 in 32 ml of dichloromethane, and the mixture was stirred at room temperature for 30 minutes Lt; / RTI > The reaction solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The organic layer was treated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 2.3 g of the title compound.

1H NMR 400 MHz(CDCl3) δ 9.24(d, 1H), 8.78(dd, 1H), 8.32(d, 1H), 7.41(dd, 1H), 4.71(d, 1H), 4.52(dt, 2H), 4.43(q, 1H), 4.15(dd, 2H), 3.85(dt, 2H), 3.72-3.64(PEG, 12H)
 1 H NMR 400 MHz (CDCl 3 )? 9.24 (d, 1 H), 8.78 (dd, 1 H), 8.32 ), 4.43 (q, 1H), 4.15 (dd, 2H), 3.85 (dt, 2H), 3.72-3.64

실험예 1: 물에 대한 용해도 평가Experimental Example 1: Evaluation of solubility in water

상기 실시예 1에서 수득한 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트 (Vit.B3-PEG-EtVit.C)를 탈이온수에 농도 별로 용해시키고 분광광도계(spectrophotometer)를 이용하여 50%의 투과도(transmittance)를 보이는 농도를 측정하였다. The Vitamin C-polyethylene glycol-vitamin B3 conjugate (Vit.B3-PEG-EtVit.C) obtained in Example 1 was dissolved in deionized water at different concentrations and a 50% transmittance was measured using a spectrophotometer. ) Were measured.

그 결과, 실시예 1에서 수득한 Vit.B3-PEG-EtVit.C는 33.4 mg/ml로 수용성 화합물임을 확인하였다.
As a result, Vit.B3-PEG-EtVit.C obtained in Example 1 was found to be a water-soluble compound at 33.4 mg / ml.

실험예 2: 유기용매에 대한 용해도 평가Experimental Example 2: Evaluation of Solubility in Organic Solvents

상기 실시예 1에서 수득한 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트(Vit.B3-PEG-EtVit.C)를 하기 표 1의 유기용매에 농도 별로 용해시키고 분광광도계(spectrophotometer)를 이용하여 50%의 투과도(transmittance)를 보이는 농도를 측정하였다. The Vitamin C-polyethylene glycol-vitamin B3 conjugate (Vit.B3-PEG-EtVit.C) obtained in Example 1 was dissolved in the organic solvent shown in Table 1 by concentration and 50% And the transmittance of the sample was measured.

그 결과, 실시예 1에서 수득한 Vit.B3-PEG-EtVit.C는 비타민 B3 및 비타민 C에 비해 유기 용매에 대한 용해도가 증가함을 확인하였다.As a result, Vit.B3-PEG-EtVit.C obtained in Example 1 was found to have an increased solubility in an organic solvent as compared to vitamin B3 and vitamin C.

No.No. 용매menstruum TC50 (15 ℃)TC 50 (15 캜) 실시예 1Example 1 비타민 CVitamin C 비타민 B3Vitamin B3 1One 디클로로메탄Dichloromethane 28.60 mg/ml28.60 mg / ml 불용성Insoluble 불용성Insoluble 22 에틸아세테이트Ethyl acetate 16.20 mg/ml16.20 mg / ml 0.90 mg/ml0.90 mg / ml 0.18 mg/ml0.18 mg / ml 33 디메틸설폭사이드Dimethyl sulfoxide 104.52 mg/ml104.52 mg / ml 41.70 mg/ml41.70 mg / ml 77.68 mg/ml77.68 mg / ml 44 메탄올Methanol 165.33 mg/ml165.33 mg / ml 79.1 mg/ml79.1 mg / ml 7.63 mg/ml7.63 mg / ml 55 에탄올ethanol 123.00 mg/ml123.00 mg / ml 20 mg/ml20 mg / ml 8.74 mg/ml8.74 mg / ml 66 이소프로판올Isopropanol 20.50 mg/ml20.50 mg / ml 4.6 mg/ml4.6 mg / ml 1.23 mg/ml1.23 mg / ml 77 아세토니트릴Acetonitrile 15.00 mg/ml15.00 mg / ml 0.70 mg/ml0.70 mg / ml 0.12 mg/ml0.12 mg / ml

실험예 3: 항산화력 평가Experimental Example 3: Evaluation of antioxidant power

상기 실시예 1에서 수득한 Vit.B3-PEG-EtVit.C의 자유라디칼 소거 효과를 DPPH(1,1-디페닐-2-피크릴히드라질)를 이용하여 측정하였다. The free radical scavenging effect of Vit.B3-PEG-EtVit.C obtained in Example 1 was measured using DPPH (1,1-diphenyl-2-picryl hydrazide).

우선 에탄올과 아세테이트 완충액(pH 5.6)을 이용하여 0.08 mg/ml의 DPPH 용액을 제조하였다. 디메틸설폭사이드에 녹인 2.0 mg/ml의 시료를 동일 용매로 희석시켜 50 μM 및 100 μM의 농도별로 시료를 제조한 후, 각각의 시료와 제조된 상기 DPPH 용액을 3:10으로 섞어 30분간 반응시키고, 분광기를 이용하여 520 nm에서 OD 값의 변화를 측정하였다. First, a 0.08 mg / ml DPPH solution was prepared using ethanol and acetate buffer (pH 5.6). A sample of 2.0 mg / ml dissolved in dimethylsulfoxide was diluted with the same solvent to prepare a sample for each concentration of 50 μM and 100 μM. Then, each sample and the prepared DPPH solution were mixed at a ratio of 3:10 and reacted for 30 minutes , And the change of the OD value at 520 nm was measured using a spectroscope.

각 시료의 자유라디칼 잔존율(%)를 도 1에 나타내었으며, 비교물질로는 니코틴산(Nicotinic acid)과 아스코르빈산(Ascorbic acid)을 사용하였다.The free radical residual ratio (%) of each sample is shown in FIG. 1, and nicotinic acid and ascorbic acid were used as comparative substances.

도 1에서 보듯이, 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 니코틴산과 유사한 항산화력을 나타내었다.
As shown in FIG. 1, the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention exhibited antioxidant activity similar to nicotinic acid.

실험예 4: 세포활성도 평가Experimental Example 4: Evaluation of cell activity

상기 실시예 1에서 수득한 Vit.B3-PEG-EtVit.C의 1차 안전성을 검증하기 위해, 인간 섬유아세포인 HS27(ATCC CRL-1634)를 배양하여 MTT 실험[참고문헌: Journal of Immunological Methods, 1983, 65, 55~63]을 통해 세포활성도(cell viability)를 측정하고, 그 결과를 도 2에 나타내었다. 비교물질로는 니코틴산과 아스코르빈산을 사용하였다.In order to verify the primary safety of Vit.B3-PEG-EtVit.C obtained in Example 1, human fibroblast HS27 (ATCC CRL-1634) was cultured and subjected to MTT experiment (Reference: Journal of Immunological Methods, 1983, 65, 55 ~ 63], and the results are shown in FIG. As comparative substances, nicotinic acid and ascorbic acid were used.

도 2에서 보듯이, 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 니코틴산과 아스코르빈산 보다 우수한 독성감소 효과를 나타내었다.As shown in FIG. 2, the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention showed better toxicity reduction effect than nicotinic acid and ascorbic acid.

실험예 4: 완충용액 중 가수분해 시험 Experimental Example 4: Hydrolysis test in buffer solution

본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트의 완충용액 중 가수분해를 확인하였다. The hydrolysis of the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention in the buffer solution was confirmed.

실시예 1에서 수득한 Vit.B3-PEG-EtVit.C를 10 mg/ml의 농도로 50 mM 포타슘포스페이트 완충용액 pH 5.5, pH 7.5 및 pH 9.5에 용해시켜 각각 10 ml의 용액을 제조하였다. 생성된 용액을 37 oC 항온기에서 100 rpm으로 흔들어 주면서 충분한 반응이 진행되도록 하였다. 시간 간격을 두고 각 시험 튜브에서 0.4 ml씩 완충용액을 회수한 후 0.6 ml의 물을 첨가하여 교반한 다음 20 μl의 양으로 HPLC 분석하였다. The Vit.B3-PEG-EtVit.C obtained in Example 1 was dissolved in 50 mM potassium phosphate buffer solution pH 5.5, pH 7.5 and pH 9.5 at a concentration of 10 mg / ml to prepare 10 ml of each solution. The resulting solution was shaken at 100 rpm in a 37 ° C thermostat to allow sufficient reaction to proceed. The buffer solution was recovered in 0.4 ml of each test tube at intervals of time, added with 0.6 ml of water, stirred and then subjected to HPLC analysis in an amount of 20 μl.

HPLC의 분석 조건은 다음과 같다. The analysis conditions of HPLC are as follows.

분석기기명 : Agilent HPLC 1260Analytical instrument: Agilent HPLC 1260

컬럼 : C18 (150 x 4.6 mm/5 um)Column: C18 (150 x 4.6 mm / 5 um)

소프트웨어 : 전체 module Open LAB CDS, Software 프로그램 EZchrom EditionSoftware: Full module Open LAB CDS, Software Program EZchrom Edition

전개용매 : 물:MeOH=3:7Developing solvent: water: MeOH = 3: 7

컬럼 온도 : 30 oC
Column temperature: 30 o C

pH 5.5, pH 7.5 및 pH 9.5의 완충용액에서 시료의 가수분해율(%)을 도 3에 나타내었다. 도 3에서 보듯이, 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 pH 7.5와 9.5인 알칼리성에서 에스테르 결합이 가수분해되어 활성 비타민 C와 비타민 B3를 방출할 수 있음을 확인하였다. 또한, 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트의 분해 속도는 완충용액의 pH가 증가할수록 빨라졌으며, 이는 에스테르 결합이 알칼리 용액에서 분해가 잘 일어나기 때문이다.
The hydrolysis rate (%) of the sample in a buffer solution of pH 5.5, pH 7.5 and pH 9.5 is shown in Fig. As shown in FIG. 3, the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention was found to be able to liberate active vitamin C and vitamin B3 by hydrolysis of an ester bond at alkaline pH of 7.5 and 9.5. The degradation rate of the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention is accelerated as the pH of the buffer solution is increased, because the ester bond is decomposed well in the alkali solution.

실험예 5: 인간 혈청 중 가수분해 시험 Experimental Example 5: Hydrolysis test in human serum

본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트의 인간 혈청 중 가수분해를 확인하였다. The hydrolysis of the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention in human serum was confirmed.

실시예 1에서 수득한 Vit.B3-PEG-EtVit.C를 10 mg/ml의 농도로 인간 혈청에 용해시켜 20 ml의 용액을 제조하였다. 생성된 용액을 37 oC 항온기에서 100 rpm으로 흔들어 주면서 충분한 반응이 진행되도록 하였다. 시간 간격을 두고 각 시험 튜브에서 2 ml씩 혈청 혼합물을 회수한 후, 2 ml의 디클로로메탄을 첨가하여 교반한 다음, 원심분리(12,000 rpm, 4 oC, 20 분)하였다. 원심분리 후 디클로로메탄 층을 2회 추출하였다. 디클로로메탄 추출물을 상온에서 농축한 후, 완전 건조시키고 100 ul의 증류수를 첨가하여 HPLC 분석하였다. Vit.B3-PEG-EtVit.C obtained in Example 1 was dissolved in human serum at a concentration of 10 mg / ml to prepare 20 ml of a solution. The resulting solution was shaken at 100 rpm in a 37 ° C thermostat to allow sufficient reaction to proceed. The serum mixture was recovered in 2 ml of each test tube at time intervals, followed by addition of 2 ml of dichloromethane, stirring, and centrifugation (12,000 rpm, 4 ° C, 20 minutes). After centrifugation, the dichloromethane layer was extracted twice. The dichloromethane extract was concentrated at room temperature, completely dried, and analyzed by HPLC using 100 ul of distilled water.

HPLC의 분석 조건은 다음과 같다. The analysis conditions of HPLC are as follows.

분석기기명 : Agilent HPLC 1260Analytical instrument: Agilent HPLC 1260

컬럼 : C18 (150 x 4.6 mm/5 um)Column: C18 (150 x 4.6 mm / 5 um)

소프트웨어 : 전체 module Open LAB CDS, Software 프로그램 EZchrom EditionSoftware: Full module Open LAB CDS, Software Program EZchrom Edition

전개용매 : 40% ACN in H2ODeveloping solvent: 40% ACN in H 2 O

컬럼 온도 : 30 oC
Column temperature: 30 o C

분석 결과를 도 3에 나타내었다. 도 3으로부터 본 발명에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트는 체내에서 에스테르 결합이 가수분해되어 활성 비타민 B3와 비타민 C를 방출할 수 있음을 확인하였다.The results of the analysis are shown in Fig. FIG. 3 shows that the vitamin C-polyethylene glycol-vitamin B3 conjugate according to the present invention is capable of hydrolyzing the ester bond in the body to release active vitamin B3 and vitamin C.

Claims (9)

삭제delete 삭제delete 하기 화학식 1-1의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트:
[화학식 1-1]
Figure 112014059368763-pat00013

상기 식에서,
X1 및 X2는 O이고,
n은 4 내지 200의 정수이며,
R1은 C1-C6의 알킬기이다.A vitamin C-polyethylene glycol-vitamin B3 conjugate represented by the following formula 1-1:
[Formula 1-1]
Figure 112014059368763-pat00013

In this formula,
X 1 and X 2 are O,
n is an integer of 4 to 200,
R 1 is a C 1 -C 6 alkyl group. 삭제delete 하기 화학식 1-2의 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트:
[화학식 1-2]
Figure 112014059368763-pat00014

상기 식에서,
X1은 O이고,
n은 4 내지 200의 정수이다.Vitamin C-polyethylene glycol-vitamin B3 conjugate of formula 1-2:
[Formula 1-2]
Figure 112014059368763-pat00014

In this formula,
X < 1 > is O,
n is an integer of 4 to 200; 삭제delete 제3항 또는 제5항에 따른 비타민 C-폴리에틸렌글리콜-비타민 B3 컨쥬게이트를 포함하는 피부노화방지용 화장료 조성물.A cosmetic composition for preventing skin aging comprising vitamin C-polyethylene glycol-vitamin B3 conjugate according to claim 3 or 5. 삭제delete 삭제delete
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KR20020042537A (en) * 1999-06-28 2002-06-05 프록시마 컨셉츠 리미티드 Epitopes Formed by Non-Covalent Association of Conjugates
KR20060080535A (en) * 2003-05-14 2006-07-10 이뮤노젠 아이엔씨 Drug conjugate composition
WO2009112682A1 (en) 2008-01-21 2009-09-17 Centre National De La Recherche Scientifique Cnrs Encapsulation of vitamin c into water soluble dendrimers
US20110092416A1 (en) 2007-03-05 2011-04-21 Robert Patrick Doyle Vitamine B12 - Peptide Conjugates for Oral Delivery

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JP3440263B2 (en) * 1998-03-27 2003-08-25 エルジー・ライフ・サイエンシーズ・リミテッド Novel ascorbic acid derivative and preparation method thereof
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KR20060080535A (en) * 2003-05-14 2006-07-10 이뮤노젠 아이엔씨 Drug conjugate composition
US20110092416A1 (en) 2007-03-05 2011-04-21 Robert Patrick Doyle Vitamine B12 - Peptide Conjugates for Oral Delivery
WO2009112682A1 (en) 2008-01-21 2009-09-17 Centre National De La Recherche Scientifique Cnrs Encapsulation of vitamin c into water soluble dendrimers

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