KR101986702B1 - Multi block copolymer-cell penetrating peptide conjugate, a preparation thereof, and the use of the same - Google Patents
Multi block copolymer-cell penetrating peptide conjugate, a preparation thereof, and the use of the same Download PDFInfo
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- KR101986702B1 KR101986702B1 KR1020120099787A KR20120099787A KR101986702B1 KR 101986702 B1 KR101986702 B1 KR 101986702B1 KR 1020120099787 A KR1020120099787 A KR 1020120099787A KR 20120099787 A KR20120099787 A KR 20120099787A KR 101986702 B1 KR101986702 B1 KR 101986702B1
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- KR
- South Korea
- Prior art keywords
- block copolymer
- permeable peptide
- cell permeable
- block
- bond
- Prior art date
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- A61K47/51—Medicinal 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 the non-active ingredient being a modifying agent
- A61K47/56—Medicinal 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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal 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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal 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
- A61K47/51—Medicinal 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 the non-active ingredient being a modifying agent
- A61K47/56—Medicinal 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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal 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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal 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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트, 이의 제조방법 및 용도에 관한 것으로, 더욱 상세하게는 친수성 및 소수성과 생체 적합성 및 생분해성을 갖는 멀티 블록 공중합체와, 상기 멀티 블록 공중합체와 화학적으로 결합된 컨쥬게이트, 이의 제조방법 및 용도에 관한 것으로, 상기 컨쥬게이트는 활성 물질을 효과적으로 포접하고 피부 흡수시 독성 및 면역에 문제가 없어 경피 흡수를 통해 효율적인 전달을 이룰 수 있어 약학 및 화장품 분야에 바람직하게 적용 가능하다.The present invention relates to a multiblock copolymer-cell permeable peptide conjugate, a method for producing the same, and a use thereof, and more particularly to a multiblock copolymer having hydrophilic and hydrophobic, biocompatibility and biodegradability, The present invention relates to a chemically conjugated conjugate, a method for producing the conjugate, and a use thereof. The conjugate effectively encapsulates an active substance and has no problem in toxicity and immunity when absorbing skin, .
Description
본 발명은 활성 물질을 효과적으로 포접하고 피부 흡수시 독성 및 면역에 문제가 없어 경피 흡수를 통해 효율적인 전달을 이룰 수 있는 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트, 이의 제조방법 및 용도에 관한 것이다.The present invention relates to a multi-block copolymer-cell permeable peptide conjugate capable of effectively delivering an active substance through a percutaneously absorbable skin without the problem of toxicity and immunity upon skin absorption, a method for producing the same, and a use thereof.
피부를 통해 활성 성분의 침투/투과 기술을 이용하여 화장품 또는 제약 분야에서 다양한 제품들이 시판되고 있다.A variety of products are commercially available in the cosmetics or pharmaceutical field using penetration / permeation of active ingredients through the skin.
이러한 전달 방식에서 피부 투과성을 증가시키기 위해 다각적인 방법이 시행되고 있으며, 일례로 활성 성분은 미립자 안에 밀봉하여 전달하는 방법, 인지질 또는 이의 유도체로 밀봉하여 전달하는 방법, 계면 활성제와 같은 투과 강화제를 사용하는 방법 등이 사용되고 있다. In order to increase the skin permeability in such a delivery system, various methods have been practiced. For example, a method of sealing the active ingredient in the fine particles, a method of sealingly delivering the product using a phospholipid or its derivative, a permeation enhancer such as a surfactant And the like are used.
그중 최근에 널리 사용되고 있는 하나의 방법으로 고분자 마이셀을 형성하고, 상기 마이셀 내 활성 성분을 포접하는 기술이 각광받고 있다[Br. J. Cancer 93, 678-697 (2005), Br. J. Cancer 92, 1240-1246 (2005)]. 고분자 마이셀에 사용하는 고분자는 친수성 고분자와 소수성 고분자로 이루어진 블록 공중합체(block copolymer)를 사용하며, 지용성 약물도 높은 함량으로 내포하고 가용화가 가능하다는 이점이 있다. Recently, a technique of forming a macromolecular micelle and encapsulating an active ingredient in the micelle has attracted attention as one of widely used methods [Br. J. Cancer 93, 678-697 (2005), Br . J. Cancer 92, 1240-1246 (2005)). Polymers used for polymer micelles have block copolymers composed of hydrophilic polymers and hydrophobic polymers, and lipophilic drugs can be contained and solubilized in high contents.
대한민국 특허공개 제2007-0042159호는 두 개의 폴리에틸렌옥사이드(polyethyleneoxide) 블록 사이에 폴리프로필렌옥사이드(polypropyleneoxide) 또는 폴리부틸렌옥사이드(polybutyleneoxide) 블록을 가지며, 40,000 달톤(Dalton) 이상의 중량 평균 분자량을 갖는 다중블록 공중합체를 형성하기 위해 디카르복실기 링커(dicarboxylic linkage)를 통해 연결된 삼중블록 공중합체를 포함하는 이온성 공중합체 조성물이 활성 성분의 전달에 효과적이라고 제시하고 있다.KOKAI Publication No. 2007-0042159 discloses a polypropylene oxide or polybutylene oxide block having two polyethylene oxide blocks and having a weight average molecular weight of 40,000 daltons or more, It has been suggested that an ionic copolymer composition comprising a triblock copolymer linked via a dicarboxylic linkage to form a copolymer is effective for delivery of the active ingredient.
그러나 이러한 장점에도 불구하고 고분자 마이셀의 피부 투과성은 그리 높지 않은 단점이 있어 경피 흡수를 통한 전달 방식에 적용하기에 미비한 문제가 있다.Despite these advantages, however, the skin permeability of the polymer micelles is not so high, which is insufficient to be applied to the delivery method through transdermal absorption.
한편, 1980년대 후천성 면역 결핍증(AIDS)를 일으키는 HIV 바이러스가 TAT 프로테인을 이용해 세포 내로 쉽게 침투할 수 있다는 것이 밝혀진 이후로 최적화된 활성을 나타내는 세포투과성 펩타이드(Cell Penetrating Peptide, CPP)의 구조적 특성 및 세포 내 흡수 기전에 대한 많은 연구가 이루어졌다. Since the HIV virus causing AIDS in 1980 can easily penetrate into cells using TAT protein, the structural characteristics of Cell Penetrating Peptide (CPP), which shows optimized activity, Much research has been done on the mechanism of absorption.
특징적으로 세포의 타입에 관계없이 대부분 세포 내로 흡수가 용이하게 진행된다. 이러한 세포투과성 펩타이드의 응용예로서 아토피 치료를 위한 TAT 펩타이드 함유 탄성 리포좀이 기존 리포좀에 비해 20% 정도 높은 효능을 나타냄을 밝혔다[Myung Joo KANG et al, Biol. Pharm. Bull. 2010, 33(1) 100-106]. 또한, 세포투과성 펩타이드와 다양한 화학적 결합에 대한 단백질 약물을 세포 내로 전달하기 위한 시스템도 개발되었다[Kylie M. Wagstaff et al., Current Medicinal Chemistry, 2006, 13, 1317-1387].Characteristically, regardless of the type of cell, absorption is readily facilitated into most cells. As an application example of such a cell permeable peptide, the elastic liposome containing TAT peptide for atopy treatment has shown 20% higher efficacy than the existing liposome [Myung Joo Kang et al . , Biol. Pharm. Bull . 2010, 33 (1) 100-106]. In addition, a system has been developed to deliver cell permeable peptides and protein drugs for various chemical interactions into cells [Kylie M. Wagstaff et al ., Current Medicinal Chemistry, 2006, 13, 1317-1387].
그러나 대부분의 세포투과성 펩타이드는 바이러스에서 유래하여 장기간 사용시 면역 작용에 심각한 문제를 일으키는 것으로 알려져 있으며, 주로 효능 성분과 세포투과성 펩타이드의 결합에 의한 소재 개발에 치중되어 있는 실정이다. However, it is known that most of the cell permeable peptides originate from viruses and cause serious problems on immune function during long-term use, and they are mainly focused on the development of materials by binding of an efficacious ingredient and a cell permeable peptide.
WO 2008/070571호에서는 세포내 형질도입 친수성 도메인 및 소수성 도메인을 구비하는 블록 공중합체로 이루어진 쉘을 포함하는 자기-조립 블록 공중합체, 및 베지클을 제시하면서, 상기 베시클이 캡슐화된 활성제, 예컨대, 진단제 또는 치료제를 포함하여 다양한 분야에 적용할 수 있음을 개시하고 있다.WO 2008/070571 discloses a self-assembling block copolymer comprising a shell consisting of a block copolymer having an intracellularly transduced hydrophilic domain and a hydrophobic domain, and a vesicle, wherein the vesicle is encapsulated with an active agent such as , A diagnostic agent or a therapeutic agent can be applied to various fields.
또한, WO 2008/010341호에서는 단백질 또는 폴리펩티드가 내포되고, 폴리에틸렌글리콜 친수성 세그먼트와, 폴리아미노산 소수성 세그먼트를 가지는 블록 공중합체를 함유하는 고분자 마이셀 조성물을 제시하고 있다. 이러한 고분자 마이셀은 고분자의 조성을 조절하여 약물의 담지율, 방출 속도 등을제어할 수 있다고 언급하고 있다.In addition, WO 2008/010341 discloses a macromolecular micelle composition containing a protein or polypeptide and containing a block copolymer having a polyethylene glycol hydrophilic segment and a polyamino acid hydrophobic segment. These polymeric micelles are said to be able to control the drug loading rate and release rate by controlling the composition of the polymer.
이에 본 발명자들은 고분자 마이셀을 통해 높은 함량으로 활성 성분을 포집하고, 세포투과성 펩타이드의 사용을 통해 피부로의 전달을 높일 수 있도록 친수성 및 소수성과 생체 적합성 및 생분해성을 갖는 멀티 블록 공중합체와, 상기 멀티 블록 공중합체와 화학적으로 결합된 컨쥬게이트 구조를 발명하였으며, 상기 컨쥬게이트가 활성 물질을 효과적으로 포접하고 피부 흡수 시 독성 및 면역에 문제가 없어 경피 흡수를 통해 효율적인 전달을 이룰 수 있음을 확인하여 본 발명을 완성하였다.Accordingly, the present inventors have found that a multi-block copolymer having hydrophilicity, hydrophobicity, biocompatibility and biodegradability and capable of collecting active ingredients with high content through polymeric micelles and increasing transmission to the skin through the use of cell permeable peptides, The present inventors have invented a conjugate structure chemically bonded to a multi-block copolymer, and confirmed that the conjugate can effectively deliver the active substance by effectively covering the active substance and preventing toxicity and immunity when absorbing the skin, Thereby completing the invention.
따라서, 본 발명의 목적은 활성 물질의 포접과 경피 흡수를 효과적으로 수행할 수 있는 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트 및 이의 제조방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a multi-block copolymer-cell permeable peptide conjugate capable of effectively performing entrapment and transdermal absorption of an active substance and a method for producing the conjugate.
또한, 본 발명의 다른 목적은 상기 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트를 약학 및 화장품 분야에 적용하는 용도를 제공하는 것이다.Another object of the present invention is to provide the use of the above-mentioned multi-block copolymer-cell permeable peptide conjugate in the fields of pharmacy and cosmetics.
상기 목적을 달성하기 위해, 본 발명은In order to achieve the above object,
하기 화학식 1로 표시되고,(1)
소수성 블록(A), 수용액에서의 분산력 향상을 위한 친수성 블록(B) 및 세포투과 펩타이드와 화학적 결합을 할 수 있는 블록(C)으로 구성되며, 블록(C)에 세포투과성 펩타이드(P)가 화학적으로 결합된 것을 특징으로 하는 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트 소재를 제공한다.(C) is composed of a hydrophobic block (A), a hydrophilic block (B) for improving the dispersibility in an aqueous solution, and a block (C) capable of chemically bonding with a cell permeable peptide, wherein the cell permeable peptide To a multi-block copolymer-cell permeable peptide conjugate.
[화학식 1][Chemical Formula 1]
(상기 화학식 1에서, a는 20∼80 몰%, b는 20∼80 몰%, c=100-(a+b) 이다)(Wherein a is 20 to 80 mol%, b is 20 to 80 mol%, and c = 100- (a + b)
또한, 본 발명은 In addition,
(a) 소수성 모노머를 중합 반응시켜 소수성 블록을 제조하고,(a) a hydrophobic monomer is polymerized to produce a hydrophobic block,
(b) 상기 소수성 블록을 개시제로 하여 친수성 모노머를 중합 반응시켜 블록 공중합체를 제조하고,(b) polymerizing the hydrophilic monomer with the hydrophobic block as an initiator to prepare a block copolymer,
(c) 상기 블록 공중합체를 거대 개시제로 하여 결합 모노머를 중합 반응시켜 멀티 블록 공중합체를 제조하고, (c) preparing a multiblock copolymer by polymerizing the binding monomer with the block copolymer as a macro initiator,
(d) 멀티 블록 공중합체와 세포투과성 펩타이드를 반응시켜 제조하는 화학식 1의 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트를 제조방법을 제공한다.(d) a multi-block copolymer-cell permeable peptide conjugate of formula (I) prepared by reacting a multi-block copolymer with a cell permeable peptide.
또한, 본 발명은 상기 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트를 포함하는 약학적 조성물 또는 화장료 조성물로의 용도를 제공한다.In addition, the present invention provides a use as a pharmaceutical composition or a cosmetic composition comprising the multi-block copolymer-cell permeable peptide conjugate.
본 발명에 따른 컨쥬게이트는 활성 물질을 효과적으로 포접하고 피부 흡수시 독성 및 면역에 문제가 없어 경피 흡수를 통해 효율적인 전달을 이룰 수 있어 약학 및 화장품 분야에 바람직하게 적용할 수 있다.The conjugate according to the present invention can be effectively applied to the field of pharmacy and cosmetics because it can efficiently infiltrate the active substance and has no problem in toxicity and immunity when absorbing the skin, thereby achieving efficient delivery through percutaneous absorption.
도 1은 실시예 1에서 제조된 멀티 블록 공중합체-CPP 컨쥬게이트의 입자 상태를 보여주는 투과전자 현미경 이미지이다.FIG. 1 is a transmission electron microscope image showing the particle state of the multi-block copolymer-CPP conjugate prepared in Example 1. FIG.
이하 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 세포투과성 펩타이드(cell penetraing peptide, CPP)를 안정화시키고 높은 효율로 피부에 효과적으로 전달할 수 있도록 상기 세포투과성 펩타이드를 양친매성 공중합체와 결합된 컨쥬게이트를 제시한다.The present invention provides a conjugate of an amphipathic copolymer of the cell permeable peptide to stabilize a cell penetrating peptide (CPP) and effectively deliver it to the skin with high efficiency.
이때 양친매성 공중합체는 생분해성(biodegradability)이 우수한 소수성 블록과, 생체 적합성(biocompatibility)이 우수한 친수성 블록으로 이루어진 블록 공중합체이다. 이러한 양친매성 공중합체는 용매 내에서 마이셀을 형성하고, 상기 마이셀 내 소수성을 띠는 유용한 활성 성분(예, 항균제, 미백제 등)을 높은 포접율로 포접할 수 있으며, 별도의 공정 없이도 분해가 가능하다.The amphipathic copolymer is a block copolymer composed of a hydrophobic block having excellent biodegradability and a hydrophilic block having excellent biocompatibility. Such an amphipathic copolymer forms micelles in a solvent, and it is possible to encapsulate useful active components (for example, antimicrobial agents, whitening agents, etc.) having hydrophobicity in the micelles at a high porosity and can be decomposed without any additional process .
본 발명에서는 상기 특성을 갖는 양친매성 공중합체를 세포투과성 펩타이드와 화학 결합을 하여 친수성 블록과 세포투과성 펩타이드로 인해 세포 투과율을 높일 수 있다.In the present invention, the amphipathic copolymer having the above characteristics can be chemically bonded with the cell permeable peptide to increase the cell permeability due to the hydrophilic block and the cell permeable peptide.
구체적으로, 본 발명에 따른 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트는 하기 화학식 1로 표시된다. 즉, 소수성 블록(A), 친수성 블록(B) 및 결합 블록(C)으로 구성되며, 상기 결합 블록(C)에 세포투과성 펩타이드(P)가 그라프트 연결되며, 이때 결합 블록(C)과 세포투과성 펩타이드(P)는 아마이드(CONH)과 같은 화학 결합으로 결합된다.Specifically, the multi-block copolymer-cell permeable peptide conjugate according to the present invention is represented by the following formula (1). In other words, a cell permeable peptide (P) is graft-connected to the binding block (C), wherein the binding block (C) and the binding block (C) The permeable peptide (P) is bound by a chemical bond such as amide (CONH).
[화학식 1][Chemical Formula 1]
(상기 화학식 1에서, a는 20∼80 몰%, b는 20∼80 몰%, c=100-(a+b) 이다)(Wherein a is 20 to 80 mol%, b is 20 to 80 mol%, and c = 100- (a + b)
소수성 블록은 고리형 에스테르 모노머가 중합되어 이루어진 것으로, 폴리락타이드, 폴리글리콜라이드, 폴리카프로락톤, 폴리디옥산-2-온, 폴리락틱-co-글리콜라이드, 폴리락틱-co-디옥산-2-온, 폴리락틱-co-카프로락톤, 및 폴리글리콜릭-co-카프로락톤으로 이루어진 군에서 선택된 1종을 포함하며, 바람직하기로 폴리카프로락톤을 포함한다. 상기 에스테르 계열의 소수성 블록은 모노머의 종류 및 세그먼트의 길이에 따라 분해 기간을 조절할 수 있으며, 다른 고분자와의 사용성이 우수한 이점이 있다.The hydrophobic block is formed by polymerizing a cyclic ester monomer, and is a block copolymer composed of polylactide, polyglycolide, polycaprolactone, polydioxan-2-one, polylactic-co-glycolide, polylactic- -One, polylactic-co-caprolactone, and polyglycolic-co-caprolactone, and preferably includes polycaprolactone. The ester-based hydrophobic block can control the decomposition period according to the kind of the monomer and the length of the segment, and has an advantage of being excellent in usability with other polymers.
또한, 친수성 블록은 폴리하이드록시알킬(C1~C4)아크릴레이드, 폴리하이드록시알킬(C1~C4)메타크릴레이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리알킬렌글리콜, 폴리비닐알콜, 및 폴리(2-메타크릴오일옥시에틸 포스포릴클로라이드(PMPC, poly(2-methacryloyloxyethyl phosphorylcholine)으로 이루어진 군에서 선택된 1종을 포함하며, 바람직하기로 폴리하이드록시에틸아크릴레이트(PHEA), 폴리메타크릴레이트(PMMA), 또는 폴리(2-메타크릴오일옥시에틸 포스포릴클로라이드(PMPC)를 사용한다.The hydrophilic block may also be a polyhydroxyalkyl (C1 to C4) acrylate, a polyhydroxyalkyl (C1 to C4) methacrylate, a polyacrylate, a polymethacrylate, a polyalkylene glycol, a polyvinyl alcohol, (2-methacryloyloxyethyl phosphorylcholine), preferably one selected from the group consisting of polyhydroxyethyl acrylate (PHEA), polymethacrylate ( PMMA), or poly (2-methacryloyloxyethylphosphoryl chloride (PMPC) is used.
상기 결합 블록은 세포투과성 펩타이드와 화학 결합을 할 수 있도록 관능기를 포함하는 것으로, 폴리아크릴산, 폴리메타크릴산, 폴리-1,3,6-트리옥산, 폴리아스파라긴산 및 폴리글루타민산으로 이루어진 군에서 선택된 1종을 포함하고, 바람직하기로 폴리아크릴산을 사용한다.Wherein the binding block comprises a functional group capable of chemically bonding to the cell permeable peptide and is selected from the group consisting of polyacrylic acid, polymethacrylic acid, poly-1,3,6-trioxane, polyaspartic acid and polyglutamic acid , Preferably polyacrylic acid.
이러한 소수성 블록(A), 친수성 블록(B) 및 결합 블록(C)으로 구성된 멀티 블록 공중합체는 세포투과성 펩타이드와 화학 결합하여 약학 또는 화장료 등의 분야에 효과적으로 적용할 수 있다. The multi-block copolymer composed of the hydrophobic block (A), the hydrophilic block (B) and the binding block (C) can be chemically bonded to the cell permeable peptide and can be effectively applied to fields such as pharmacy or cosmetics.
상기 화학 결합은 결합 블록과 세포투과성 펩타이드가 화학반응을 통해 직접 연결되는 것으로, 결합 블록의 말단기와 펩타이드의 말단기의 종류에 따라 달라질 수 있다. 일례로 아마이드 결합, 에테르 결합, 티오에테르 결합, 에스테르 결합, 티오에스테르 결합, 카보네이트 결합, 카바메이트 결합, 포스페이트 결합, 및 옥심 결합일 수 있으며, 바람직하기로는 아마이드 결합이다.The chemical bond is directly connected through a chemical reaction between the binding block and the cell permeable peptide, and may be varied depending on the terminal group of the binding block and the terminal group of the peptide. For example, an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond, preferably an amide bond.
상기 멀티 블록 공중합체는 용도에 따라 달라질 수 있으나 중량평균분자량이 1000∼1000000, 바람직하게는 2000∼200000이며, 더욱 바람직하게는 4000∼60000인 것을 사용한다. 만약, 그 분자량이 상기 범위 미만이면 세포투과성 펩타이드를 효과적으로 포접하여 안전한 분산액을 이룰 수 없고, 반대로 상기 범위를 초과하면 용해성이나 피부 투과성에 저하되는 문제가 발생한다.The multi-block copolymer may vary depending on the use, but has a weight-average molecular weight of 1,000 to 1,000,000, preferably 2,000 to 200,000, and more preferably 4,000 to 600,000. If the molecular weight is less than the above range, the cell permeable peptide is effectively enclosed and a safe dispersion can not be obtained. On the other hand, if the molecular weight exceeds the above range, the solubility and the skin permeability are deteriorated.
이러한 소수성 블록(A), 친수성 블록(B) 및 결합 블록(C)으로 구성된 멀티 블록 공중합체와 연결 가능한 세포투과성 펩타이드는 본 발명에서 특별히 한정하지 않으며, 세포투과성이 있다고 공지된 모든 세포투과성 펩타이드가 사용될 수 있다.The cell permeable peptide which can be linked to the multi-block copolymer composed of the hydrophobic block (A), the hydrophilic block (B) and the binding block (C) is not particularly limited in the present invention, and all the cell permeable peptides known to have cell permeability Can be used.
일례로, 5∼30개의 아미노산 서열로 구성되고, 아르기닌, 라이신 및 히스티딘으로 구성된 군에서 선택된 하나 이상의 아미노산 함량이 70∼80% 인 것을 특징으로 하는 인간 유래 세포투과성 펩타이드일 수 있다.For example, the peptide may be composed of 5 to 30 amino acid sequences, and the content of one or more amino acids selected from the group consisting of arginine, lysine and histidine is 70 to 80%.
구체적으로, 본 발명에서 사용하는 세포투과성 펩타이드는 특별히 한정하지 않으며, 세포투과성이 있다고 공지된 바의 모든 펩타이드는 사용 가능하다. 본 발명의 실시예에서는 국내사 프로셀제약의 M1000, M1004제품을 사용하였다.Specifically, the cell permeable peptide used in the present invention is not particularly limited, and all peptides known to have cell permeability can be used. In the examples of the present invention, M1000 and M1004 products of Domestic Propecell Pharma were used.
상기 세포투과성 펩타이드는 멀티 블록 공중합체와 1:1 내지 1:10의 비율로 사용하여 연결될 수 있으며, 이때 세포투과성 펩타이드의 종류와 멀티 블록 공중합체의 모노머의 조성에 따라 적절히 조절할 수 있다.
The cell permeable peptide may be used in a ratio of 1: 1 to 1:10 with a multi-block copolymer. The cell permeable peptide may be appropriately adjusted depending on the type of the cell permeable peptide and the composition of the monomer of the multi-block copolymer.
이러한 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트의 제조는 크게 멀티 블록 공중합체의 제조와, 세포투과성 펩타이드와의 반응 단계를 포함한다.The preparation of such a multi-block copolymer-cell permeable peptide conjugate largely involves the preparation of a multi-block copolymer and the step of reacting with a cell permeable peptide.
구체적으로, Specifically,
(a) 소수성 모노머를 중합반응시켜 소수성 블록을 제조하고,(a) a hydrophobic monomer is polymerized to produce a hydrophobic block,
(b) 상기 소수성 블록을 개시제로 하여 친수성 모노머를 중합반응시켜 블록 공중합체를 제조하고,(b) polymerizing the hydrophilic monomer with the hydrophobic block as an initiator to prepare a block copolymer,
(c) 상기 블록 공중합체를 거대 개시제로 하여 결합 모노머를 중합반응시켜 멀티 블록 공중합체를 제조하고, (c) preparing a multiblock copolymer by polymerizing the binding monomer with the block copolymer as a macro initiator,
(d) 멀티 블록 공중합체와 세포투과성 펩타이드를 반응시켜 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트를 제조한다.(d) A multi-block copolymer-cell permeable peptide conjugate is prepared by reacting a multi-block copolymer with a cell permeable peptide.
상기 (a) 내지 (c)의 단계에서 모노머의 중합반응은 양이온 중합, 음이온 중합, 개환 중합, 또는 라디칼 중합 반응을 통해 이루어질 수 있으며, 방법 또한 벌크 중합, 유화중합, 서스펜전 중합 등 다양한 방법이 사용될 수 있다. 바람직하기로는 용매 하에 개시제, 촉매 및 소수성 모노머를 리빙 개환 중합을 통해 소수성 블록을 제조하고, 이후 이온 중합을 통해 멀티 블록 공중합체를 제조할 수 있다.The polymerization reaction of the monomers in the steps (a) to (c) may be carried out through cation polymerization, anionic polymerization, ring-opening polymerization, or radical polymerization, and the method may also be carried out by various methods such as bulk polymerization, emulsion polymerization, Can be used. Preferably, a hydrophobic block is prepared by living ring-opening polymerization of an initiator, a catalyst and a hydrophobic monomer in a solvent, and then a multi-block copolymer is prepared through ionic polymerization.
이때 사용하는 용매, 개시제, 촉매 등의 본 발명에서 특별히 한정하지 않으며, 당업자에 의해 각각의 모노머에 적합한 조성을 선택할 수 있다. 중합반응 또한 0∼100℃의 넓은 온도 범위에서 필요한 경우 압력 인가 하에 진행할 수 있다.The solvent, initiator, catalyst, etc. to be used herein are not particularly limited in the present invention, and a composition suitable for each monomer can be selected by those skilled in the art. The polymerization reaction can also be carried out under pressure, if necessary, in a wide temperature range from 0 to 100 < 0 > C.
중합반응시 모노머의 함량은 최종 얻고자 하는 멀티 블록 공중합체의 분자량, 중합도 등을 고려하여 선택할 수 있으며, 이러한 분자량이나 중합도는 컨쥬게이트의 용도나 목적, 발현하고자 하는 기능에 맞춰서 적절하게 설정될 수 있다.The content of the monomer in the polymerization reaction can be selected in consideration of the molecular weight and the degree of polymerization of the multi-block copolymer to be finally obtained. The molecular weight and degree of polymerization can be appropriately set in accordance with the purpose or purpose of the conjugate, have.
또한, 필요한 경우 멀티 블록 공중합체와 세포투과성 펩타이드는 화학 결합으로 연결되며, 이들은 직접 연결되거나 별도의 링커를 통해 연결될 수 있다.In addition, if necessary, the multiblock copolymer and the cell permeable peptide are linked by a chemical bond, and they can be connected directly or through a separate linker.
상기 화학 결합 또는 링커를 통한 연결은 결합 세그먼트의 말단기와 펩타이드의 말단기의 종류에 따라 달라질 수 있으며, 일례로 아마이드 결합, 에테르 결합, 티오에테르 결합, 에스테르 결합, 티오에스테르 결합, 카보네이트 결합, 카바메이트 결합, 포스페이트 결합, 및 옥심 결합일 수 있다. 바람직하기로는 아마이드 결합이다.The chemical bond or the linkage through a linker may vary depending on the terminal group of the bonding segment and the terminal group of the peptide, and examples thereof include an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, Mate bond, phosphate bond, and oxime bond. Preferably, it is an amide bond.
이때 링커는 멀티 블록 공중합체의 결합 세그먼트의 말단, 또는 세포투과성 펩타이드의 말단과 연결될 수 있으며, 상기 화학 결합을 이룰 수 있는 물질이면 어느 것이든 가능하다.In this case, the linker can be connected to the end of the binding segment of the multi-block copolymer, or to the end of the cell permeable peptide, and can be any substance capable of achieving the chemical bond.
일례로, 디사이클로헥실 카르보디이미드(dicyclohexylcarbodimide, DCC), 1,4-비스-말레이미도부탄(1,4-bis-maleimidobutane, BMB), 1,11-비스-말레이미도테트라에틸렌글리콜(1,11-bismaleimidotetraethyleneglycol,BM[PEO]4), 1-에틸-3-[3-디메틸 아미노프로필] 카보디이미드 하이드로클로라이드(1-ethyl-3-[3-dimethyl aminopropyl] carbodiimide hydrochloride, EDC), 숙시니미딜-4-[N-말레이미도메틸시클로헥산-1-카복시-[6-아미도카프로에이트]](succinimidyl-4-[N-maleimidomethylcyclohexane-1-carboxy-[6-amidocaproate]], SMCC) 및 그의 설폰화염(sulfo-SMCC), 숙시미딜 6-[3-(2-피리딜디티오)-로피오나미도] 헥사노에이트](succimidyl 6-[3-(2-pyridyldithio)-ropionamido] hexanoate, SPDP) 및 그의 설폰화염(sulfo-SPDP),m-말레이미도벤조일-N-하이드로시숙시니미드 에스터(m-maleimidobenzoyl-N-hydroxysuccinimide ester, MBS) 및 그의 설폰화염(sulfo-MBS), 숙시미딜[4-(p-말레이미도페닐) 부틸레이트](succimidyl[4-(p-maleimidophenyl) butyrate], SMPB) 및 그의 설폰화염(sulfo-SMPB) 등이 가능하며, 바람직하기로 디사이클로헥실 카르보디이미드(dicyclohexylcarbodimide, DCC)를 사용한다.
For example, dicyclohexylcarbodimide (DCC), 1,4-bis-maleimidobutane (BMB), 1,11-bis-maleimidotetraethylene glycol (1, 1-ethyl-3- [3-dimethyl aminopropyl] carbodiimide hydrochloride (EDC), 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride, 4- [N-maleimidomethylcyclohexane-1-carboxy- [6-amidocaproate]], SMCC), and dicyclohexylcarbodiimide Succinimidyl 6- [3- (2-pyridyldithio) -propionamido] hexanoate (sulfo-SMCC), succinimidyl 6- [3- (2- pyridyldithio) , SPDP) and its sulfone-SPDP, m-maleimidobenzoyl-N-hydroxysuccinimide ester, MBS and sulfo-MBS, Diallyl 4- (p-Maley Succinimidyl [4- (p-maleimidophenyl) butyrate], SMPB) and sulfo-SMPB, and preferably dicyclohexylcarbodimide (DCC) use.
이러한 방법을 통해 제조된 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트는 다양한 분야, 즉 약학적 조성물 또는 화장료 조성물에 적용될 수 있다.The multi-block copolymer-cell permeable peptide conjugate prepared by this method can be applied to various fields, i.e., a pharmaceutical composition or a cosmetic composition.
구체적으로, 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트는 분산 상에서 캡슐 형태로 마이셀을 형성하고, 상기 마이셀 내부에 약제 또는 화장료 분야에서 유용한 활성 성분을 포접하여 피부에 적용시 상기 활성 성분의 피부 내부로의 침투가 효과적으로 이루어질 수 있다.Specifically, the multi-block copolymer-cell permeable peptide conjugate forms micelles in the form of capsules in a dispersed phase and encapsulates active ingredients useful in the field of drugs or cosmetics inside the micelles, Can be effectively carried out.
활성 성분은 본 발명에서 특별히 한정하지 않으며, 치료제, 피부노화방지제, 피부 습윤제, 주름방지제, 퇴화방지제(anti-atrophy agents), 피부 스무딩제(skin smoothing agents), 항박테리아제, 항진균제, 살충제, 항기생충제, 항균제, 항감염제, 항양진제(anti-pruriginous agents), 외부 마취제, 항바이러스제, 각질제거제(keratolytic agents), 자유라디칼 분해제, 지루성 방지제(antiseborrheic agents), 비듬방지제, 피부의 분화, 증식 또는 색소 형성 조절제 및 침투 가속제, 박리제(desquamating agent), 탈색소 또는 프로착색제(depigmenting or propigmenting agents), 항글리케이션제(antiglycation agent), 타이트닝제(tightening agent), 진피또는 표피 거대분자의 합성 촉진제 및/또는 분해 방지제; 피부아세포 및/또는 케라티노사이트의 증식 촉진제 또는 케라티노사이트의 분화 촉진제; 근육 이완제; 오염방지 및/또는 항자유라디칼제; 슬리밍제(slimming agents), 안티셀룰라이트제(anticellulite agents), 미세순환에 작용하는 제제; 세포의 에너지 대사에 작용하는 제제; 세정제, 모발 컨디셔닝제, 모발스타일링제, 모발 성장 촉진제, 햇빛 차단 및/또는 자외선 방지 화합물(sunscreen and/or sunblock compounds), 메이크업제(make-up agents), 세제, 약제, 유화제, 연화제, 방부제, 방취제, 피부의학적으로 수용할 수 있는 운반체, 항여드름제, 안티케이킹제(anti-caking agents), 항기포제, 항산화제, 결합제, 생물학적 활성제, 효소, 효소 억제제, 효소 유도제, 조효소, 식물 추출물, 식물 유도체, 식물 조직 추출물, 식물 씨 추출물, 식물유, 세라마이드 등이 가능하다.The active ingredient is not particularly limited in the present invention and may be selected from the group consisting of therapeutic agents, skin antiaging agents, skin wetting agents, anti-wrinkle agents, anti-atrophy agents, skin smoothing agents, antibacterial agents, Anti-inflammatory agents, antifungal agents, antifungal agents, anti-pruriginous agents, external anesthetics, antiviral agents, keratolytic agents, free radical scavengers, antiseborrheic agents, (S), growth or pigmentation regulators and penetration accelerators, desquamating agents, depigmenting or propigmenting agents, antiglycation agents, tightening agents, synthesis of dermis or epidermal macromolecules Accelerators and / or decomposition inhibitors; A growth promoter or keratinocyte differentiation promoter of skin cells and / or keratinocytes; Muscle relaxants; Anti-fouling and / or anti-free radical agents; Slimming agents, anticellulite agents, agents acting on the microcirculation; Agents acting on energy metabolism of cells; Hair conditioning agents, sunscreen and / or sunblock compounds, make-up agents, detergents, medicaments, emulsifiers, softeners, preservatives, Anti-caking agents, anti-foaming agents, antioxidants, binders, biologically active agents, enzymes, enzyme inhibitors, enzyme inducers, coenzymes, plant extracts, plants Derivatives, plant tissue extracts, plant seed extracts, vegetable oils, ceramides, and the like.
이때 약학적 조성물로 적용되는 경우, 제형, 사용방법 및 사용목적에 따라 약리학적으로 허용 가능한 담체 또는 부형제를 더욱 포함할 수 있다. When the composition is applied as a pharmaceutical composition, it may further include a pharmacologically acceptable carrier or excipient depending on the formulation, method of use, and purpose of use.
약학적으로 허용가능한 담체 또는 부형제로는 물, 덱스트린, 칼슘카보네이트, 락토스, 프로필렌 글리콜, 리퀴드 파라핀, 생리식염수, 덱스트로스, 수크로즈, 솔비톨, 만니톨, 자이리톨, 에리스리톨, 말티톨, 전분, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 폴리비닐피롤리돈, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유가 있으며, 이들은 1종 이상 사용될 수 있으나, 이에 한정되는 것은 아니며 통상의 담체 및 부형제는 모두 사용가능하다. 또한, 항비만 조성물을 약제화하는 경우, 통상의 충진제, 증량제, 결합제, 붕해제, 계면활성제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등을 더욱 포함할 수 있다.Pharmaceutically acceptable carriers or excipients include water, dextrin, calcium carbonate, lactose, propylene glycol, liquid paraffin, physiological saline, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gelatin, calcium phosphate , Calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. These may be used alone or in combination, but are not limited thereto Conventional carriers and excipients are all usable. In addition, when the anti-obesity composition is weakly formulated, it may further contain conventional fillers, extenders, binders, disintegrators, surfactants, anti-coagulants, lubricants, wetting agents, flavorings, emulsifiers or preservatives.
본 발명의 조성물은 경구 투여하거나 비경구 투여할 수 있으며, 투여량은 투여방법, 복용자의 연령, 성별 및 체중, 건강 상태, 배설률, 식이, 투여시간 및 질환의 중증도 등을 고려하여 결정하는 것이 좋다. 일례로, 본 발명의 콜라겐 펩티드는 1일 0.1 내지 100 ㎎/㎏(체중)으로 1회 이상 투여가능하다. 그러나 상기한 투여량은 예시하기 위한 일례에 불과하며 상기 범위에 한정되진 않는다.The composition of the present invention can be administered orally or parenterally. The dose is determined in consideration of the administration method, the age, sex and weight of the recipient, health condition, excretion rate, diet, administration time and severity of disease . For example, the collagen peptide of the present invention can be administered at least once at a dose of 0.1 to 100 mg / kg (body weight) per day. However, the above-mentioned dosage is merely an example for illustrative purposes and is not limited to the above range.
또한, 화장료 제품으로 사용될 경우 크림, 로션, 젤, 밀크, 밤 등의 제형일 수 있으며, 보다 바람직하기로는 크림 제형으로 사용된다. 이러한 제형의 마사지 화장료 조성물은 바디스킨 케어, 얼굴 스킨케어, 베이비케어, 아프터선 케어, 미백 케어, 항셀룰라이트 케어, 클렌징 등의 용도에 사용될 수 있다.In addition, when it is used as a cosmetic product, it may be a cream, a lotion, a gel, a milk, a night, and the like, more preferably a cream formulation. Such a formulated massage cosmetic composition can be used for a body skin care, a face skin care, a baby care, an after sun care, a whitening care, an anti-cellulite care, a cleansing and the like.
또한, 각 제형의 조성들은 그 제형의 제제화에 필요하고 적절한 각종의 기제와 첨가물을 함유할 수 있으며, 그 효과를 떨어트리지 않는 범위 내에서 비이온 계면활성제, 실리콘 폴리머, 체질안료, 향료, 방부제, 살균제, 산화 안정화제, 유기 용매, 이온성 또는 비이온성 증점제, 유연화제, 산화방지제, 자유 라디칼 파괴제, 불투명화제, 안정화제, 에몰리언트 (emollient), 실리콘, α-히드록시산, 소포제, 보습제, 비타민, 곤충 기피제, 향료, 보존제, 계면활성제, 소염제, 물질 P 길항제, 충전제, 중합체, 추진제, 염기성화 또는 산성화제, 또는 착색제 등 공지의 화합물을 포함하여 제조된다.
In addition, the compositions of each formulation may contain various bases and additives necessary for formulation of the formulation, and may contain non-ionic surfactants, silicone polymers, extender pigments, flavorings, preservatives, But are not limited to, disinfectants, oxidative stabilizers, organic solvents, ionic or nonionic thickeners, plasticizers, antioxidants, free radical scavengers, opacifiers, stabilizers, emollients, silicones, A preservative, a surfactant, an anti-inflammatory agent, a substance P antagonist, a filler, a polymer, a propellant, a basicizing or acidifying agent, or a coloring agent.
[실시예][Example]
이하, 본 발명을 보다 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다. 그러나 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 아래에서 상술하는 실시예들에 한정되는 것으로 해석돼서는 안 된다. 본 발명의 실시예들은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다.
Hereinafter, the present invention will be described in more detail with reference to examples. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
실시예 1: 서열번호 1의 세포투과성 펩타이드와 연결된 PCL-b-AA-co-PHEMA 컨쥬게이트 제조Example 1: Preparation of PCL-b-AA-co-PHEMA conjugate linked to the cell permeable peptide of SEQ ID NO:
하기 반응식 1에 나타낸 바의 반응식을 통해 컨쥬게이트를 제조하였다.A conjugate was prepared through the reaction formula shown in Scheme 1 below.
[반응식 1][Reaction Scheme 1]
(단계 1)(Step 1)
본 발명에서 언급한 세포투과 펩타이드가 화학적으로 결합된 블록공중합체의 합성 단계에 대해서 위 그림에 도시하였다. 개시제로 사용된 PCL-Br 거대 개시제 합성은 선행연구에서 밝힌 조건을 참고하였다. (Duxbury et. al., J. AM. CHEM. SOC., 2005, 127, 2384-2385; Yuan et. al., Polymer Bulletin, 2005, 55, 225-233) The synthesis steps of the chemically coupled block copolymer of the cell permeable peptide mentioned in the present invention are shown in the above figure. The synthesis of PCL-Br macroinitiators used as initiators was based on the conditions described in previous studies. (Duxbury et al, J. AM CHEM SOC, 2005, 127, 2384-2385;....... Yuan et al, Polymer Bulletin, 2005, 55, 225-233)
합성한 PCL-Br 거대 개시제의 분자량은 500~2,000 g/mol 이었으며, 그 중 분자량 1000 g/mol 인 경우 10g의 ε-카프로락톤을 150mL의 톨루엔에 용해시킨 후 온도를 120℃까지 높였다. 여기에 1mL의 SnOct2와 1g의 헥산올을 투입하여 반응시켜 PCL-OH를 합성하고 정제한 후, 4g을 THF 30 mL에 용해시켰다. 이어 2-브로모이소부티릴 브로마이드 0.224 g을 투입하여 거대 개시제인 PCL-Br을 합성하였다.The molecular weight of the synthesized PCL-Br macromonomer was 500 to 2,000 g / mol. When the molecular weight was 1,000 g / mol, 10 g of ε-caprolactone was dissolved in 150 mL of toluene and then the temperature was increased to 120 ° C. Then, 1 mL of SnOct 2 and 1 g of hexanol were added and reacted to synthesize PCL-OH, and 4 g of the PCL-OH was dissolved in 30 mL of THF. Then, 0.224 g of 2-bromoisobutyryl bromide was added to synthesize PCL-Br as a macro initiator.
<단계 2><Step 2>
상기 <단계 1> 에서 합성한 PCL-Br 거대 개시제 3g을 용액 [bmim]PF6 - 또는 [bmim] CF3SO3 - 30mL에 첨가한 후 반응기 온도를 25℃로 맞추어 완전히 용해시켰다. 촉매와 리간드 그리고 비닐 그룹을 가진 모노머(HEMA)와 CPP와 결합사이트를 형성할 MAA를 투입한 후 20 시간 동안 반응시켰다. 최종생성물은 THF에 침전시킨 후 원심 분리하여 건조 후 냉장 보관하였다. Wherein a PCL-Br giant initiator 3g synthetic <Step 1> In the solution [bmim] PF 6 - or [bmim] CF 3 SO 3 - and then the reactor temperature was added to 30mL to completely dissolve it at a 25 ℃. Monomer (HEMA) with catalyst, ligand and vinyl group and MAA to form CPP and binding site were added and reacted for 20 hours. The final product was precipitated in THF, centrifuged, dried and refrigerated.
<단계 3><Step 3>
상기 <단계 2> 에서 합성한 PCL-b-AA-co-PHEMA의 소수성 블록과 친수성 블록의 비율이 1:1∼1:5 이었으며, 총 평균 분자량은 1,000-15,000 g/mol로 측정되었다.The ratio of the hydrophobic block to the hydrophilic block of PCL-b-AA-co-PHEMA synthesized in Step 2 was 1: 1 to 1: 5 and the total average molecular weight was measured to be 1,000 to 15,000 g / mol.
이를 DCC(dicyclohexylcarbodiimide)와 함께 DMF에 용해시킨 후 60 oC에서 반응시켰다. 정제한 하이드로숙신이미드(Hydroxysuccinimide)가 결합된 블록공중합체와 CPP(프로셀제약, 제품명 M1000)를 DMF에 투입 후 40℃ 에서 반응시켜 최종목적으로 세포투과 펩타이드 결합 블록공중합체 컨쥬게이트를 회수하였다.
It was dissolved in DMF together with DCC (dicyclohexylcarbodiimide) and reacted at 60 ° C. Purified hydroxysuccinimide-blocked block copolymer and CPP (Procel Pharmaceutical, product name: M1000) were added to DMF and reacted at 40 ° C to recover a cell permeable peptide conjugate block copolymer conjugate .
실시예 2: 서열번호 1의 세포투과성 펩타이드와 연결된 PCL-b-AA-co-PMMA 컨쥬게이트 제조Example 2: Preparation of PCL-b-AA-co-PMMA conjugate linked to the cell permeable peptide of SEQ ID NO:
HEMA 대신 MMA를 사용한 것을 제외하고 상기 실시예 1과 동일하게 수행하고, 하기 반응식 2에 나타낸 바의 반응식을 통해 컨쥬게이트를 제조하였다.The procedure of Example 1 was repeated except that MMA was used in place of HEMA, and a conjugate was prepared through the reaction formula shown in Reaction Scheme 2 below.
[반응식 2][Reaction Scheme 2]
실시예 3: 서열번호 1의 세포투과성 펩타이드와 연결된 PCL-b-AA-co-PMPC 컨쥬게이트 제조Example 3: Preparation of PCL-b-AA-co-PMPC conjugate linked to the cell permeable peptide of SEQ ID NO:
HEMA 대신 MPC를 사용한 것을 제외하고 상기 실시예 1과 동일하게 수행하고, 하기 반응식 3에 나타낸 바의 반응식을 통해 컨쥬게이트를 제조하였다.The procedure of Example 1 was repeated except that MPC was used in place of HEMA, and a conjugate was prepared through the reaction formula shown in Reaction Scheme 3 below.
[반응식 3][Reaction Scheme 3]
비교예 1Comparative Example 1
실시예 3의 멀티 블록 공중합체와 CPP를 화학 결합을 하지 않고 1:1의 중량비로 단순 혼합하여 멀티 블록 공중합체-CPP 혼합물을 제조하였다.
The multi-block copolymer of Example 3 and CPP were simply mixed at a weight ratio of 1: 1 without chemical bonding to prepare a multi-block copolymer-CPP mixture.
실험예 1Experimental Example 1
실시예 1에서 제조된 CPP 결합 전 멀티 블록 공중합체의 입자 상태를 확인하기 위해 투과전자 현미경으로 측정하여 도 1에 나타내었다.The measurement of the particle state of the multi-block copolymer before CPP bonding prepared in Example 1 was carried out by a transmission electron microscope and is shown in FIG.
도 1을 보면, 멀티 블록 공중합체의 입자는 30nm 이하의 크기를 가짐을 알 수 있다.Referring to FIG. 1, the particles of the multi-block copolymer have a size of 30 nm or less.
실험예 2Experimental Example 2
실시예 1 및 2에서 얻어진 블록 공중합체의 중합도를 GPC(Gel Permeation Chromatography)를 사용하여 측정하였으며, 얻어진 결과를 도 2에 나타내었다.The degree of polymerization of the block copolymers obtained in Examples 1 and 2 was measured using GPC (Gel Permeation Chromatography), and the obtained results are shown in FIG.
도 2의 (a)는 PCL-b-PHEMA의 GPC 스펙트럼이고, (b)는 PCL-b-PMMA의 GPC 스펙트럼이다. 도 2의 결과로부터, 각 블록 공중합체의 총 평균 분자량이 1,000-15,000 g/mol임을 알 수 있다.2 (a) is a GPC spectrum of PCL-b-PHEMA, and (b) is a GPC spectrum of PCL-b-PMMA. From the results of FIG. 2, it can be seen that the total average molecular weight of each block copolymer is 1,000-15,000 g / mol.
Claims (13)
소수성 블록(A), 친수성 블록(B) 및 결합 블록(C)으로 구성되며, 상기 결합 블록(C)에 세포투과성 펩타이드(P)가 화학 결합된 것을 특징으로 하고,
상기 친수성 블록은 폴리하이드록시에틸아크릴레이트(PHEA) 또는 폴리(2-메타크릴오일옥시에틸 포스포릴클로라이드(PMPC, poly(2-methacryloyloxyethyl phosphorylcholine)인 것인 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트:
[화학식 1]
(상기 화학식 1에서, a는 20∼80 몰%, b는 20∼80 몰%, c=100-(a+b) 이다)(1)
Characterized in that a cell permeable peptide (P) is chemically bonded to the binding block (C), wherein the hydrophobic block (A), the hydrophilic block (B) and the binding block (C)
Wherein the hydrophilic block is polyhydroxyethyl acrylate (PHEA) or poly (2-methacryloyloxyethyl phosphorylcholine), wherein the hydrophilic block is a poly-block copolymer-cell permeable peptide conjugate:
[Chemical Formula 1]
(Wherein a is 20 to 80 mol%, b is 20 to 80 mol%, and c = 100- (a + b)
(b) 상기 소수성 블록을 개시제로 하여 친수성 모노머를 중합반응시켜 블록 공중합체를 제조하고,
(c) 상기 블록 공중합체를 거대 개시제로 하여 결합 모노머를 중합반응시켜 멀티 블록 공중합체를 제조하고,
(d) 멀티 블록 공중합체와 세포투과성 펩타이드를 반응시켜 제조하는 제1항에 따른 화학식 1의 멀티 블록 공중합체-세포투과성 펩타이드 컨쥬게이트를 제조방법:
[화학식 1]
(상기 화학식 1에서, a는 20∼80 몰%, b는 20∼80 몰%, c=100-(a+b) 이다)(a) a hydrophobic monomer is polymerized to produce a hydrophobic block,
(b) polymerizing the hydrophilic monomer with the hydrophobic block as an initiator to prepare a block copolymer,
(c) preparing a multiblock copolymer by polymerizing the binding monomer with the block copolymer as a macro initiator,
(d) preparing a multi-block copolymer-cell permeable peptide conjugate of formula (1) according to claim 1 prepared by reacting a multi-block copolymer with a cell permeable peptide;
[Chemical Formula 1]
(Wherein a is 20 to 80 mol%, b is 20 to 80 mol%, and c = 100- (a + b)
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