KR20230008234A - 상처 치유를 위한 방법 및 조성물 - Google Patents
상처 치유를 위한 방법 및 조성물 Download PDFInfo
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- KR20230008234A KR20230008234A KR1020227045205A KR20227045205A KR20230008234A KR 20230008234 A KR20230008234 A KR 20230008234A KR 1020227045205 A KR1020227045205 A KR 1020227045205A KR 20227045205 A KR20227045205 A KR 20227045205A KR 20230008234 A KR20230008234 A KR 20230008234A
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Abstract
본 발명은 상처 치유, 또는 생물학적 또는 의학적 표면의 변형과 같은 적용에서 이용을 위한 나노규모 마이크로시트의 대규모 제조에 관한 것이다.
Description
관련된 출원에 대한 교차 참조
본 발명은 2016년 7월 29일자 제출된 U.S. 특허가출원 62/368,646에 우선권을 주장하고, 이것은 전체적으로 참조로서 편입된다.
발명의 분야
본 발명은 상처 치유, 또는 생물학적 또는 의학적 표면의 변형과 같은 적용에서 이용을 위한 나노규모 마이크로시트의 대규모 제조에 관계한다.
발명의 배경
생리활성 작용제를 내포하는 분자로 된 얇은 중합성 시트는 상처의 부위에서 상처 치유를 증진하고 세균 감염을 예방하는데 유용한 것으로 밝혀졌다. 가령, 본원에서 전체적으로 참조로서 포함되는 공동계류중인 U.S. 특허공보 2015/0283297을 참조한다. 하지만, 이런 얇은 중합성 시트의 대규모 제조는 기존에 설명된 바가 없다. 기존에 설명된 방법은 소규모 생산 기술인 배치 생산에 주로 의존하는데, 이들 기술은 시약의 이용에서 느리고 비효율적일 뿐만 아니라 상대적으로 작은 표면적을 갖는 마이크로시트의 생산에 한정된다.
당해 분야에서 요구되는 것은 나노- 내지 마이크로규모 중합성 시트를 효율적인 방식으로 생산하기 위한 대규모 방법이다.
발명의 요약
본 발명은 상처 치유, 또는 생물학적 또는 의학적 표면의 변형과 같은 적용에서 이용을 위한 나노규모 마이크로시트의 대규모 제조에 관계한다.
일부 구체예에서, 본 발명은 다음을 포함하는 물품을 제공한다: 낮은 표면 에너지 표면을 포함하고 0.52 제곱 미터보다 큰 전체 표면적을 갖는 가요성 기재; 그리고 낮은 표면 에너지 표면에 인접하고 이것과 접촉하는 나노규모 중합체, 상기 나노규모 중합체 층은 0.5 nm 내지 10000 nm의 두께를 갖는다.
일부 구체예에서, 나노규모 중합체 층은 중합체 다중층이다. 일부 구체예에서, 중합체 다중층은 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질의 교호 층을 포함한다. 일부 구체예에서, 적어도 하나의 양으로 하전된 고분자전해질은 폴리(알릴아민 염산염) (PAH), 폴리-리신 (PLL), 폴리(에틸렌 이민) (PEI), 폴리(히스티딘), 폴리(N,N-디메틸 아미노아크릴레이트), 폴리(N,N,N-트리메틸아미노아크릴레이트 염화물), 폴리(메티아크릴아미도프로필트리메틸 염화암모늄), 그리고 천연 또는 합성 다당류(polysaccharides), 예를 들면, 키토산으로 이루어진 군에서 선택된다. 일부 구체예에서, 적어도 하나의 음으로 하전된 고분자전해질은 폴리(아크릴산) (PAA), 폴리(스티렌술포네이트) (PSS), 알긴산염, 히알루론산, 헤파린, 헤파란 황산염, 콘드로이틴 황산염, 덱스트란 황산염, 폴리(메타크릴산), 산화된 셀룰로오스, 카르복시메틸 셀룰로오스, 폴리아스파르트산, 그리고 폴리글루탐산으로 이루어진 군에서 선택된다. 일부 구체예에서, 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질은 합성 고분자전해질이다.
일부 구체예에서, 나노규모 중합체 층은 분사 코팅, 침지 코팅, 담금 코팅, 스핀 코팅, 슬롯 다이 코팅, 잉크젯 코팅, 아닐록스 코팅, 스크린 코팅, 오프셋 인쇄 프린팅, 철판 인쇄 코팅, 그라비야 코팅, 로토그라비야 코팅, 리버스 롤 코팅, 미터링 (Meyer) 막대 코팅, 블레이드 코팅, 나이프 오버 롤 코팅, 에어 나이프 코팅, 커튼 코팅, 용융 압출 코팅, 용매 주조, 그리고 이들의 임의의 조합으로 이루어진 군에서 선택되는 방법에 의해, 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질을 적용함으로써 형성된다.
일부 구체예에서, 가요성 기재는 0.65 제곱 미터보다 큰 표면적을 갖는다.
일부 구체예에서, 물품은 나노규모 중합체 층 내로 통합된 생리활성 작용제를 더욱 포함한다. 일부 구체예에서, 생리활성 작용제는 나노규모 중합체 층의 3차원 구조 내에 산재되거나, 또는 중합체 다중층의 층 내에 산재된다. 일부 구체예에서, 생리활성 작용제는 항균제, 항생물막 작용제, 성장 인자, 지혈 작용제, 생리활성 펩티드, 생리활성 폴리펩티드, 진통제, 국부 마취제, 오피오이드, 오피오이드 길항제 또는 혼합된 효현제/길항제, 항응고제, 항염증제, 그리고 약물 분자 또는 약물 화합물로 이루어진 군에서 선택된다. 일부 구체예에서, 항균제는 소형 분자 항균제, 하전된 소형 분자 항균제, 항균성 폴리펩티드, 금속성 입자, 그리고 금속 이온 항균제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항균제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 항균제는 은 이온, 은 염, 또는 은 나노입자이다. 일부 구체예에서, 소형 분자 항균제는 은, 클로르헥시딘, 항생제, 폴리헥사메틸렌 비구아니드 (PHMB), 요오드, 카덱소머 요오드, 포비돈 요오드 (PVI), 과산화수소 및 식초 (아세트산)로 이루어진 군에서 선택된다. 일부 구체예에서, 항생물막 작용제는 소형 분자 항생물막 작용제, 하전된 소형 분자 항생물막 작용제, 항생물막 폴리펩티드, 항생물막 효소, 금속성 입자, 그리고 금속 이온 항생물막 작용제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항생물막 작용제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 항생물막 작용제는 갈륨 이온, 갈륨 이온 염, 갈륨 이온 나노입자, 갈륨 합금, 또는 갈륨 및 은의 합금이다. 일부 구체예에서, 항생물막 효소는 디스퍼신 B이다. 일부 구체예에서, 국부 마취제는 부피바카인, 리도카인, 아르티카인, 프릴로카인 및 메피바카인으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드는 코데인, 펜타닐, 히드로코돈, 히드로코돈 및 아세트아미노펜, 히드로모르폰, 메페리딘, 모르핀, 옥시코돈, 옥시코돈 및 아세트아미노펜, 옥시코돈 및 날록손으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드 길항제 또는 혼합된 효현제/길항제는 날록손, 디프레노르핀, 날트렉손, 부프레노르핀, 부프레모르핀/날록손으로 이루어진 군에서 선택된다.
일부 구체예에서, 물품은 나노규모 중합체 층이 기재의 낮은 표면 에너지 표면 및 두 번째 중합체 층 사이에 있도록, 나노규모 중합체 층에 인접하고 이것과 접촉하는 두 번째 중합체 층을 더욱 포함한다. 일부 구체예에서, 두 번째 중합체 층은 나노규모 층으로부터 생리활성 작용제의 방출을 1 내지 1000 배, 1 내지 100 배, 10 내지 1000 배, 20 내지 1000 배, 50 내지 1000 배, 100 내지 1000 배, 10 내지 500 배, 50 내지 500 배, 10 내지 200 배 또는 20 내지 200 배 감소시킨다.
일부 구체예에서, 두 번째 중합체 층은 희생 중합체 층이다. 일부 구체예에서, 희생 중합체 층은 분해가능하거나 또는 생분해성이다. 일부 구체예에서, 희생 중합체 층은 수용성 중합체를 포함한다. 일부 구체예에서, 수용성 중합체는 신장 여과에 의해 제거가능하다. 일부 구체예에서, 수용성 중합체는 23 kDa보다 적은 분자량을 갖는다. 일부 구체예에서, 수용성 중합체를 포함하는 희생 중합체 층은 생리활성 나노규모 중합체 층이 표면에 적층되도록, 표면상 수분에 노출될 때 용해된다. 일부 구체예에서, 희생 중합체 층은 폴리비닐 알코올 (PVA)을 포함한다. 일부 구체예에서, 두 번째 중합체 층은 폴리아크릴산 (PAA), 폴리비닐피롤리돈 (PVP), 카르복시메틸 셀룰로오스 (CMC), 히드록시프로필 셀룰로오스, 히드록시프로필 메틸셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 히드록시에틸 셀룰로오스 (HEC), 알긴산염, 폴리비닐아세테이트 (PVAc), 폴리유산 (PLA), 폴리유산-코-글리콜산 (PLGA), 폴리글리콜산, 또는 폴리무수물을 포함한다. 일부 구체예에서, 두 번째 중합체 층에서 중합체는 이온성으로, 물리적으로 또는 화학적으로 교차연결된다. 일부 구체예에서, 희생 층은 계면활성제, 유화제, 적심제, 유동성 조절제, 가소제, 피부연화제, 보습제, 붕괴제, 윤활제, 결합제, 상용화 작용제, 방전 작용제 및 충전제로 이루어진 군에서 선택되는 한 가지 또는 그 이상의 첨가제를 포함한다.
일부 구체예에서, 두 번째 중합체 층은 비희생 중합체 층이다. 일부 구체예에서, 비희생 중합체 층은 콜라겐, 하이드로겔, 수성콜로이드, 폴리우레탄, 또는 실리콘을 포함한다. 일부 구체예에서, 나노규모 중합체 층과 조합된 두 번째 중합체 층은 기재의 낮은 표면 에너지 표면으로부터 박리가능하다.
일부 구체예에서, 두 번째 중합체 층은 생리활성 작용제를 포함한다. 일부 구체예에서, 생리활성 작용제는 항균제, 항생물막 작용제, 성장 인자, 지혈 작용제, 생리활성 펩티드, 생리활성 폴리펩티드, 진통제, 국부 마취제, 오피오이드, 오피오이드 효현제, 오피오이드 길항제 또는 혼합된 효현제/길항제, 항응고제, 항염증제, 그리고 약물 분자 또는 약물 화합물로 이루어진 군에서 선택된다. 일부 구체예에서, 항균제는 소형 분자 항균제, 하전된 소형 분자 항균제, 항균성 폴리펩티드, 금속성 입자, 그리고 금속 이온 항균제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항균제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 항균제는 은 이온, 은 염, 또는 은 나노입자이다. 일부 구체예에서, 소형 분자 항균제는 은, 클로르헥시딘, 항생제, 폴리헥사메틸렌 비구아니드 (PHMB), 요오드, 카덱소머 요오드, 포비돈 요오드 (PVI), 과산화수소 및 식초 (아세트산)로 이루어진 군에서 선택된다. 일부 구체예에서, 항생물막 작용제는 소형 분자 항생물막 작용제, 하전된 소형 분자 항생물막 작용제, 항생물막 폴리펩티드, 항생물막 효소, 금속성 입자, 그리고 금속 이온 항생물막 작용제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항생물막 작용제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 항생물막 작용제는 갈륨 이온, 갈륨 이온 염, 갈륨 이온 나노입자, 갈륨 합금, 또는 갈륨 및 은의 합금이다. 일부 구체예에서, 항생물막 효소는 디스퍼신 B이다. 일부 구체예에서, 국부 마취제는 부피바카인, 리도카인, 아르티카인, 프릴로카인 및 메피바카인으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드는 코데인, 펜타닐, 히드로코돈, 히드로코돈 및 아세트아미노펜, 히드로모르폰, 메페리딘, 모르핀, 옥시코돈, 옥시코돈 및 아세트아미노펜, 옥시코돈 및 날록손으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드 길항제 또는 혼합된 효현제/길항제는 날록손, 디프레노르핀, 날트렉손, 부프레노르핀, 부프레모르핀/날록손으로 이루어진 군에서 선택된다.
일부 구체예에서, 두 번째 중합체 층은 약 0.1 μm 두께 내지 약 100 μm 두께, 약 0.1 μm 두께 내지 약 50 μm 두께, 약 1 μm 두께 내지 약 20 μm 두께, 또는 약 1 μm 두께 내지 약 10 μm 두께이다. 일부 구체예에서, 나노규모 중합체 층에서 거의 0.01 내지 100 μg/cm2의 농도에서 생리활성 작용제. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 하루에 약 0.01 내지 100 μg/cm2의 속도로 방출되도록 하는 양으로 나노규모 중합체 층에서 제공된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 5, 10, 20, 25 또는 30 일까지 동안 하루에 약 0.01 내지 100 μg/cm2의 속도로 방출되도록 하는 양으로 나노규모 중합체 층에서 제공된다. 일부 구체예에서, 생리활성 작용제는 두 번째 중합체 층에서 거의 0.01 μg/cm2 내지 10 mg/cm2의 농도로 포함된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 하루에 약 0.01 μg/cm2 내지 10 mg/cm2의 속도로 방출되도록 하는 양으로 두 번째 중합체 층에서 제공된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 5, 10, 20, 25 또는 30 일까지 동안 하루에 약 0.01 μg/cm2 내지 10 mg/cm2의 속도로 방출되도록 하는 양으로 두 번째 중합체 층에서 제공된다. 일부 구체예에서, 두 번째 중합체 층은 횡단면에서 계측될 때 평균 두께의 500, 400, 300, 200, 100, 50, 20 또는 10%보다 적은 편차로 균일한 두께를 갖는다.
일부 구체예에서, 물품은 두 번째 또는 그 이상의 생리활성 작용제(들)를 더욱 포함한다.
일부 구체예에서, 가요성 기재 상에서 낮은 표면 에너지 표면은 10 내지 100 mJ/cm2 (가령, 10 내지 60 mJ/cm2)의 표면 에너지를 갖는다.
일부 구체예에서, 가요성 기재는 낮은 표면 에너지의 가요성 중합성 시트이거나, 또는 낮은 표면 에너지 표면은 가요성 중합체 위에 코팅된 이형 코팅(release coating)에 의해 제공된다. 일부 구체예에서, 이형 코팅은 실리콘 이형 코팅, 폴리디메틸 실록산 (PDMS) 코팅, 탄화플루오로 코팅, 폴리아크릴레이트 코팅, 폴리스티렌 코팅, 폴리스티렌아크릴 코팅, 크롬 스테아르산염 복합체 코팅, 또는 폴리올레핀 코팅이다. 일부 구체예에서, 가요성 중합성 시트는 폴리에스테르 필름, 폴리에틸렌 테레프탈염산 (PET) 필름, 이축 연신 PET 필름, 폴리카보네이트, 폴리에틸렌 (고밀도 폴리에틸렌, 중밀도 폴리에틸렌, 저밀도 폴리에틸렌, 선형 저밀도 폴리에틸렌 포함) 필름, 폴리염화비닐 필름, 폴리비닐리덴 염화물 필름, 폴리비닐리덴 플루오르화물 필름, 나일론 필름, 폴리스티렌 필름, 아세트산염 필름, 폴리우레탄 필름, 에틸렌 비닐 아세트산염 공중합체 필름, 캐스트 폴리프로필렌 필름, 단축 연신 폴리프로필렌 필름 및 이축 연신 폴리프로필렌 필름으로 이루어진 군에서 선택되는 중합체 필름을 포함한다. 일부 구체예에서, 본 발명은 다음을 포함하는, 물품의 제조 공정을 제공한다: a) 낮은 표면 에너지 표면을 포함하고 0.52 제곱 미터보다 큰 표면적을 갖는 가요성 기재를 제공하고; b) 나노규모 중합체 층을 낮은 표면 에너지 표면상에 약 0.5 nm 내지 10000 nm 두께로 적층하고; 그리고 c) 상기 물품을 제공하기 위해, 생리활성 작용제를 나노규모 중합체 층 내로 도입하여 생리활성 나노규모 중합체 층을 제공함. 일부 구체예에서, 낮은 표면 에너지 표면을 포함하는 가요성 기재의 표면적은 0.65 제곱 미터보다 크다.
일부 구체예에서, 적층은 롤투롤 (roll to roll) 코팅 과정을 통해 일어난다. 일부 구체예에서, 롤투롤 코팅 과정은 가요성 기재를 첫 번째 롤로부터 적어도 두 번째 롤로 이전하고, 그리고 가요성 기재가 첫 번째 롤 및 두 번째 롤 사이에서 이전되는 동안, 가요성 기재의 낮은 표면 에너지 표면을 나노규모 중합체 층으로 코팅하는 것을 포함한다. 일부 구체예에서, 나노규모 중합체 층은 분사 코팅, 침지 코팅, 담금 코팅, 스핀 코팅, 슬롯 다이 코팅, 잉크젯 코팅, 아닐록스 코팅, 스크린 코팅, 오프셋 인쇄 프린팅, 철판 인쇄 코팅, 그라비야 코팅, 로토그라비야 코팅, 리버스 롤 코팅, 미터링 (Meyer) 막대 코팅, 블레이드 코팅, 나이프 오버 롤 코팅, 에어 나이프 코팅, 커튼 코팅, 용융 압출 코팅, 용매 주조, 그리고 이들의 임의의 조합으로 이루어진 군에서 선택되는 코팅 또는 프린팅 방법에 의해, 가요성 기재의 낮은 표면 에너지 표면 위에 코팅된다.
일부 구체예에서, 나노규모 중합체 층은 중합체 다중층이다. 일부 구체예에서, 나노규모 중합체 층은 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질의 교호 층에 의해 형성된다. 일부 구체예에서, 적어도 하나의 양으로 하전된 고분자전해질은 폴리(알릴아민 염산염) (PAH), 폴리-리신 (PLL), 폴리(에틸렌 이민) (PEI), 폴리(히스티딘), 폴리(N,N-디메틸 아미노아크릴레이트), 폴리(N,N,N-트리메틸아미노아크릴레이트 염화물), 폴리(메티아크릴아미도프로필트리메틸 염화암모늄), 그리고 자연 또는 합성 다당류, 예를 들면, 키토산으로 이루어진 군에서 선택된다. 일부 구체예에서, 적어도 하나의 음으로 하전된 고분자전해질은 폴리(아크릴산) (PAA), 폴리(스티렌술포네이트) (PSS), 알긴산염, 히알루론산, 헤파린, 헤파란 황산염, 콘드로이틴 황산염, 덱스트란 황산염, 폴리(메타크릴산), 산화된 셀룰로오스, 카르복시메틸 셀룰로오스, 폴리아스파르트산, 그리고 폴리글루탐산으로 이루어진 군에서 선택된다. 일부 구체예에서, 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질은 합성 고분자전해질이다.
일부 구체예에서, 고분자전해질의 분자량은 1 - 10000 kDa, 100 내지 10000 kDa, 500 내지 10000 kDa, 1000 내지 10000 kDa, 50 내지 500 kDa 또는 500 내지 5000 kDa이다. 일부 구체예에서, 고분자전해질은 1 내지 10000 kDa, 100 내지 10000 kDa, 500 내지 10000 kDa, 1000 내지 10000 kDa, 50 내지 500 kDa 또는 500 내지 5000 kDa의 범위에서 다중모드 분자량 분포를 갖거나, 또는 1 - 10000 kDa, 100 내지 10000 kDa, 500 내지 10000 kDa, 1000 내지 10000 kDa, 50 내지 500 kDa 또는 500 내지 5000 kDa의 범위에서 단일모드 또는 다중모드 분자량 분포의 복수 중합체의 혼합물이다. 일부 구체예에서, 수성 용액에서 고분자전해질의 농도는 중합체 반복 단위에 근거하여, 1 내지 10000 mM, 10 내지 10000 mM, 100 내지 10000 mM, 10 내지 1000 mMM, 10 내지 500 mM, 10 내지 50 mM, 1 내지 50 mM, 또는 1 내지 100 mM이다. 일부 구체예에서, 수성 고분자전해질 용액의 pH는 중합체가 최소한 0.01% 하전되도록 조정된다. 일부 구체예에서, 무기 또는 유기 염의 농도는 수성 고분자전해질 용액에서 1 내지 10000 mM, 10 내지 10000 mM, 100 내지 10000 mM, 10 내지 1000 mMM, 10 내지 500 mM, 10 내지 50 mM, 1 내지 50 mM, 또는 1 내지 100 mM이다.
일부 구체예에서, 나노규모 중합체 층의 코팅 동안 가요성 기재의 낮은 표면 에너지 표면상에서 중합체 제제의 체류 시간은 헹굼에 앞서, 1 내지 600 초, 50 내지 600 초, 100 내지 600 초, 또는 200 내지 600 초이다.
일부 구체예에서, 이들 공정은 생리활성 작용제를 나노규모 중합체 층 내로 통합하는 것을 더욱 포함한다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 나노규모 중합체 층의 3차원 구조 내에 산재되도록, 나노규모 중합체 층 내로 통합된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 중합체 다중층의 층 내에 산재되도록, 나노규모 중합체 다중층 내에 도입된다.
일부 구체예에서, 생리활성 작용제는 항균제, 항생물막 작용제, 성장 인자, 지혈 작용제, 생리활성 펩티드, 생리활성 폴리펩티드, 진통제, 국부 마취제, 오피오이드, 오피오이드 효현제, 오피오이드 길항제 또는 혼합된 효현제/길항제, 항응고제, 항염증제, 그리고 약물 분자 또는 약물 화합물로 이루어진 군에서 선택된다. 일부 구체예에서, 항균제는 소형 분자 항균제, 하전된 소형 분자 항균제, 항균성 폴리펩티드, 금속성 입자, 그리고 금속 이온 항균제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항균제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 나노입자는 은 나노입자이다. 일부 구체예에서, 소형 분자 항균제는 은, 클로르헥시딘, 항생제, 폴리헥사메틸렌 비구아니드 (PHMB), 요오드, 카덱소머 요오드, 포비돈 요오드 (PVI), 과산화수소 및 식초 (아세트산)로 이루어진 군에서 선택된다. 일부 구체예에서, 항생물막 작용제는 소형 분자 항생물막 작용제, 하전된 소형 분자 항생물막 작용제, 항생물막 폴리펩티드, 항생물막 효소, 금속성 입자, 그리고 금속 이온 항생물막 작용제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항생물막 작용제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 항생물막 작용제는 갈륨 이온, 갈륨 이온 염, 갈륨 이온 나노입자, 갈륨 합금, 또는 갈륨 및 은의 합금이다. 일부 구체예에서, 항생물막 효소는 디스퍼신 B이다. 일부 구체예에서, 진통제는 부피바카인, 리도카인, 아르티카인, 프릴로카인 및 메피바카인으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드는 코데인, 펜타닐, 히드로코돈, 히드로코돈 및 아세트아미노펜, 히드로모르폰, 메페리딘, 모르핀, 옥시코돈, 옥시코돈 및 아세트아미노펜, 옥시코돈 및 날록손으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드 길항제 또는 혼합된 효현제/길항제는 날록손, 디프레노르핀, 날트렉손, 부프레노르핀, 부프레모르핀/날록손으로 이루어진 군에서 선택된다.
일부 구체예에서, 생리활성 작용제는 나노규모 중합체 층의 형성 동안 나노규모 중합체 층 내로 도입된다. 일부 구체예에서, 생리활성 작용제는 나노규모 중합체 층의 형성 후 나노규모 중합체 층 내로 도입된다.
일부 구체예에서, 생리활성 나노규모 중합체 층을 제공하기 위해 생리활성 작용제를 나노규모 중합체 층 내로 도입하는 것은 은 이온을 나노규모 중합체 다중층 내로 도입하고 은 이온을 인 시츄(in situ)로 환원시켜 은 나노입자를 제공하는 것을 포함한다. 일부 구체예에서, 나노규모 필름은 1 내지 3600 초, 100 내지 3600 초, 200 내지 3600 초, 400 내지 3600 초 또는 600 내지 3600 초 동안, 0.1 - 10000 mM, 1 내지 10000 mM, 10 내지 10000 mM, 100 내지 10000 mM, 10 내지 1000 mMM, 10 내지 500 mM, 10 내지 50 mM, 1 내지 50 mM, 또는 1 내지 100 mM의 농도의 질산은 용액에서 담금에 의해 은 이온이 넣어진다. 일부 구체예에서, 나노규모 필름에서 은 이온은 1 내지 3600 초, 100 내지 3600 초, 200 내지 3600 초, 400 내지 3600 초 또는 600 내지 3600 초 동안, 0.1 내지 10000 mM, 1 내지 10000 mM, 10 내지 10000 mM, 100 내지 10000 mM, 10 내지 1000 mMM, 10 내지 500 mM, 10 내지 50 mM, 1 내지 50 mM, 또는 1 내지 100 mM의 농도의 환원제 용액의 용액에 나노규모 필름을 담금으로써 은 나노입자로 환원된다. 일부 구체예에서, 환원제는 수소화붕소나트륨이다.
일부 구체예에서, 생리활성 나노규모 중합체 층을 제공하기 위해 생리활성 작용제를 나노규모 중합체 층 내로 통합하는 것은 하전된 소형 분자 항균제를 상이한 전하를 갖는 고분자전해질 층 중간에 도입하는 것을 포함한다.
일부 구체예에서, 이들 공정은 도입 단계의 1 내지 20회 반복을 더욱 포함한다.
일부 구체예에서, 이들 공정은 나노규모 중합체 층의 숫자를 제어함으로써, 나노규모 중합체 층을 형성하는 pH를 제어함으로써 및/또는 도입 주기의 횟수를 제어함으로써 나노규모 중합체 매트릭스 마이크로시트에서 생리활성 작용제의 양을 제어하는 것을 더욱 포함한다. 일부 구체예에서, 이들 공정은 생리활성 용액의 농도를 제어함으로써 및/또는 생리활성 용액에서 나노규모 중합체 층의 체류 시간을 제어함으로써 나노규모 중합체 매트릭스 마이크로시트에서 생리활성 작용제의 양을 제어하는 것을 더욱 포함한다.
일부 구체예에서, 이들 공정은 나노규모 중합체 층이 가요성 중합체 기재의 낮은 표면 에너지 표면 및 두 번째 중합체 층 사이에 있도록, 두 번째 중합체 층을 나노규모 중합체-층 위에 형성하거나 또는 적층하는 것을 더욱 포함한다. 일부 구체예에서, 두 번째 중합체 층은 나노규모 층으로부터 생리활성 작용제의 방출을 1 내지 1000 배, 1 내지 100 배, 10 내지 1000 배, 20 내지 1000 배, 50 내지 1000 배, 100 내지 1000 배, 10 내지 500 배, 50 내지 500 배, 10 내지 200 배 또는 20 내지 200 배 늦춘다.
일부 구체예에서, 두 번째 중합체 층은 희생 중합체 층이다. 일부 구체예에서, 희생 중합체 층은 분해가능하거나 또는 생분해성이다. 일부 구체예에서, 희생 중합체 층은 수용성 중합체를 포함한다. 일부 구체예에서, 수용성 중합체는 폴리비닐 알코올 (PVA)이다. 일부 구체예에서, 수용성 중합체는 23 kDa보다 적은 분자량을 갖는다. 일부 구체예에서, 수용성 중합체는 신장 여과에 의해 제거가능하다. 일부 구체예에서, 수용성 중합체를 포함하는 희생 중합체 층은 생리활성 나노규모 중합체 층이 표면에서 적층되도록, 표면상에 수분에 노출될 때 용해된다. 일부 구체예에서, 두 번째 중합체 층은 폴리아크릴산 (PAA), 폴리비닐피롤리돈 (PVP), 카르복시메틸 셀룰로오스 (CMC), 히드록시프로필 셀룰로오스, 히드록시프로필 메틸셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 히드록시에틸 셀룰로오스 (HEC), 알긴산염, 폴리비닐아세테이트 (PVAc), 폴리유산 (PLA), 폴리유산-코-글리콜산 (PLGA), 폴리글리콜산, 또는 폴리무수물을 포함한다.
일부 구체예에서, 두 번째 중합체 층에서 중합체는 이온성으로, 물리적으로 또는 화학적으로 교차연결된다.
일부 구체예에서, 두 번째 중합체 층은 계면활성제, 유화제, 적심제, 유동성 조절제, 가소제, 피부연화제, 보습제, 붕괴제, 윤활제, 결합제, 상용화 작용제, 방전 작용제 및 충전제로 이루어진 군에서 선택되는 한 가지 또는 그 이상의 첨가제를 포함한다.
일부 구체예에서, 두 번째 중합체 층은 비희생 중합체 층이다. 일부 구체예에서, 비희생 중합체 층은 콜라겐, 하이드로겔, 수성콜로이드, 폴리우레탄, 또는 실리콘을 포함한다.
일부 구체예에서, 두 번째 중합체 층은 약 0.1 μm 두께 내지 약 100 μm 두께, 약 0.1 μm 두께 내지 약 50 μm 두께, 약 1 μm 두께 내지 약 20 μm 두께, 또는 약 1 μm 두께 내지 약 10 μm 두께이다.
일부 구체예에서, 나노규모 중합체 층과 조합되어 두 번째 중합체 층은 자립형 마이크로시트를 제공하기 위해 기재의 낮은 표면 에너지 표면으로부터 박리가능하다.
일부 구체예에서, 이들 공정은 생리활성 작용제를 두 번째 중합체 층 내로 도입하는 것을 더욱 포함한다. 일부 구체예에서, 생리활성 작용제는 항균제, 항생물막 작용제, 성장 인자, 지혈 작용제, 생리활성 펩티드, 생리활성 폴리펩티드, 진통제, 항응고제, 항염증제, 그리고 약물 분자 또는 약물 화합물로 이루어진 군에서 선택된다. 일부 구체예에서, 항균제는 소형 분자 항균제, 하전된 소형 분자 항균제, 항균성 폴리펩티드, 금속성 입자, 그리고 금속 이온 항균제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항균제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 나노입자는 은 나노입자이다. 일부 구체예에서, 소형 분자 항균제는 은, 클로르헥시딘, 항생제, 폴리헥사메틸렌 비구아니드 (PHMB), 요오드, 카덱소머 요오드, 포비돈 요오드 (PVI), 과산화수소 및 식초 (아세트산)로 이루어진 군에서 선택된다. 일부 구체예에서, 항생물막 작용제는 소형 분자 항생물막 작용제, 하전된 소형 분자 항생물막 작용제, 항생물막 폴리펩티드, 항생물막 효소, 금속성 입자, 그리고 금속 이온 항생물막 작용제로 이루어진 군에서 선택된다. 일부 구체예에서, 금속 이온 항생물막 작용제는 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자이다. 일부 구체예에서, 금속 이온 항생물막 작용제는 갈륨 이온, 갈륨 이온 염, 갈륨 이온 나노입자, 갈륨 합금, 또는 갈륨 및 은의 합금이다. 일부 구체예에서, 항생물막 효소는 디스퍼신 B이다. 일부 구체예에서, 국부 마취제는 부피바카인, 리도카인, 아르티카인, 프릴로카인 및 메피바카인으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드는 코데인, 펜타닐, 히드로코돈, 히드로코돈 및 아세트아미노펜, 히드로모르폰, 메페리딘, 모르핀, 옥시코돈, 옥시코돈 및 아세트아미노펜, 옥시코돈 및 날록손으로 이루어진 군에서 선택된다. 일부 구체예에서, 오피오이드 길항제 또는 혼합된 효현제/길항제는 날록손, 디프레노르핀, 날트렉손, 부프레노르핀, 부프레모르핀/날록손으로 이루어진 군에서 선택된다.
일부 구체예에서, 생리활성 작용제는 나노규모 중합체 층에 거의 0.01 내지 100 μg/cm2의 농도로 도입된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 하루에 약 0.01 내지 100 μg/cm2의 속도로 방출되도록 하는 양으로 나노규모 중합체 층에서 제공된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 5, 10, 20, 25 또는 30 일까지 동안 하루에 약 0.01 내지 100 μg/cm2의 속도로 방출되도록 하는 양으로 나노규모 중합체 층에서 제공된다. 일부 구체예에서, 생리활성 작용제는 두 번째 중합체 층에서 거의 0.01 μg/cm2 내지 10 mg/cm2의 농도로 제공된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 하루에 약 0.01 μg/cm2 내지 10 mg/cm2의 속도로 방출되도록 하는 양으로 두 번째 중합체 층에서 제공된다. 일부 구체예에서, 생리활성 작용제는 생리활성 작용제가 5, 10, 20, 25 또는 30 일까지 동안 하루에 약 0.01 μg/cm2 내지 10 mg/cm2의 속도로 방출되도록 하는 양으로 두 번째 중합체 층에서 제공된다.
일부 구체예에서, 이들 공정은 조합된 나노규모 중합체 층 및 두 번째 중합체 층에서 두 번째 또는 그 이상의 생리활성 작용제(들)를 포함하는 것을 더욱 포함한다.
일부 구체예에서, 가요성 기재 상에서 낮은 표면 에너지 표면은 10 내지 100 mJ/cm2의 표면 에너지를 갖는다. 일부 구체예에서, 가요성 기재는 낮은 표면 에너지의 가요성 중합성 시트이거나, 또는 낮은 표면 에너지 표면은 가요성 중합체 위에 코팅된 이형 코팅(release coating)에 의해 제공된다. 일부 구체예에서, 이형 코팅은 실리콘 이형 코팅, 폴리디메틸 실록산 (PDMS) 코팅, 탄화플루오로 코팅, 폴리아크릴레이트 코팅, 폴리스티렌 코팅, 폴리스티렌아크릴 코팅, 크롬 스테아르산염 복합체 코팅, 또는 폴리올레핀 코팅이다. 일부 구체예에서, 가요성 중합성 시트는 폴리에스테르 필름, 폴리에틸렌 테레프탈염산 (PET) 필름, 이축 연신 PET 필름, 폴리카보네이트, 폴리에틸렌 (고밀도 폴리에틸렌, 중밀도 폴리에틸렌, 저밀도 폴리에틸렌, 선형 저밀도 폴리에틸렌 포함) 필름, 폴리염화비닐 필름, 폴리비닐리덴 염화물 필름, 폴리비닐리덴 플루오르화물 필름, 나일론 필름, 폴리스티렌 필름, 아세트산염 필름, 폴리우레탄 필름, 에틸렌 비닐 아세트산염 공중합체 필름, 캐스트 폴리프로필렌 필름, 단축 연신 폴리프로필렌 필름 및 이축 연신 폴리프로필렌 필름으로 이루어진 군에서 선택되는 중합체 필름을 포함한다.
일부 구체예에서, 이들 공정은 자립형 마이크로시트를 제공하기 위해, 기재의 낮은 표면 에너지 표면으로부터 두 번째 중합체 층과 연관하여 나노규모 중합체 층을 벗겨내는 것을 더욱 포함한다. 일부 구체예에서, 이들 공정은 나노규모 중합체 층이 위에 적층되는 기재를 원하는 모양과 크기로 절단하고, 그리고 기재의 낮은 표면 에너지 표면으로부터 두 번째 중합체 층과 연관하여 나노규모 중합체 층을 벗겨내는 것을 더욱 포함한다. 일부 구체예에서, 이들 공정은 기재의 낮은 표면 에너지 표면으로부터 두 번째 중합체 층과 연관하여 나노규모 중합체 층을 벗겨내고, 그리고 두 번째 중합체 층과 연관하여 나노규모 중합체 층을 원하는 모양과 크기로 절단하는 것을 더욱 포함한다.
범위가 앞서 제공된 요약에서 제공되는 경우에, 본 발명은 언급된 범위의 범위에 들어가는 부분범위를 포함하는 것으로 이해될 것이다.
정의
다음의 개시에서 진술된 발명에 관한 이해를 용이하게 하기 위해, 다수의 용어가 아래에 규정된다.
용어 "상처"는 상이한 방식 (가령, 연장된 장기 요양으로부터 압박 궤양 및 외상에 의해 유도된 상처)으로 시작되고 다양한 특징을 갖는, 피부 및 피하 조직에 대한 손상을 광범위하게 지칭한다. 본원에서 설명된 방법과 조성물은 내부와 외부 조직에 대한 상처, 그리고 의료 시술 (가령, 외과 시술) (가령, 복부 수술, 탈장 수술, 위장관 수술, 비만 수술, 재건 수술, 경질막 수술 등) 동안 유도된 상처를 비롯한 모든 유형의 상처의 치료에 유용하다. 상처는 상처의 깊이에 따라서 4가지 등급 중에서 한 가지로 분류될 수 있다: i) 등급 I: 상피에 한정된 상처; ii) 등급 II: 진피 내로 확장되는 상처; iii) 등급 III: 피하 조직 내로 확장되는 상처; 및 iv) 등급 IV (또는 전층 상처): 뼈가 노출되는 상처 (가령, 골성 압통점, 예를 들면, 대전자 또는 천골).
용어 "부분층 상처"는 등급 I-III을 포괄하는 상처를 지칭한다; 부분층 상처의 실례는 화상 상처, 압박 궤양, 정맥 정체 궤양 및 당뇨병성 궤양을 포함한다. 용어 "깊은 상처"는 등급 III 및 등급 IV 상처 둘 모두를 포함하는 것으로 의미된다. 본 발명은 깊은 상처 및 만성 상처를 비롯한 모든 상처 유형을 치료하는 것을 예기한다.
용어 "만성 상처"는 30 일 이내에 치유되지 않는 상처를 지칭한다.
관용구 "상처 치유를 증진한다," "상처 치유를 증강한다," 기타 등등은 상처 수축의 육아 조직의 형성의 유도 및/또는 상피화 (다시 말하면, 상피에서 새로운 세포의 산출)의 유도를 지칭한다. 상처 치유는 감소하는 상처 부위에 의해 편의하게 계측된다.
용어 "생리활성 작용제"는 상처의 치료 및 치유에 유용한 원하는 약리학적, 생리학적 효과를 유도하는 공지된 또는 잠재적인 화학적 화합물을 지칭하는데, 여기서 상기 효과는 방지적 또는 치료적일 수 있다. 상기 용어는 또한, 영양 인자, 세포외 매트릭스, 효소, 효소 저해제, 디펜신, 폴리펩티드, 항감염성 작용제 (이온성 은, 원소성 은 및 은 나노입자를 포함하지만 이들에 한정되지 않음), 완충제, 비타민 및 무기질, 진통제, 항응고제, 응고 인자, 항염증제, 혈관수축제, 혈관확장제, 이뇨제, 그리고 항암제를 포함하지만 이들에 한정되지 않는, 본원에서 특정적으로 언급된 활성제의 제약학적으로 허용되는, 약리학적으로 활성 유도체를 포괄한다.
용어 "중합체 다중층"은 다중층 구조를 형성하기 위한 중합체(들)의 순차적이고 반복된 적용에 의해 형성된 조성물을 지칭한다. 가령, 고분자전해질 다중층은 상처 또는 지지체에 음이온성 및 양이온성 고분자전해질의 교대 첨가에 의해 형성된 중합체 다중층이다. 용어 "중합체 다중층"은 또한, 상처에 또는 고체 지지체에 중합체(들)의 순차적이고 반복된 적용에 의해 형성된 조성물을 지칭한다. 이에 더하여, 용어 "중합체 층"은 복수 층 내에 하나의 층으로서, 또는 상처 또는 지지체 상에서 단지 한 가지 유형의 고분자전해질 분자의 단일 층으로서 존재하는, 중합체 분자, 예를 들면, 음이온성 또는 양이온성 고분자전해질 분자로 구성되는 단일 층을 지칭할 수 있다. 상처 기부 또는 지지체에 이들 중합체의 전달은 바람직한 구체예에서 순차적이지만, 용어 "중합체 다중층"의 이용은 코팅의 결과적인 구조의 면에서 한정되지 않는다. 중합체, 예를 들면, 고분자전해질의 상호 확산은 발생하면, 음이온성 및 양이온성 고분자전해질의 분포의 면에서 충분히 혼합될 수 있는 구조를 야기할 수 있는 것으로 당업자에 의해 충분히 이해된다. 용어 고분자전해질은 중합체 종류뿐만 아니라 나노미립자 종류를 포함하고, 그리고 이것은 범위를 제한하지 않고, 단지 이들 종류가 복수의 하전된 또는 부분적으로 하전된 기를 소유한다는 것을 지시하는 것으로 또한 이해된다. 또한, 다중층 구조는 정전 상호작용 등, 예를 들면, 수소 결합을 비롯한 다양한 상호작용을 통해 형성될 수 있는 것으로 당업자에 의해 충분히 이해된다. 따라서, 용어 "고분자전해질"의 이용은 상처 기부 구조체의 형성을 야기하는 상호작용의 면에서 한정되지 않는다.
용어 "개체"는 인간, 비인간 영장류, 설치류, 개, 고양이 등이 포함되지만 이들에 한정되지 않는 임의의 동물 (가령, 포유동물)을 지칭하는데, 이것은 특정 치료의 수용자이다. 전형적으로, 용어 "개체" 및 "환자"는 본원에서 교체가능하게 이용된다.
용어 "계면활성제"는 액체 또는 고체의 표면 및 계면 성질을 변경하는 양친매성 물질을 지칭한다. 계면활성제는 2가지 액체 사이에 표면장력을 감소시킬 수 있다. 세정제, 적심제, 유화제, 분산 작용제 및 거품 저해제는 모두 계면활성제이다.
용어 "용매"는 물질을 용해시킬 수 있는 액체를 지칭한다. 용어 "유기 용매"는 석유-기초된 산물로부터 유래된 용매를 지칭한다.
용어 "고분자전해질"은 양이온 및 음이온을 포함하는 많은 반복 이온성 성분 단위를 내포하는 수용성 거대분자 중합체 물질을 지칭한다.
용어 "기능화된"은 다른 기능기 (가령, 술피드릴 기)와 반응하여 공유 결합을 형성할 수 있는 새로운 반응성 기능기 (가령, 말레이미도 또는 숙신이미딜 기)를 산출하거나 또는 도입하기 위한, 기존의 분자 분절의 변형을 지칭한다. 가령, 카르복실산 (--COOH) 기를 내포하는 성분은 공지된 절차를 이용한 N-히드록시-숙신이미드 또는 N-히드록시술포숙신이미드와의 반응에 의해 기능화되어, 활성화된 카르복실산염 (이것은 반응성 친전자성 기이다), 다시 말하면, 각각 N-히드록시숙신이미드 에스테르 또는 N-히드록시술포숙신이미드 에스테르의 형태에서 새로운 반응성 기능기를 형성할 수 있다. 다른 실례에서, 카르복실산 기는 이번에도 공지된 절차를 이용한 아실 할로겐화물, 예를 들면, 아실 염화물과의 반응에 의해 기능화되어, 무수물의 형태에서 새로운 반응성 기능기를 제공할 수 있다.
본원에서 이용된 바와 같이, 용어 "수성 용액"은 용액, 현탁액, 분산액, 콜로이드, 그리고 물을 내포하는 기타 유사한 것을 포함한다.
용어 "특이적인 단백질 결합"은 서로에 대해 높은 친화성 및 특이성을 갖는 2개 또는 그 이상의 단백질 사이의 상호작용을 지칭한다. 단백질은 기능하기 위해 생체내에서 특정한 다른 단백질에 결합해야 한다. 이들 단백질은 전형적으로 생체내에 존재하는 수 천 개의 단백질 중에서 단지 하나 또는 소수의 다른 단백질에만 결합해야 한다; 이들 상호작용은 본 발명에서 생리활성 작용제를 상처에 부착하기 위해 시험관내에서 이용된다. 본 발명의 맥락에서, 특이적인 단백질 결합 상호작용은 비오틴 및 아비딘, 뉴트라비딘 또는 스트렙타비딘; 글루타티온-S-전달효소 및 글루타티온; 그리고 니켈-니트릴로트리아세트산 및 폴리히스티딘 사이에 것들을 포함하지만 이들에 한정되지 않는다.
용어 "장치"는 치료적 또는 방지적 목적으로 개체의 신체 또는 체액에 접촉하는 물체를 지칭한다. 일부 장치는 개체의 신체 또는 체액에 부분적으로 또는 간접적으로 접촉할 수 있고 (가령, 카테터, 투석 배관, 진단 센서, 약물 전달 장치), 반면 다른 장치는 개체의 신체 내에 완전하게 파묻히거나 또는 이것에 의해 둘러싸인다 (가령, 스텐트, 심박조율기, 내적으로 이식된 제세동기, 혈관형성술 풍선, 정형외과적 장치, 척추 케이지, 이식가능한 약물 펌프, 인공 디스크, 귀 디스크).
용어 "선택적 독성"은 포유류 대 미생물 세포에 대한 차별적인 독성 효과의 성질을 지칭한다. 가령, 선별적인 독성 물질은 포유류 세포의 성장 및 생존력을 허용하면서, 세균 세포를 효과적으로 사멸시킬 수 있다.
용어 "독성"은 독물의 투여에 앞서 동일한 세포 또는 조직과 비교하여, 개체, 세포 또는 조직에 대한 임의의 유해한 또는 해로운 효과를 지칭한다.
본원에서 이용된 바와 같이, 용어 "나노입자" 및 "나노규모 입자"는 교체가능하게 이용되고, 그리고 나노미터에서 계측되는 크기를 갖는 나노규모 입자, 예를 들면, 약 1000, 500 또는 100 nm보다 작은 적어도 하나의 치수를 갖는 나노유효범위 입자를 지칭한다. 나노입자의 실례는 나노비드, 나노섬유, 나노혼, 나노오니온, 나노로드 및 나노로프를 포함한다.
본원에서 이용된 바와 같이, 용어 "마이크로입자" 및 "마이크로규모 입자"는 교체가능하게 이용되고, 그리고 마이크로미터에서 계측되는 크기를 갖는 마이크로규모 입자, 예를 들면, 약 10 마이크로미터, 5 마이크로미터 또는 2 마이크로미터보다 작은 적어도 하나의 치수를 갖는 마이크로규모 입자를 지칭한다.
용어 "상처 드레싱"은 흡수, 접착, 보호, 삼투압조절, pH-조절, 또는 압력-유도 성질을 갖는, 상처의 근위에 배치되는 물질을 지칭한다. 상처 드레싱은 상처와 직접적으로 또는 간접적으로 접촉할 수 있다. 상처 드레싱은 크기 또는 모양에 의해 제한되지 않는다. 실제로, 많은 상처 드레싱 물질은 상처의 크기에 합치하도록 절단되거나 또는 설정될 수 있다. 상처 드레싱 물질의 실례는 거즈, 접착 테이프, 붕대, 그리고 상처 드레싱의 Band-Aid® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 Nexcare® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 Kendall Curity Tefla® 라인으로부터 접착성 붕대 및 비-접착성 패드, 상처 드레싱의 Tegaderm® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 Steri-Strip® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 COMFEEL® 라인, 접착성 붕대와 패드, 상처 드레싱의 Duoderm® 라인, 접착성 붕대와 패드, 상처 드레싱의 TEGADERM™ 라인, 접착성 붕대와 패드, 상처 드레싱의 OPSITE® 라인, 접착성 붕대와 패드, 그리고 생물학적 상처 드레싱을 포함하지만 이들에 한정되지 않는 상업적으로 가용한 상처 드레싱을 포함하지만 이들에 한정되지 않는다. "생물학적 상처 드레싱"은 상처 표면과 접촉하여 배치될 수 있는 세포 및/또는 한 가지 또는 그 이상의 생체분자 또는 생체분자의 단편을 포함하는, 예를 들면, 이들로 코팅되거나 또는 이들을 통합하는 유형의 상처 드레싱이다. 생체분자는 인공 조직 매트릭스의 형태에서 제공될 수 있다. 이런 생체분자의 실례는 콜라겐, 히알루론산, 글리코사미노글리칸, 라미닌, 비트로넥틴, 섬유결합소, 케라틴, 항균성 폴리펩티드, 그리고 이들의 조합을 포함하지만 이들에 한정되지 않는다. 적합한 생물학적 상처 드레싱의 실례는 BIOBRANE™, Integra™, Apligraf®, Dermagraft®, Oasis®, Transcyte®, Cryoskin® 및 Myskin®을 포함하지만 이들에 한정되지 않는다.
본원에서 이용된 바와 같이, 용어 "항균성 은 조성물"은 은을 활성 항균제로서 포함하는 조성물을 지칭한다. "항균성 은 조성물"의 실례는 은 나노입자, 원소성 은, 제로가 은, 지르코늄 인산염 (ZP-Ag)에 의해 운반된 다가 은 이온 (가령, Wound Repair and Regeneration, 16: 800-804를 참조한다), 그리고 은 내포 화합물, 예를 들면, 은 술파디아진 및 관련된 화합물을 포함하지만 이들에 한정되지 않는다. 용어 "방출가능한 항균성 은 조성물"은 항균 활성이 관찰될 수 있도록, 물질, 예를 들면, 중합성 다중층 고체 지지체로부터 방출될 수 있는 항균성 은 조성물을 지칭한다. 항균성 은 조성물의 방출은 물질의 규정된 면적 또는 용적으로부터 방출된 조성물의 양으로서 규정될 수 있다.
발명의 상세한 설명
본 발명은 상처 치유, 또는 생물학적 또는 의학적 표면의 변형과 같은 적용에서 이용을 위한 나노규모 마이크로시트의 대규모 제조에 관계한다. 일부 바람직한 구체예에서, 낮은 표면 에너지 표면을 나타내는 가요성 중합성 시트를 포함하는 기재가 활성 성분을 내포하는 자립형 나노- 또는 마이크로-규모 중합성 필름을 만들기 위한 연속적인 롤투롤 층상 코팅 과정에서 활용된다. 상기 과정은 대규모로 수행된다. 바람직하게는, 낮은 표면 에너지 표면을 나타내는 가요성 중합성 시트는 최소한 0.65, 1, 2, 5, 10, 100 또는 500 제곱 미터, 또는 0.65 내지 1.0, 0.65 내지 5.0, 0.65 내지 10, 0.65 내지 20, 0.65 내지 50, 0.65 내지 100, 0.65 내지 200, 0.65 내지 300, 0.65 내지 400, 0.65 내지 500, 1 내지 10, 1 내지 20, 1 내지 50, 1 내지 100, 1 내지 200, 1 내지 300, 1 내지 400, 1 내지 500, 2 내지 10, 2 내지 20, 2 내지 50, 2 내지 100, 2 내지 200, 2 내지 300, 2 내지 400, 2 내지 500, 5 내지 10, 5 내지 20, 5 내지 50, 5 내지 100, 5 내지 200, 5 내지 300, 5 내지 400, 5 내지 500, 10 내지 20, 10 내지 50, 10 내지 100, 10 내지 200, 10 내지 300, 10 내지 400, 10 내지 500, 20 내지 50, 20 내지 100, 20 내지 200, 20 내지 300, 20 내지 400, 20 내지 500, 50 내지 100, 50 내지 200, 50 내지 300, 50 내지 400 또는 50 내지 500 제곱 미터의 표면적을 갖는 낮은 표면 에너지 표면을 제공한다. 기재의 낮은 표면 에너지 표면을 코팅하기 위한 적합한 기술은 침지, 담금, 스프레이, 스핀, 슬롯 다이, 잉크젯, 철판 인쇄, 그라비야, 리버스 롤 코팅, 미터링 (Meyer) 막대, 블레이드, 에어 나이프, 커튼, 용융 압출, 용매 주조, 그리고 이들의 임의의 조합을 포함하지만 이들에 한정되지 않는다. 가령, US 특허 공보 20140079884, US 특허 공보 20160068703, US 특허 공보 20120269973, US 특허 공보 20160114294, US 특허 공보 20140112994, US 특허 공보 20150086599, Shiratori, Japanese Journal of Applied Physics Vol. 44, No. 3, 2005, L126 - L128, 그리고 Grunlan, Industrial & Engineering Chemistry Research Vol. 53, 2014, 6409 - 6416을 참조하는데, 이들 모두 본원에서 전체적으로 참조로서 편입된다. 일반적으로, 중합체 층이 대규모로 적층되는 표면은 높은 에너지 표면, 예를 들면, 플라즈마 처리에 의해 변형된 표면이었다. 본 발명에서, 놀랍게도, 상처에 적용에서 이용을 위한 또는 생물학적 또는 의학적 표면의 변형을 위한 나노- 내지 마이크로규모 중합성 시트를 제공하기 위해 바람직하게는 희생 층을 포함하는 결함-없는 분자로 된 얇은 중합성 시트가 기재로부터 벗겨질 수 있도록, 분자로 된 얇은 중합체 층이 연속적인 공정 동안 기재 물질의 대규모 롤에서 적층될 수 있는 것으로 밝혀졌다. 생리활성 작용제는 바람직하게는, 생리활성 작용제의 원하는 방출 수준을 제공하기 위해 나노- 내지 마이크로규모 중합성 시트 내에 도입된다.
A. 낮은 표면 에너지 표면을 갖는 기재
일부 구체예에서, 본 발명은 낮은 표면 에너지 표면을 갖는 기재를, 분자로 된 얇은 나노- 또는 마이크로규모 중합체 층이 적층되는 기재로서 활용한다. 바람직한 구체예에서, 낮은 표면 에너지 표면을 갖는 기재는 가요성 중합성 시트이다. 일부 구체예에서, 가요성 중합성 시트는 연속적인 롤투롤 공정에서 이용을 위한 보관 및 롤 위에 감김이 용이하다. 전술된 바와 같이, 낮은 표면 에너지 표면을 나타내는 가요성 중합성 시트는 최소한 0.65, 1, 2, 5, 10, 100 또는 500 제곱 미터, 또는 0.65 내지 1.0, 0.65 내지 5.0, 0.65 내지 10, 0.65 내지 20, 0.65 내지 50, 0.65 내지 100, 0.65 내지 200, 0.65 내지 300, 00.65 내지 400, 0.65 내지 500, 1 내지 10, 1 내지 20, 1 내지 50, 1 내지 100, 1 내지 200, 1 내지 300, 1 내지 400, 1 내지 500, 2 내지 10, 2 내지 20, 2 내지 50, 2 내지 100, 2 내지 200, 2 내지 300, 2 내지 400, 2 내지 500, 5 내지 10, 5 내지 20, 5 내지 50, 5 내지 100, 5 내지 200, 5 내지 300, 5 내지 400, 5 내지 500, 10 내지 20, 10 내지 50, 10 내지 100, 10 내지 200, 10 내지 300, 10 내지 400, 10 내지 500, 20 내지 50, 20 내지 100, 20 내지 200, 20 내지 300, 20 내지 400, 20 내지 500, 50 내지 100, 50 내지 200, 50 내지 300, 50 내지 400 또는 50 내지 500 제곱 미터의 표면적을 갖는 낮은 표면 에너지 표면을 제공한다. 본 발명은 임의의 특정 가요성 중합성 시트의 이용에 한정되지 않는다. 바람직한 물질은 폴리에스테르 필름, 폴리에틸렌 테레프탈염산 (PET) 필름, 이축 연신 PET 필름, 폴리카보네이트, 폴리에틸렌 (고밀도 폴리에틸렌, 중밀도 폴리에틸렌, 저밀도 폴리에틸렌, 선형 저밀도 폴리에틸렌 포함) 필름, 폴리염화비닐 필름, 폴리비닐리덴 염화물 필름, 폴리비닐리덴 플루오르화물 필름, 나일론 필름, 폴리스티렌 필름, 아세트산염 필름, 폴리우레탄 필름, 에틸렌 비닐 아세트산염 공중합체 필름, 캐스트 폴리프로필렌 필름, 단축 연신 폴리프로필렌 필름 및 이축 연신 폴리프로필렌 필름을 포함하지만 이들에 한정되지 않는다. 시트의 바람직한 두께는 0.5 - 5 mil이다. 일부 바람직한 구체예에서, 가요성 중합성 시트는 10 내지 100 mJ/cm2, 그리고 가장 바람직하게는 약 15 내지 약 45 mJ/cm2의 표면 에너지를 갖는 표면을 갖는다. 일부 구체예에서, 낮은 표면 에너지 표면은 가요성 중합성 시트 상에 이형 필름의 포함에 의해 제공된다. 일부 구체예에서, 이형 코팅은 실리콘 이형 필름, 폴리디메틸 실록산 (PDMS) 코팅, 탄화플루오로 코팅, 폴리아크릴레이트 코팅, 폴리스티렌 코팅, 폴리스티렌아크릴 코팅, 크롬 스테아르산염 복합체 코팅, 또는 폴리올레핀 코팅이다. 적합한 이형 필름은 St. Gobain Performance Plastics, Worcester MA에 의해 제공된 것들, 예를 들면, Saint Gobain 4130, 4159 및 7819 이형 코팅을 포함하지만 이들에 한정되지 않는다. 바람직한 구체예에서, 가요성 중합성 시트의 박리 특징은 고분자전해질의 결함-없는 층상 적층을 뒷받침할 뿐만 아니라 파열 또는 다른 결함 없이 상처 드레싱 코팅의 손쉽고 완전한 벗겨짐을 허용하고, 따라서 치료적 작용제, 예를 들면, 아래에 더욱 상세하게 설명되는 바와 같은 항균제 및 진통제를 통합할 수 있는 자립형 중합성 필름을 유발한다.
일부 바람직한 구체예가 가요성 중합성 시트를 활용하는 것으로 본원에서 설명되긴 했지만, 일부 구체예에서 다른 물질이 가요성 중합성 시트를 대신할 수 있는 것으로 이해될 것이다. 따라서, 일부 구체예에서, 낮은 표면 에너지 표면을 갖는 기재는 바람직하게는, 이형 코팅으로 코팅된 종이 또는 셀룰로오스 기재, 예를 들면, 글라신 또는 특별한 윤이 나는 크래프트지일 수 있다.
B. 나노규모 중합체 층
바람직한 구체예에서, 본 발명은 분자로 된 얇은, 나노- 내지 마이크로규모 중합체 층이 적층되는 전술된 바와 같은 낮은 표면 에너지 표면을 갖는 가요성 중합성 시트를 제공한다. 일부 구체예에서, 나노규모 중합체 층, 예를 들면, 중합체 다중층은 치수에서 나노규모 내지 마이크로규모이다. 따라서, 일부 구체예에서, 나노규모 중합체 매트릭스는 약 1 nm 내지 10000 nm 두께, 약 1 nm 내지 5000 nm 두께, 약 1 nm 내지 500 nm 두께, 약 1 nm 내지 100 nm 두께, 약 1 nm 내지 약 25 nm 두께, 약 1 nm 내지 약 10 nm 두께, 또는 약 500 nm, 100 nm, 25 nm 또는 10 nm 두께 이하이다. 매트릭스의 나노규모 치수 (다시 말하면, 나노규모 두께)는 더욱 큰 두께를 갖는 매트릭스 구조와 비교하여 활성제의 효과량 (다시 말하면, 대조와 비교하여 상처 치유를 가속화하는 활성제의 양)의 전달을 여전히 허용하면서, 활성제의 더욱 적은 총량의 부하를 허용하는 것으로 예기된다. 더욱 낮은 전체 부하 수준은 특히, 항균성 화합물이 중합체 다중층 내로 통합될 때 상처 환경에서 감소된 독성을 유발하는 것으로 예기된다.
일부 구체예에서, 본 발명은 상처, 생물학적 조직, 각막, 렌즈, 뼈, 힘줄, 외과용 그물망, 상처 드레싱, 생물의학 장치, 건강 관리에 이용되는 장치, 또는 다른 표면에 적용될 수 있는 나노규모 중합체 층을 포함하는 조성물을 제공한다. 일부 구체예에서, 나노규모 중합체 층은 기능화된다. 일부 구체예에서, 나노규모 중합체 층은 기능화되지 않는다. 일부 구체예에서, 나노규모 중합체 층은 하나 또는 그 이상의 중합체, 바람직하게는 생체적합성 중합체를 포함하거나, 또는 한 가지 또는 그 이상의 단백질로부터 형성되거나, 또는 중합체 및 단백질의 조합이다. 일부 구체예에서, 나노규모 중합체 층은 합성 중합체, 예를 들면, 합성 고분자전해질로부터 형성된다. 다른 구체예에서, 나노규모 중합체 층은 자연발생 중합체, 예를 들면, 다당류로부터 형성된다. 일부 구체예에서, 나노규모 중합체 층은 조직 표면 또는 상처 기부에 공유 상호작용 및/또는 결합을 허용하도록, 또는 나노규모 중합체 층에 - 생리활성 작용제의 적용을 허용하도록 기능화된다. 일부 구체예에서, 생리활성 작용제, 예를 들면, 항균제, 예를 들면, 은, 폴리헥사메틸렌 비구아니드 (PHMB), 클로르헥시딘, 또는 요오드 화합물, 또는 항생제가 나노규모 중합체 층 내로 통합된다. 생리활성 작용제는 바람직하게는 나노규모 중합체 층의 3차원 구조 전역에서 함침되거나, 통합되거나 또는 산재된다. 가령, 만약 나노규모 중합체 층이 고분자전해질 다중층 (PEM)이면, 생리활성 작용제는 바람직하게는, 중합체 다중층의 층 사이에 또는 내에 통합된다.
일부 구체예에서, 층은 중합체 다중층이다. 일부 구체예에서, 다중층 구조는 고분자전해질의 층 (다시 말하면, 고분자전해질 다중층을 형성)을 포함하고, 반면 다른 구체예에서, 다중층은 전하를 갖지 않는 중합체 (다시 말하면, 비이온성 중합체) 또는 하전된 및 하전되지 않은 중합체 층의 조합을 포함한다. 일부 구체예에서, 양이온성 및 음이온성 고분자전해질 층의 교대된 흡착에 의해 조립된 고분자전해질 필름은 상처 표면을 제어된 방식으로 변형하기 위한 신규하고 유망한 기술이 될 것으로 예기된다 (Decher et al, 1992, Thin Solid Films 210/211:831; Decher, 1997, Science 277: 1232). 이런 다중층의 가장 중요한 성질 중에서 한 가지는 이들이 과잉의 양성 및 음성 전하를 교대로 전시한다는 것이다 (Caruso et al, 1999, J Am Chem Soc 121 :6039; Ladam et al, 2000, Langmuir 16: 1249). 이것은 이들의 빌드업의 모터가 될 수 있을 뿐만 아니라 (Joanny, 1999, Eur. Phys. J. Biol. 9: 117), 이것은 단순한 접촉에 의해, 매우 다양한 화합물, 예를 들면, 염료, 입자 (Cassagneau et al, 1998, J. Am. Chem. Soc. 120:7848; Caruso et al, 1999, Langmuir 15:8276; Lvov et al, 1997, Langmuir 13:6195), 점토 마이크로평판 (Ariga et al, 1999, Appl. Clay Sci. 15: 137) 및 단백질 (Keller et al, 1994, J. Am. Chem. Soc. 116:8817; Lvov et al, 1995, J. Am. Chem. Soc. 117:6117; Caruso et al., 1997, Langmuir 13:3427)을 흡착하는 것을 허용한다.
고분자전해질 층은 고분자전해질 다중층을 형성하기 위한, 표면에 음이온성 고분자전해질 및 양이온성 고분자전해질의 교대 적용에 의해 형성된다. 일부 구체예에서, 한 가지 또는 그 이상의 생리활성 작용제, 예를 들면, 앞서 설명된 것들이 다중층 내로 통합된다. 바람직하게는, 최소한 4개의 층, 그리고 더욱 바람직하게는, 최소한 6개의 층이 고분자전해질 다중층을 형성하는데 이용된다.
본 발명에서 유용한 양이온성 고분자전해질은 임의의 생체적합성 수용성 다가양이온성 중합체, 예를 들면, 펜던트 기로서 부착된 양자화된 헤테로환을 갖는 임의의 중합체일 수 있다. 본원에서 이용된 바와 같이, "수용성"은 전체 중합체가 20 및 37° 섭씨 사이의 온도에서, 수성 용액, 예를 들면, 완충된 식염수, 또는 미량의 추가된 유기 용매를 보조용매로서 갖는 완충된 식염수에서 가용성이어야 한다는 것을 의미한다. 일부 구체예에서, 물질은 그 자체로는 수성 용액에서 충분히 가용성 (리터당 최소한 1 그램의 정도까지 가용성인 것으로 본원에서 규정됨)이지 않을 것이지만, 다가양이온성 중합체를 수용성 다가비이온성 물질, 예를 들면, 폴리에틸렌 글리콜과 합체함으로써 용해될 수 있다.
대표적인 양이온성 고분자전해질은 중성 pH에서 순 양성 전하를 갖는 자연 및 비자연 폴리아미노산, 양으로 하전된 다당류, 그리고 양으로 하전된 합성 중합체를 포함한다. 적합한 다가양이온성 물질의 실례는 중합체 중추 또는 중합체 측쇄 상에서 아민 기를 갖는 폴리아민, 예를 들면, 폴리-L-리신 (PLL), 그리고 폴리(D-리신), 폴리(오르니틴), 폴리(아르기닌) 및 폴리(히스티딘)을 포함하지만 이들에 한정되지 않는, 자연 또는 합성 아미노산 또는 아미노산의 혼합물의 다른 양으로 하전된 폴리아미노산, 그리고 비펩티드 폴리아민, 예를 들면, 폴리(아미노스티렌), 폴리(아미노아크릴레이트), 폴리 (N-메틸 아미노아크릴레이트), 폴리 (N-에틸아미노아크릴레이트), 폴리(N,N-디메틸 아미노아크릴레이트), 폴리(N,N-디에틸아미노아크릴레이트), 폴리(아미노메타크릴레이트), 폴리(N-메틸 아미노-메타크릴레이트), 폴리(N-에틸 아미노메타크릴레이트), 폴리(N,N-디메틸 아미노메타크릴레이트), 폴리(N,N-디에틸 아미노메타크릴레이트), 폴리(에틸렌이민), 사차 아민의 중합체, 예를 들면, 폴리(N,N,N-트리메틸아미노아크릴레이트 염화물), 폴리(메티아크릴아미도프로필트리메틸 염화암모늄), 그리고 자연 또는 합성 다당류, 예를 들면, 키토산을 포함한다.
일반적으로, 중합체는 최소한 5개의 전하를 포함해야 하고, 그리고 다가양이온성 물질의 분자량은 조직 또는 다른 표면에 원하는 정도의 결합을 산출하는데 충분하고, 최소한 1000 g/몰의 분자량을 가져야 한다.
본 발명에서 유용한 다가음이온 물질은 임의의 생체적합성 수용성 다가음이온 중합체, 예를 들면, 펜던트 기로서 부착된 카르복실산 기를 갖는 임의의 중합체일 수 있다. 적합한 물질은 알긴산염, 카라기닌, 푸르셀라란, 펙틴, 크산탄, 히알루론산, 헤파린, 헤파란 황산염, 콘드로이틴 황산염, 폴리아크릴산 (PAA), 데르마탄 황산염, 덱스트란 황산염, 폴리(메트)아크릴산, 산화된 셀룰로오스, 카르복시메틸 셀룰로오스 및 크로스카르멜로스, 펜던트 카르복실 기를 내포하는 합성 중합체 및 공중합체, 예를 들면, 중추 내에 말레산 또는 푸마르산을 내포하는 것들을 포함한다. 지배적으로 음성 전하의 폴리아미노산 역시 적합하다. 이들 물질의 실례는 폴리아스파르트산, 폴리글루탐산, 그리고 다른 자연 및 비자연 아미노산과 이들의 공중합체를 포함한다. 폴리페놀성 물질, 예를 들면, 탄닌 및 리그닌은 만약 그들이 충분히 생체적합성이면 이용될 수 있다. 바람직한 물질은 알긴산염, 펙틴, 카르복시메틸 셀룰로오스, 헤파린 및 히알루론산을 포함한다.
일부 구체예에서, 이용되는 양이온성 고분자전해질은 PLL이고, 그리고 이용되는 음이온성 고분자전해질은 폴리(L-글루타민산) (PGA)이다. 조금 더 바람직한 구체예에서, 이용되는 양이온성 고분자전해질은 폴리알릴아민 염산염 (PAH)이고, 그리고 이용되는 음이온성 고분자전해질은 폴리아크릴산 (PAA)이다. 실제로, 폴리(에틸렌 이민) (PEI), 폴리(나트륨 4-스티렌술포네이트) (PSS), 폴리(아크릴산) (PAC), 폴리 (말레산-코-프로필렌) (PMA-P), 그리고 폴리(비닐 황산염) (PVS)을 포함하지만 이들에 한정되지 않는 다양한 고분자전해질의 이용이 예기된다. 히알루론산 및 콘드로이틴 황산염을 비롯한 자연발생 고분자전해질을 이용하는 것이 또한 가능하다. 또 다른 추가의 구체예에서, 중합체는 덴드리머, 합체된 중합체, 또는 별 구조 중합체이다.
일부 구체예에서, 다중층 구조는 하전되지 않은 중합체로부터 또는 하전된 및 하전되지 않은 중합체의 조합으로부터 형성된다. 하전되지 않은 중합체의 실례는 덱스트란, 덱스트란 황산염, 디에틸아미노에틸 (DEAE)-덱스트란, 히드록시에틸 셀룰로오스, 에틸(히드록시에틸) 셀룰로오스, 아크릴아미드, 폴리에틸렌 산화물, 폴리프로필렌 산화물, 폴리에틸렌 산화물 - 폴리프로필렌 산화물 공중합체, PAANa, 피콜, 폴리비닐피롤리딘 및 폴리아크릴산을 포함하지만 이들에 한정되지 않는다.
일부 구체예에서, 다중층 구조는 단독으로 또는 본원에서 설명된 다른 중합체와 조합으로, 한 가지 또는 그 이상의 양쪽성 중합체로부터 형성된다. 일부 구체예에서, 양쪽성 중합체는 아크릴산 (AA), DMAEMA (디메틸아미노에틸 메타크릴레이트), APA (2-아미노프로필 아크릴레이트), MorphEMA (모르폴리노에틸 메타크릴레이트), DEAEMA (디에틸아미노에틸 메타크릴레이트), t-부틸AEMA (t-부틸아미노에틸 메타크릴레이트), PipEMA (피페리디노에틸 메타크릴레이트), AEMA (아미노에틸 메타크릴레이트), HEMA (2-히드록시 에틸 메타크릴레이트), MA (메틸 아크릴레이트), MAA (메타크릴산) APMA (2-아미노프로필 메타크릴레이트), AEA (아미노에틸 아크릴레이트) 중에서 한 가지 또는 그 이상을 포함한다. 일부 구체예에서, 양쪽성 중합체는 (a) 카르복실산, (b) 일차 아민 및 (c) 이차 및/또는 삼차 아민을 포함한다. 양쪽성 중합체는 4 내지 8, 바람직하게는 5 내지 7의 등전점을 갖고, 그리고 10,000 내지 150,000의 범위에서 수평균 분자량을 갖는다.
중합체 층은 다음의 기술을 포함하지만 이들에 한정되지 않는 다양한 방법에 의해 기재의 낮은 표면 에너지 표면상에 형성될 수 있다: 분사 코팅, 침지 코팅, 담금 코팅, 스핀 코팅, 슬롯 다이 코팅, 잉크젯 코팅, 아닐록스 코팅, 스크린 코팅, 오프셋 인쇄 프린팅, 철판 인쇄 코팅, 그라비야 코팅, 로토그라비야 코팅, 리버스 롤 코팅, 미터링 (Meyer) 막대 코팅, 블레이드 코팅, 나이프 오버 롤 코팅, 에어 나이프 코팅, 커튼 코팅, 용융 압출 코팅, 용매 주조, 그리고 이들의 임의의 조합. 일부 바람직한 구체예에서, 가요성 중합성 시트는 롤 상에 제공되거나 또는 롤 위에 감긴다. 시트의 리딩 에지가 이후, 하나 또는 그 이상의 롤 (다시 말하면, 일련의 롤)을 지나 라우팅되고 받침 롤 위에 감긴다. 이러한 라우팅 절차 동안, 기본 층상 코팅이 적합한 용매에서 용액으로부터 반대 전하의 최소한 2가지 상이한 물질의 순차적 적층에 의해 가요성 중합성 시트 기재의 낮은 표면 에너지 표면에서 적층된다. 이들 중합체는 다가 중합체 염일 수 있고, 그리고 이들의 용액은 0.1 - 10000 mM 및 더욱 바람직하게는 0.5 - 50 mM의 농도에서 일가 또는 다가 유기 또는 무기 염, 예를 들면, 하지만 제한 없이 일가 또는 이가 또는 삼가 금속 양이온의 염화물, 황산염, 질산염 또는 아세트산염을 내포할 수 있다. 일부 구체예에서, 시트는 하나 또는 그 이상의 분무기 (다시 말하면, 일련의 분무기) 및/또는 린스 분지 및 건조기를 지나 라우팅된다. 다른 구체예에서, 시트는 중합체 용액을 내포하는 하나 또는 그 이상의 분지 및/또는 하나 또는 그 이상의 린스 분지 및 건조기를 통해 라우팅된다. 일부 바람직한 구체예에서, 중합체 다중층을 형성하는 각 중합체는 바람직한 용매 (가령, 수성 용액)에서 가요성 시트 기재의 < 600 초, 바람직하게는 1-90 초의 체류 시간을 허용하고, 그 이후에 임의선택적으로 헹굼 및 건조함으로써 적층된다. 일부 바람직한 구체예에서, 최종 중합체 다중층 코팅의 두께는 5 - 10000 nm, 바람직하게는 5 - 5000 nm 두께, 그리고 가장 바람직하게는 100 - 1000 nm 두께이다. 일부 바람직한 구체예에서, 아래에 더욱 상세하게 설명되는 바와 같은 생리활성 작용제가 이후, 중합체 다중층 내에 도입된다.
C. 두 번째 중합체 층
일부 구체예에서, 두 번째 중합체 층은 나노- 내지 마이크로규모 중합체 층에서 적층되거나 또는 상기 층과 연관된다. 일부 바람직한 구체예에서, 두 번째 중합체 필름은 1-50 μm, 바람직하게는 5-25 μm의 두께를 갖고, 그리고 나노- 내지 마이크로규모 중합체 층의 적층을 위해 전술된 바와 같은 나노- 내지 마이크로규모 중합체 층 위에 코팅된다.
일부 구체예에서, 나노규모 중합체 매트릭스는 두 번째 중합체 층, 예를 들면, 비희생 중합체 층에 의해 뒷받침된다. 가령, 일부 구체예에서, 나노규모 중합체 매트릭스는 하이드로겔, 수성콜로이드 및/또는 콜라겐을 지지체로서 포함하는 두 번째 중합체 층, 예를 들면, 비희생 중합체 층에 의해 뒷받침된다.
다른 구체예에서, 나노규모 중합체 매트릭스는 희생 중합체 층, 바람직하게는 분해성 또는 분해가능한 지지체 물질, 예를 들면, 분해가능한 중합체로부터 형성된 희생 중합체 층에서 뒷받침된다. 바람직한 구체예에서, 마이크로시트의 희생 중합체 층은 수용성이다. 일부 구체예에서, 희생 중합체 층은 비독성 중합체로 만들어지고, 그리고 일부 구체예에서, 희생 중합체 층은 폴리비닐 알코올 (PVA)이다. 일부 구체예에서, 희생 중합체 층은 폴리아크릴산 (PAA), 폴리비닐피롤리돈 (PVP), 카르복시메틸 셀룰로오스 (CMC), 나트륨 카르복시메틸 셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 에틸메틸 셀룰로오스, 히드록시에틸 셀룰로오스 (HEC), 히드록실프로필 셀룰로오스 (HPC), 히드록시프로필 메틸셀룰로오스 (HPMC), 알긴산염, 폴리비닐아세테이트 (PVAc), 폴리유산 (PLA), 폴리유산-코-글리콜산 (PLGA), 폴리글리콜산, 또는 폴리무수물로 만들어진다. 일부 구체예에서, 나노규모 중합체 층이 먼저, 전술된 바와 같은 고체 지지체 상에 형성되고, 그리고 이후, 희생 중합체 층이 예로서, 분사 코팅, 스핀 코팅, 슬롯 다이 코팅, 아닐록스 코팅, 스크린 코팅, 잉크젯 코팅, 오프셋 인쇄 프린팅, 철판 인쇄 코팅, 그라비야 코팅, 로토그라비야 코팅, 리버스 롤 코팅, 미터링 (Meyer) 막대 코팅, 블레이드 코팅, 나이프 오버 롤 코팅, 에어 나이프 코팅, 커튼 코팅, 용융 압출 코팅, 용매 주조, 그리고 이들의 임의의 조합에 의해 나노규모 중합체 매트릭스 상에 형성된다. 바람직한 구체예에서, 희생 중합체 층 물질은 수성 환경에서, 또는 수분이 존재하는 환경, 예를 들면, 상처 기부, 내부 신체 표면, 상피 표면 등과 같은 습성 표면에서 분해가능하다. 바람직한 구체예에서, 희생 중합체 층 물질은 표면상에 나노규모 중합체 매트릭스의 적용 후 수성 용액에서 분해가능하다. 일부 구체예에서, 희생 중합체 층은 치수에서 마이크로규모이고, 그리고 0.2 μm 내지 1000 μm, 0.2 μm 내지 500 μm, 0.2 μm 내지 200 μm, 0.2 μm 내지 100 μm, 1 μm 내지 50 μm, 1 μm 내지 20 μm, 0.2 μm 내지 10 μm 또는 1 μm 내지 10 μm의 범위일 수 있고, 그리고 바람직하게는, 두께에서 100, 50, 20 또는 10 μm보다 적다.
일부 구체예에서, 자립형 필름은 조합된 나노- 내지 마이크로규모 중합체 층 및 두 번째 중합체 층을 기재로부터 벗겨냄으로써 획득된다. 두 번째 중합체 층에 인접한 나노- 내지 마이크로규모 중합체 층을 포함하는 이러한 자립형 필름은 마이크로시트로서 지칭될 수 있다. 일부 구체예에서, 조합된 나노- 내지 마이크로규모 중합체 층 및 두 번째 중합체 층을 뒷받침하는 기재는 마이크로시트가 벗겨지기 전에, 미리 결정된 크기 및/또는 상태로 절단된다. 일부 구체예에서, 마이크로시트의 희생 중합체 층은 아래에 더욱 상세하게 설명되는 바와 같은 생리활성 작용제, 항균제, 항생물막 작용제, 마이크로입자, 나노입자, 자성 입자를 내포한다. 일부 구체예에서, 희생 중합체 층에서 마이크로입자 또는 나노입자는 생리활성 작용제 또는 항균제를 내포한다. 일부 구체예에서, 두 번째 중합체 층은 항생물막 작용제를 포함한다. 이러한 기술은 장치 및 연관된 방법의 구체예, 키트 구체예, 그리고 치료 방법 구체예에서 이용되는 항생물막 작용제에만 한정되지 않는다. 가령, 일부 구체예에서, 항생물막 작용제는 소형 분자 항생물막 작용제, 하전된 소형 분자 항생물막 작용제, 항생물막 폴리펩티드, 항생물막 효소 (가령, 디스퍼신 B), 금속성 입자, 또는 금속 이온 항생물막 작용제 (가령, 금속 이온, 금속 이온 염, 또는 금속 이온 나노입자)이다. 게다가, 일부 구체예에서, 금속 이온 항생물막 작용제는 갈륨 이온, 갈륨 이온 염, 갈륨 이온 나노입자, 갈륨의 합금, 또는 갈륨 및 은의 합금이다.
D. 생리활성 작용제
일부 구체예에서, 나노- 내지 마이크로규모 중합성 시트는 한 가지 또는 그 이상의 생리활성 작용제를 상처에 전달하는 약물 전달 골격으로서 기능할 수 있다. 전달하는 것이 바람직할 수 있는 생리활성 작용제는 영양 인자, 세포외 매트릭스 (ECM), ECM 단편 또는 합성 구조체, 효소, 효소 저해제, 디펜신, 폴리펩티드, 항감염성 작용제 (항균제, 항바이러스제 및 항진균제 포함), 완충제, 비타민 및 무기질, 진통제, 항응고제, 응고 인자, 항염증제, 혈관수축제, 혈관확장제, 이뇨제 및 항암제를 포함하지만 이들에 한정되지 않는다. 이에 더하여, 활성제는 클로르헥시딘, 요오드 기초된 항균제, 예를 들면, PVP-요오드; 셀레늄 기초된 항균제, 예를 들면, 7-아자벤즈이소셀레나졸-3(2H)-온, 셀레늄 이황화물 및 셀렌화물; 은 기초된 항균제 (가령, 은 술파디아진, 이온성 은, 원소성 은, 은 나노입자) 및 갈륨 기초된 항균제를 포함할 것이다. 셀렌화물의 경우에, 전형적인 단백질 및 탄수화물 부착 화학의 표준 및 변이의 이용으로, 카르복실 및 아미노 내포 셀렌화물이 많은 중합체, 펩티드, 항체, 스테로이드 및 약물에 일과적으로 부착될 수 있다. 부착된 셀렌화물을 갖는 중합체 및 다른 분자는 생물학적 용액에서, 세포에서 또는 불용성 매트릭스, 예를 들면, 실리콘에 부착된 상태에서 초과산화물을 용량 의존성 방식으로 산출한다.
매우 다양한 생리활성 작용제가 마이크로시트로 총칭되는 고분자전해질 층 또는 두 번째 중합체 층 내로 통합될 수 있다. 본 발명은 한 가지 또는 그 이상의 생리활성 작용제가 마이크로시트로부터 방출되는 특정 기전으로만 한정되지 않는다. 실제로, 본 발명을 실시하기 위해 기전에 관한 이해가 필요하지 않다. 그럼에도 불구하고, 일부 구체예에서, 본 발명은 고분자전해질 층으로부터 확산에 의한, 마이크로시트 층으로부터 한 가지 또는 그 이상의 통합된 작용제의 상처로의 방출을 예기한다. 다른 구체예에서, 한 가지 또는 그 이상의 생리활성 작용제는 시간의 추이에서 또는 환경 조건에 대한 응답으로 마이크로시트 층으로부터 방출될 수 있다. 한 가지 또는 그 이상의 생리활성 작용제는 분해성 연쇄, 예를 들면, 가수분해 또는 효소적 분해를 통한 분해에 감수성인 연쇄에 의해 부착될 수 있다. 연쇄는 예로서, 일정한 pH에서 분해에 감수성인 연쇄일 수 있다.
일부 구체예에서, 상처 조절제에 대한 구배를 형성하기 위해 한 가지 또는 그 이상의 생리활성 작용제가 적용된다. 일반적으로, 구배는 상처에 상처 조절제의 적용 이후에 상처 내에 하나 또는 그 이상의 첫 번째 원하는 위치에서 더욱 높은 농도의 생리활성 작용제 및 상처에 상처 조절제의 적용 이후에 상처 내에 하나 또는 두 번째 위치에서 더욱 낮은 농도의 생리활성 작용제를 나타낸다. 가령, 생리활성 작용제의 농도는 특정 조성물의 더욱 높은 농도가 수직 방식으로 상처 기부의 원위에서보다 상처 기부의 근위에서 더욱 크도록 하는 구배에서 상처 기부 내에 층을 이룬다. 조성물의 농도가 상처 기부의 근위보다 원위에서 더욱 큰 정반대 경우 역시 예기된다. 수평 구배가 축적되는 상처 기부 내에 조성물의 농도 역시 예기된다. 지형적 구배 또한 예기되는데, 여기서 조성물은 상처 기부 내에 또는 생체적합성 입자상에서 조성물의 농도가 기재의 지형을 추종하도록 적층된다, 예를 들면, 더욱 높은 농도의 조성물이 파상의 정점과 비교하여 예시적인 기재의 파상의 골짜기에서 적층된다.
일부 구체예에서, 구배는 상처 조절제의 중심에서 더욱 높은 농도의 생리활성 작용제를 포함하고, 상처 조절제의 중심으로부터 멀어질수록 더욱 낮은 농도의 생리활성 작용제로 이행한다. 따라서, 상처 조절제가 상처에 적용될 때, 구배는 상처의 중심에서 더욱 높은 농도의 생리활성 작용제 및 상처의 주변으로 향함에 따라서 더욱 낮은 농도의 생리활성 작용제를 유발한다. 일부 구체예에서, 구배는 상처 조절제의 중심에서 더욱 낮은 농도의 생리활성 작용제를 포함하고, 상처 조절제의 중심으로부터 멀어질수록 더욱 높은 농도의 생리활성 작용제로 이행한다. 따라서, 구배는 상처의 중심에서 더욱 낮은 농도의 생리활성 작용제 및 상처의 주변으로 향함에 따라서 더욱 높은 농도의 생리활성 작용제를 유발한다. 만약 2가지 또는 그 이상의 생리활성 작용제가 활용되면, 이들은 유사한 구배로서 제공될 수 있거나, 또는 이들 구배는 2가지 또는 그 이상의 생리활성 작용제의 농도가 상처 전역에서 달라지도록 변할 수 있다. 높은 또는 낮은 농도의 구배는 매트릭스 및 구배가 다양한 상처 모양에 합치할 수 있도록, 임의의 모양, 예를 들면, 환상, 사각형, 직사각형, 난원형, 장방형 등일 수 있다. 가령, 긴 절개 유형 상처의 경우에, 구배는 상처의 길이를 따라서 신장하고 상처에 집중될 수 있는 세로축에 중심이 있을 수 있다. 다른 실례로서, 구배는 거의 환형 또는 난원형인 개방형 상처, 붐 (bum), 욕창 및 궤양에 적용을 위해 환형 또는 난원형-모양일 수 있다. 다른 구체예에서, 구배는 한 가지 패턴으로 배열된 일련의 특질을 포함한다. 가령, 구배는 매트릭스의 세로축을 따라서, 한 가지 또는 그 이상의 생리활성 작용제의 일련의 줄무늬 또는 높은 농도 및 낮은 농도를 형성할 수 있다. 대안으로, 구배는 체커보드 패턴, 어레이, 동심성 원, 중첩하는 원 또는 난원형 등을 형성할 수 있다.
본 발명은 상처에 매우 다양한 생리활성 작용제의 전달을 예기한다. 일부 구체예에서, 본 발명은 아그린, 암피레굴린, 아르테민, 카디오트로핀-1, EGF를 비롯한 표피 성장 인자; 섬유모세포 성장 인자 (가령, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6 및 FGF-7); LIF, CSF-1, CSF-2, CSF-3, 에리트로포이에틴, ECGF를 비롯한 내피 세포 성장 인자; FGF-관련된 및 ECGF-관련된 성장 인자 (가령, 내피 세포 자극 혈관형성 인자, 종양 혈관형성 인자, 망막-유래된 성장 인자 (RDGF), 혈관 내피 성장 인자 (VEGF), 뇌-유래된 성장 인자 (BDGF-A 및 B), 성상세포 성장 인자 (AGF 1 및 2), 장막-유래된 성장 인자, 섬유모세포-자극 인자 (FSF) 및 배아 암종-유래된 성장 인자 (ECDGF)); 신경영양 성장 인자 (가령, 신경 성장 인자 (NGF), 뉴투린, 뇌-유래된 신경영양 인자 (BDNF), 뉴로트로핀-3, 뉴로트로핀-4 및 섬모 신경영양 인자 (CNTF)); 신경교 성장 인자 (가령, GGF-I, GGF-II, GGF-III, 아교세포 성숙 인자 (GMF) 및 신경교-유래된 신경영양 인자 (GDNF)); 간 성장 인자 (가령, 헤마토포이에틴 A, 헤마토포이에틴 B 및 HGF를 비롯한 간세포 성장 인자); 전립선-유래된 성장 인자 (PGF)를 비롯한 전립선 성장 인자; 유방-유래된 성장 인자 1 (MDGF-1) 및 유방 종양-유래된 인자 (MTGF)를 비롯한 유방 성장 인자; 비근육세포-유래된 성장 인자 (NMDGF)를 비롯한 심장 성장 인자; 멜라닌세포 자극 호르몬 (MSH) 및 흑색종 성장-자극 활성 (MGSA)을 비롯한 멜라닌세포 성장 인자; 혈관형성 인자 (가령, 안지오제닌, 안지오트로핀, 혈소판-유래된 ECGF, VEGF 및 플레이오트로핀); TGF-α 및 TGF-β를 비롯한 전환 성장 인자; TGF-유사 성장 인자 (가령, TGF-베타1, TGF-베타2, TGF-베타3, GDF-1, CDGF, 종양-유래된 TGF-유사 인자, ND-TGF 및 인간 상피 변환 인자); 성장 인자-유사 성질을 갖는 조절 펩티드 (가령, 봄베신 및 봄베신-유사 펩티드 라나텐신 및 리토린, 안지오텐신, 엔도텔린, 심방 나트륨이뇨 인자, 혈관작용 장관 펩티드 및 브래디키닌); PDGF-A, PDGF-B 및 PDGF-AB를 비롯한 혈소판 유래 성장 인자; 신경펩티드 (가령, 물질 P, 칼시토닌 유전자-조절된 펩티드 (CGRP) 및 신경펩티드 Y); 노르에피네프린, 아세틸콜린 및 카르바콜을 비롯한 신경전달물질 및 이들의 유사체; 헤지호그, 헤레굴린/뉴레귤린, IL-1, 파골세포-활성화 인자 (OAF), 림프구-활성화 인자 (LAF), 간세포-자극 인자 (HSF), B-세포-활성화 인자 (BAF), 종양 저해 인자 2 (TIF-2), 각질세포-유래된 T-세포 성장 인자 (KD-TCGF), IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, 간질 세포-유래된 사이토킨 (SCDC), IL-12, IL-13, IL-14, IL-15, 인슐린, IGF-1, IGF-2 및 IGF-BP를 비롯한 인슐린-유사 성장 인자; INF-알파, INF-베타 및 INF-감마를 비롯한 인터페론; 렙틴, 미드킨, 종양 괴사 인자 (TNF-알파 및 베타), 네트린, 사포신, 세마포린, 소마트렘, 소마트로핀, 줄기 세포 인자, VVGF, 뼈 형성 단백질 (BMP), 부착 분자, 다른 사이토킨, 헤파린-결합 성장 인자, 그리고 티로신 키나아제 수용체 리간드를 포함하지만 이들에 한정되지 않는 영양 인자의 전달을 제공한다. 일부 구체예에서, 생리활성 작용제는 펩티드, 예를 들면, AcEEED인데, 이것은 알파 평활근 액틴에 대한 N 말단 펩티드이고, 그리고 근섬유모세포의 수축성 성질을 저해하는 것으로 밝혀졌다.
일부 구체예에서, 본 발명은 세포외 기질 단백질, 진핵 세포주로부터 유래된 재구성된 기저막-유사 복합체, 콜라겐, 섬유결합소, 라미닌, VCAM-1, 비트로넥틴 및 젤라틴, 세균 세포외 기질, 겔 매트릭스 및 중합성 매트릭스의 선천적 구조체, 선천적 구조체의 단편 및 합성 유사체를 포함하지만 이들에 한정되지 않는 ECM의 전달을 제공한다. 일부 구체예에서, 생리활성 작용제는 RGD, EILDV, VCAM-1 및 이들의 재조합된 또는 합성 유사체, 효소, 효소 저해제, 그리고 폴리펩티드에 의해 예시되지만 이들에 한정되지 않는 인테그린 결합 서열이다.
일부 구체예에서, 본 발명은 세린 단백질분해효소 키모트립신, 트립신, 엘라스타아제 및 칼리크레인을 포함하지만 이들에 한정되지 않는 엑소펩티다아제 및 엔도펩티다아제 (프로테아제 및 단백질분해효소로서 또한 알려져 있음), 세균 효소, 시스테인 프로테아제 파파인, 악티닌, 브로멜라인, 카텝신, 세포질 칼페인, 기생충성 프로테아제, 아스파르트산 단백질분해효소, 프로테아제 펩신 및 키모신의 펩신 패밀리, 리소좀 카텝신 D, 레닌, 진균 프로테아제, 바이러스 프로테아제, AIDS 바이러스 레트로펩신, 그리고 금속단백분해효소 (MMP), 콜라겐분해효소, Maggott 효소, MMP1, MMP2, MMP8, MMP13, 젤라틴분해효소, MMP2, MMP9, MMP3, MMP7, MMP10, MMP11 및 MMP12를 포함하지만 이들에 한정되지 않는 효소의 전달을 제공한다.
일부 구체예에서, 본 발명은 카프토프릴, 티오르판, 포스포르아미돈, 테프로티드, 프로테아제 및 단백질분해효소 저해제, 금속단백분해효소 저해제, 그리고 엑소펩티다아제 저해제를 포함하지만 이들에 한정되지 않는 효소 저해제의 전달을 제공한다.
일부 구체예에서, 본 발명은 알파-디펜신 HNP 1, 2, 3 및 4, 그리고 베타-디펜신 HBD-1 및 HBD-2를 포함하지만 이들에 한정되지 않는 디펜신의 전달을 제공한다.
일부 구체예에서, 본 발명은 섬유결합소, 세로토닌, PAF, PDEGF, TNFa, IL1, IL6, IGF, IGF-1, IGF-2, IL-1, PDGF, FGF, KGF, VEGF, 브래디키닌, 프로티모신-알파 및 티모신-알파1을 포함하지만 이들에 한정되지 않는 폴리펩티드의 전달을 제공한다.
일부 구체예에서, 본 발명은 마가이닌 (가령, 마가이닌 I, 마가이닌 II, 제놉신, 제놉신 전구체 단편, 카에룰레인 전구체 단편), 마가이닌 I 및 II 유사체 (가령, PGLa, 마가이닌 A, 마가이닌 G, 펙시가닌, Z-12, 펙시가이닌 아세트산염, D35, MSI-78A, MG0 (K10E, K11E, F12W-마가이닌 2), MG2+ (K10E, F12W-마가이닌-2), MG4+ (F12W-마가이닌 2), MG6+ (fl2W, E19Q-마가이닌 2 아미드), MSI-238, 반전된 마가이닌 II 유사체 (가령, 53D, 87-ISM 및 A87-ISM), Ala-마가이닌 II 아미드, 마가이닌 II 아미드), 세크로핀 P1, 세크로핀 A, 세크로핀 B, 인돌리시딘, 니신, 라날렉신, 락토페리신 B, 폴리-L-리신, 세크로핀 A (1-8)-마가이닌 II (1-12), 세크로핀 A (1-8)-멜리틴 (1-12), CA(1-13)-MA(1-13), CA(1-13)-ME(1-13), 그라미시딘, 그라미시딘 A, 그라미시딘 D, 그라미시딘 S, 알라메티신, 프로테그린, 히스타틴, 데르마셉틴, 렌티바이러스 양친매성 펩티드 또는 유사체, 파라신 I, 리코톡신 I 또는 II, 글로보마이신, 그라미시딘 S, 수르팍틴, 랄리노마이신, 발리노마이신, 폴리믹신 B, PM2 ((+/-) 1-(4-아미노부틸)-6-벤질인단), PM2c ((+/-)-6-벤질-1-(3-카르복시프로필)인단), PM3 ((+/-) 1-벤질-6-(4-아미노부틸)인단), 타키플레신, 부포린 I 또는 II, 미스구린, 멜리틴, PR-39, PR-26, 9-페닐노닐아민, (KLAKKLA)n, (KLAKLAK)n, 여기서 n = 1, 2 또는 3, (KALKALK)3, KLGKKLG)n 및 KAAKKAA)n, 여기서 N = 1, 2 또는 3, 파라닥신, Bac 5, Bac 7, 세라톡신, 음델린 1 및 5, 봄빈-유사 펩티드, PGQ, 카텔리시딘, HD-5, Oabac5alpha, ChBac5, SMAP-29, Bac7.5, 락토페린, 그라눌리신, 티오닌, 헤베인 및 크노틴-유사 펩티드, MPG1, 1bAMP, 스나킨, 지질 전달 단백질, 그리고 식물 디펜신을 포함하지만 이들에 한정되지 않는 항균제의 전달을 제공한다. 상기 화합물에 대한 예시적인 서열은 표 1에서 제공된다. 일부 구체예에서, 항균성 펩티드는 L-아미노산으로부터 합성되고, 반면 다른 구체예에서, 펩티드는 D-아미노산으로부터 합성되거나, 또는 이들을 포함한다.
일부 구체예에서, 본 발명은 로라카르베프, 세팔렉신, 세파드록실, 세픽사임, 세프티부텐, 세프프로질, 세프포독심, 세프라딘, 세푸록심, 세파클로르, 네오마이신/폴리믹신/바시트라신, 디클록사실린, 니트로푸란토인, 니트로푸란토인 거대결정, 니트로푸란토인/니트로푸란 맥, 디리트로마이신, 게미플록사신, 암피실린, 가티플록사신, 페니실린 V 칼륨, 시프로플록사신, 에녹사신, 아목시실린, 아목시실린/클라불라네이트 칼륨, 클라리트로마이신, 레보플록사신, 목시플록사신, 아지트로마이신, 스파르플록사신, 세프디니르, 오플록사신, 트로바플록사신, 로메플록사신, 메테나민, 에리트로마이신, 노르플록사신, 클린다마이신/벤조일 과산화물, 퀴누프리스틴/달포프리스틴, 독시사이클린, 아미카신 황산염, 반코마이신, 카나마이신, 네틸마이신, 스트렙토마이신, 토브라마이신 황산염, 젠타마이신 황산염, 테트라사이클린, 프라미세틴, 미노사이클린, 날리딕식산, 데메클로시클린, 트리메토프림, 미코나졸, 콜리스티메테이트, 피페라실린 나트륨/타조박탐 나트륨, 파로모마이신, 콜리스틴/네오마이신/히드로코르티손, 아메바구제제, 술피속사졸, 펜타미딘, 술파디아진, 클린다마이신 인산염, 메트로니다졸, 옥사실린 나트륨, 나프실린 나트륨, 반코마이신 염산염, 클린다마이신, 세포탁심 나트륨, 코-트리목사졸, 티카르실린 이나트륨, 피페라실린 나트륨, 티카르실린 이나트륨/클라불라네이트 칼륨, 네오마이신, 다프토마이신, 세파졸린 나트륨, 세폭시틴 나트륨, 세프티족심 나트륨, 페니실린 G 칼륨 및 나트륨, 세프트리악손 나트륨, 세프타지딤, 이미페넴/실라스타틴 나트륨, 아즈트레오남, 시녹사신, 에리트로마이신/술피속사졸, 세포테탄 이나트륨, 암피실린 나트륨/술박탐 나트륨, 세포페라존 나트륨, 세파만돌 나페이트, 젠타마이신, 술피속사졸/페나조피리딘, 토브라마이신, 린코마이신, 네오마이신/폴리믹신 B/그라미시딘, 클린다마이신 염산염, 란소프라졸/클라리트로마이신/아목시실린, 알라트로플록사신, 리네졸리드, 비스무트 차살리실산염/메트로니다졸/테트라사이클린, 에리트로마이신/벤조일 과산화물, 무피로신, 포스포마이신, 펜타미딘 이세티오네이트, 이미페넴/실라스타틴, 트롤레안도마이신, 가티플록사신, 클로람페니콜, 시클로세린, 네오마이신/폴리믹신 B/히드로코르티손, 엘타페넴, 메로페넴, 세팔로스포린, 플루코나졸, 세페파임, 술파메톡사졸, 술파메톡사졸/트리메토프림, 네오마이신/폴리믹신 B, 페니실린, 리팜핀/이소니아지드, 에리트로마이신 에스톨레이트, 에리트로마이신 에틸숙시네이트, 에리트로마이신 스테아르산염, 암피실린 삼수화물, 암피실린/프로베니시드, 술파살라진, 술파닐아미드, 나트륨 술파세타미드, 다프손, 독시사이클린 하이클레이트, 트리멘토프림/술파, 메테나민 만델레이트, 말라리아원충박멸제, 피리메타민, 히드록시클로로퀸, 클로로퀸 인산염, 트리코모노사이드, 구충제, 아토바쿠온, 바시트라신, 바시트라신/폴리믹신 b, 젠타마이신, 네오마이신/폴리믹신/데스메스, 네오마이신 술프/데스메스, 술파세타미드/프레드니솔론, 술파세타미드/페닐에프린, 토브라마이신 황산염/데스메스, 비스무트 트리브로모페네이트, 은 이온 화합물, 은 나노입자, 제로가 은, 다가 은, 원소성 은 및 은 내포 화합물, 예를 들면, 은 술파디아진 및 관련된 화합물, 갈륨 이온 화합물, 갈륨 이온 염, 갈륨 이온 나노입자, 갈륨의 합금, 그리고 갈륨 및 은의 합금을 포함하지만 이들에 한정되지 않는 항균제의 전달을 제공한다.
일부 구체예에서, 본 발명은 아만타딘, 아시클로비르, 포스카넷, 인디나비르, 리바비린, 엔푸비르티드, 엠트리시타빈, 라미부딘, 아바카비르 황산염, 포미비어센, 발라시클로비르, 테노포비르, 시도포비르, 아타자나비르, 암프레나비르, 델라비딘 메실레이트, 팜시클로비르, 아데포비르, 디다노신, 에파비렌즈, 트리플루리딘, 이니디나비르, 라미부딘, 비다라빈, 로피나비르/리토나비르, 간시클로비르, 자나미비르, 아바카비르/라미부딘/지도부딘, 라미부딘/지도부딘, 넬피나비르, 넬피나비르 메실레이트, 네비라핀, 리토나비르, 사퀴나비르, 사퀴나비르 메실레이트, 리만타딘, 스타부딘, 도코사놀, 잘시타빈, 이독수리딘, 지도부딘, 지도부딘/디다노신, 발간시클로비르, 펜시클로비르, 라미부딘, 그리고 오셀타미비르를 포함하지만 이들에 한정되지 않는 항바이러스제의 전달을 제공한다.
일부 구체예에서, 본 발명은 암포테리신 B, 니스타틴, 니스타틴/트리암시놀론, 이트라코나졸, 케토코나졸, 미코나졸, 술코나졸, 클로트리마졸, 클로트리마졸/베타메타손, 에닐코나졸, 에코나졸, 옥시코나졸, 티오코나졸, 테르코나졸, 부토코나졸, 티아벤다졸, 플루시토신, 부테나핀, 시클로피록스, 하로프로진, 나프티핀, 톨나프테이트, 나타마이신, 운데실렌산, 마페니드, 다프손, 클리오퀴놀, 클리오퀴놀/히드로코르티손, 칼륨 요오드화물, 은 술파디아진, 젠티안 바이올렛, 카르볼-푹신, 실로푼진, 세르타코나졸, 보리코나졸, 플루코나졸, 테르비나핀, 카스포펀진, 다른 국소 아졸 약물, 그리고 그리세오풀빈을 포함하지만 이들에 한정되지 않는 항진균제의 전달을 제공한다.
일부 구체예에서, 본 발명은 말레산, 인산, 글리신, 클로로아세트산, 포름산, 벤조산, 아세트산, 피리딘, 피페라진, MES, 비스-트리스, 탄산염, ACES, ADA MOPSO, PIPES, 인산, BES, MOPS, TES, HEPES, DIPSO, TAPSO, 트리에탄올아민, HEPSO, Tris, 트리신, 비신, TAPS, 붕산염, 암모니아, CHES, 에탄올아민, CAPSO, 글리신, 탄산염, CAPS, 메틸아민, 피페리딘, 그리고 인산을 포함하지만 이들에 한정되지 않는 완충제의 이용과 전달을 제공한다.
일부 구체예에서, 본 발명은 비타민 A, 카로티노이드, 비타민 D, 비타민 E, 비타민 K, 비타민 C/아스코르빈산, B1/티아민, B2/리보플라빈, B3/니아신, B5/판토텐산, B6/피리독신, B12/코발라민, 비오틴, 칼슘, 마그네슘, 인, 염화나트륨, 칼륨, 붕소, 크롬, 구리, 요오드, 철, 망간, 셀레늄, 그리고 아연을 포함하지만 이들에 한정되지 않는 비타민 및 무기질의 전달을 제공한다.
일부 구체예에서, 본 발명은 아세트아미노펜, 아닐레리딘, 아세틸살리실산, 부프레노르핀, 부토르파놀, 펜타닐, 펜타닐 구연산염, 코데인, 로페콕시브, 히드로코돈, 히드로모르폰, 히드로모르폰 염산염, 레보르파놀, 알펜타닐 염산염, 메페리딘, 메페리딘 염산염, 메타돈, 모르핀, 날부핀, 아편, 레보메타딜, 히알루론산염 나트륨, 수펜타닐 구연산염, 캡사이신, 트라마돌, 레플루노미드, 옥시코돈, 옥시모르폰, 셀레콕시브, 펜타조신, 프로폭시펜, 벤조카인, 리도카인, 데조신, 클로니딘, 부탈비탈, 페노바르비탈, 테트라카인, 페나조피리딘, 술파메톡사졸/페나조피리딘, 그리고 술피속사졸/페나조피리딘을 포함하지만 이들에 한정되지 않는 진통제의 전달을 제공한다.
일부 구체예에서, 본 발명은 아밀로카인, 암부카인, 아르티카인, 벤조카인, 벤조나테이트, 부피바카인, 부타카인, 부타닐리카인, 클로로프로카인, 신코카인, 시클로메티카인, 디부카인, 디페로돈, 디메티소퀸, 디메토카인, 오이카인, 에티도카인, 헥실카인, 포모카인, 포토카인, 히드록시프로카인, 이소부카인, 레보부피비카인, 요오도카인, 메피바카인, 메프릴카인, 메타부톡시카인, 니트라카인, 오르토카인, 옥세타카인, 옥시부프로카인, 파라에톡시카인, 페나카인, 피페로카인, 피리도카인, 프라모카인, 프릴로카인, 프리마카인, 프로카인, 프로카인아미드, 프로파라카인, 프로폭시카인, 피로카인, 퀴니소카인, 로피바카인, 트리메카인, 테트라카인, 톨리카인, 그리고 트로파코카인을 포함하지만 이들에 한정되지 않는 국부 마취제 (이들은 또한, 당해 분야에서 공지된 바와 같이 진통제일 수 있다)의 전달을 제공한다.
일부 구체예에서, 본 발명은 날록손, 디프레노르핀, 날트렉손, 부프레노르핀, 부프레모르핀/날록손, 날로데인, 날로르핀, 레발로르판, 날메펜, 날록솔, 알비모판, 날데메딘, 엘룩사돌린, 아시마돌린, 날록세골, 메틸날트렉손, 데조신, 날록세골, 엡타조신, 부토르파놀, 레보르파놀, 날부핀, 펜타조신, 페나조신, 시프로딤, 날트린돌, 노르비날토르피민, 그리고 J113,393을 포함하지만 이들에 한정되지 않는 오피오이드 길항제 및/또는 혼합된 오피오이드 효현제/길항제 (이들은 또한, 당해 분야에서 공지된 바와 같이 오피오이드 진통제일 수 있다)의 전달을 제공한다.
일부 구체예에서, 본 발명은 쿠마린, 1,3-인단디온, 아니신디온, 폰다파리눅스, 헤파린, 레피루딘, 항트롬빈, 와파린, 에녹사파린, 디피리다몰, 달테파린, 알데파린, 나드로파린, 그리고 틴자파린을 포함하지만 이들에 한정되지 않는 항응고제의 전달을 제공한다.
일부 구체예에서, 본 발명은 인자 I (피브리노겐), 인자 II (프로트롬빈), 인자 III (트롬보플라스틴, 조직 인자), 인자 IV (칼슘), 인자 V (불안정 인자), 인자 VII (안정 인자), 인자 VIII (항혈우병 글로불린, 항혈우병 글로불린, 항혈우병 인자 A), 인자 IX (혈장 트롬보플라스틴 성분, 크리스마스 인자, 항혈우병 인자 B), 인자 X (스튜어트 인자, 프라워 인자, 스튜어트 프라워 인자), 인자 XI (혈장 트롬보플라스틴 선행물질, 항혈우병 인자 C), 인자 XII (하게만 인자, 표면 인자, 접촉 인자), 그리고 인자 XIII (섬유소 안정 인자, 피브린 안정화 효소, 피브리나아제)를 포함하지만 이들에 한정되지 않는 응고 인자의 전달을 제공한다.
일부 구체예에서, 본 발명은 디클로페낙 (볼타렌, 아비트렌, 알보란, 알미랄, 알론핀, 안페낙스, 아르트리테스, 베타렌, 블레신, 볼라보민, 카타플람, 클로펙, 클로펜, 코르드랄란, 쿠린플람, 디클로맥스, 디클로시안, 딕스날, 디페낙, 에코페낙, 히제민, 인플라맥, 인플라낙, 클로타렌, 리도닌, 모노플람, 나보알, 오리타렌, 레메탄, 사비스민, 실리노, 스타렌, 츄도민, 볼타롤, 보렌, 보베란 및 부르돈으로서 또한 알려져 있음), 디플루니살 (돌로비드, 아도말, 디플로니드, 디플루닐, 돌리살, 돌로비스, 돌로시드, 도노비드, 도파논, 도르비드, 두고돌, 플로바실, 플루니겟, 플루오도닐, 플루스타, 일라센, 노알돌, 레우플로스 및 유니살로서 또한 알려져 있음), 에토돌락 (로딘으로서 또한 알려져 있음), 페노프로펜 (날폰, 페노프렉스, 페노프론, 페프론, 날게식 및 프로게식으로서 또한 알려져 있음), 플루르비프로펜 (안사이드 및 오쿠플루르로서 또한 알려져 있음), 이부프로펜 (루펜, 모트린, 아케스-N-페인, 아드빌, 누프린, 돌게식, 젠프릴, 할트란, 이비폰, 이브렌, 이부메드, 이부프린, 이부프로-600, 이부프롬, 이부-탭, 이부텍스, 이펜, 메디프렌, 미돌 200, 모트린-IB, 크램프 엔드, 프로펜, 로-프로펜, 트렌다르, 알락산, 브로펜, 알팜, 브루펜, 알고펜, 부르포르트, 아메르솔, 브루존, 안드란, 부부론, 안플라겐, 부타코르텔론, 압시펜, 데플렘, 아르토펜, 돌기트, 아트릴, 돌로실, 블룸, 돈저스트, 블루톤, 에아시폰, 에부팍, 엠플람, 에모딘, 펜비드, 펜스판, 포커스, 이보수레, 이부펜, 이부푸그, 이부겐, 이부메틴, 이부피락, 임분, 이나브린, 인플람, 이르펜, 리브로펜, 리미돈, 로판, 미노세딘, 나파세틴, 노바폰, 노브겐, 노보겐트, 노보프로펜, 누로펜, 옵티펜, 파두덴, 팍소펜, 페로펜, 프로아르티날, 프론탈긴, Q-프로펜, 렐코펜, 레모펜, 로이데닌, 세클로딘, 타레인 및 조펜으로서 또한 알려져 있음), 인도메타신 (인다메스, 인도신, 아무노, 안탈긴, 아레우마틴, 아르길렉스, 아르테렉신, 아르트렉신, 아르트리노보, 바빌론, 보니돈, 보우티신, 쿠론-인도시드, 시달곤, 콘포르티드, 콘포르틴드, 도메시드, 두라메타신, 엘레메타신, 이디신, 임브릴론, 인아시드, 인다신, 인데신, 인도캅, 인도센, 인도시드, 인도플렉스, 인돌라그, 인돌라르, 인도메드, 인도메, 인도메타시눔, 인도메티시나, 인도메틴, 인도비스, 인독스, 인도주, 인드레닌, 인딜론, 인플라존, 인판, 라우지트, 리오메타세, 메타센, 메틴돈, 메토시드, 메졸린, 모빌란, 노보메타신, 페랄곤, 레플록스, 류마시드, 류마신, 살리나크, 세르빈도메트, 토시산 및 보눔으로서 또한 알려져 있음), 케토프로펜 (오루디스, 알레우마트, 알레우문, 알루마트, 아네올, 아르센탄, 덱살, 에파텍, 파스툼, 켄두릴, 케페니드, 케프로펜, 케토펜, 케토날, 케토솔란, 케바돈, 메로, 낙살, 오루바일, 프로페니드, 살리엔트, 토펜 및 트레오신으로서 또한 알려져 있음), 케토롤락 (토라돌로서 또한 알려져 있음), 메클로페나메이트 (메클로펜, 메클로멘 및 모벤스로서 또한 알려져 있음), 메페남산 (폰스텔, 알파인, 아프로스탈, 베노스탄, 보나볼, 코슬란, 디스만, 디스펜, 에코판, 리살고, 마닉, 메팍, 메픽, 메픽스, 파르케메드, 폰덱스, 폰스펜, 폰스탄, 폰스틸, 폰탈, 랄젝 및 유페남으로서 또한 알려져 있음), 나부메톤 (렐라펜으로서 또한 알려져 있음), 나프록센 (나프로신, 아나프록스, 알레베, 아프라낙스, 아프로낙스, 아르트리실, 아르트릭센, 아르트록센, 보닐, 콘젝스, 다나프록스, 디코달, 디스메날기트, 페멕스, 플라낙스, 플렉시펜, 플로기낙스, 기빅센, 헤아들론, 라라플렉스, 레이저, 레니아르틸, 나팍솔, 나익산, 날릭산, 나포톤, 나프렌, 나프렐란, 나프리움, 나프리우스, 나프론타그, 나프룩스, 나프센, 나르마, 낙센, 낙시드, 노보나프록스, 니코프렌, 파트센, 프렉산, 프로덱신, 라흐센, 록센, 사리틸론, 시나르트린, 신톤, 수토니, 신플렉스, 토헥센, 베라돌, 빈센 및 제나르로서 또한 알려져 있음), 옥사프로진 (데이프로로서 또한 알려져 있음), 피록시캄 (펠덴, 알기돌, 안티플로그, 아르피록스, 아티뎀, 베스토캄, 부타시논, 데신플람, 딕소날, 도블렉산, 돌로넥스, 펠린, 펠록스, 풀딘, 인덴, 인펠드, 인플라멘, 람포플렉스, 랄라팜, 메도프틸, 노보피로캄, 오스테랄, 필록스, 피랄덴, 피람, 피락스, 피리캄, 피로캄, 피로캅스, 피록산, 피록세돌, 피록심, 피톤, 포시덴, 피록시, 레우캄, 렉시캄, 리아센, 로식, 시날지코, 소틸렌, 스토펜 및 준덴으로서 또한 알려져 있음), 술린닥 (클리노릴, 아플로닥, 알고세틸, 안트리비드, 아르트리덱스, 아르트로신, 비플라세, 시티레우마, 클리순닥, 림바랄, 린다크, 린닥, 모빌린, 류모필, 수닥, 술렌, 술릭, 술린달, 술로릴 및 술레우마로서 또한 알려져 있음), 톨메틴 (톨렉틴, 도니손, 미도실, 레우톨 및 살피텍스로서 또한 알려져 있음), 셀레콕시브 (셀레브렉스로서 또한 알려져 있음), 멜록시캄 (모빅으로서 또한 알려져 있음), 로페콕시브 (비옥스로서 또한 알려져 있음), 발데콕시브 (벡스트라로서 또한 알려져 있음), 아스프린 (아나신, 아스크립틴, 베이어, 부페린, 에코트린 및 엑세드린으로서 또한 알려져 있음)을 비롯한 비스테로이드성 항염증성 약물 (NSAIDs), 그리고 코르티손, 프레드니손 및 덱사메타손을 비롯한 스테로이드성 항염증성 약물을 포함하지만 이들에 한정되지 않는 항염증제의 전달을 제공한다.
일부 구체예에서, 본 발명은 에피네프린 (아드레날린, 수스피린), 페닐에프린 염산염 (네오-시네프린), 옥시메타졸린 염산염 (아프린), 노르에피네프린 (레보페드), 그리고 카페인을 포함하지만 이들에 한정되지 않는 혈관수축제의 전달을 제공한다.
일부 구체예에서, 본 발명은 보센탄 (트라클레르), 에포프로스테놀 (플롤란), 트레프로스티닐 (레모둘린), 시탁센탄, 니페디핀 (아달라트, 프로카르디아), 니카르디핀 (카르덴), 베라파밀 (칼란, 코베라-HS, 이소프틴, 베렐란), 딜티아젬 (딜라코르 XR, 딜티아 XT, 티아메이트, 티아작, 카르디젬), 이스라디핀 (디나서크), 니모디핀 (니모톱), 암로디핀 (노바스크), 펠로디핀 (플렌딜), 니솔디핀 (술라르), 베프리딜 (바스코르), 히드랄라진 (아프레솔린), 미녹시딜 (로니텐), 이소소르비드 이질산염 (딜라트레이트-SR, 이소-비드, 이소네이트, 이소르비드, 이소르딜, 이소트레이트, 소르비트레이트), 이소르비드 모노니트레이트 (임두르), 프라조신 (미니프레스), 실로스타졸 (플레탈), 트레프로스티닐 (레모둘린), 시클란데레이트, 이속수프린 (바소딜란), 나일리드린 (아릴딘), 질산염 (데포니트, 미니트란, 니트로-비드, 니트로디스크, 니트로-두르, 니트롤, 트랜스덤-니트로), 베나제프릴 (로텐신), 베나제프릴 및 히드로클로로티아지드 (로텐신 HCT), 카프토프릴 (카포텐), 카프토프릴 및 히드로클로로티아지드 (카포지드), 에날라프릴 (바소텍), 에날라프릴 및 히드로클로로티아지드 (바세레틱), 포시노프릴 (모노프릴), 리시노프릴 (프리니빌, 제스트릴), 리시노프릴 및 히드로클로로티아지드 (프린지드, 제스토레틱), 모엑시프릴 (유니바스크), 모엑시프릴 및 히드로클로로티아지드 (유니레틱), 페린도프릴 (아세온), 퀴나프릴 (아쿠프릴), 퀴나프릴 및 히드로클로로티아지드 (아쿠레틱), 라미프릴 (알타세), 트란돌라프릴 (마비크), 파파베린 (세레스판, 게나비드, 파바비드, 파바비드 HP, 파바셀스, 파바코트, 파바겐, 파바린, 파바세드, 파바틴, 파바팀, 파베롤란)을 포함하지만 이들에 한정되지 않는 혈관확장제의 전달을 제공한다.
일부 구체예에서, 본 발명은 아세타졸아미드 (디아목스), 디클로르페나미드 (다라니드), 메타졸라미드 (넵타존), 벤드로플루메티아지드 (나투레틴), 벤즈티아지드 (엑스나), 클로로티아지드 (디우릴), 클로르탈리돈 (히그로톤), 히드로클로로티아지드 (에시드릭스, 히드로디우릴, 마이크로지드), 히드로플루메티아지드 (디우카르딘), 인다파미드 (로졸), 메티클로티아지드 (엔두론), 메톨라존 (자록솔린, 미크록스), 폴리티아지드 (레네세), 퀴네타존 (히드로목스), 트리클로르메티아지드 (나쿠아), 부메타니드 (부멕스), 에타크리닉산 (에데크린), 푸로세미드 (라식스), 토르세미드 (데마덱스), 아밀로리드 (미다모르), 아밀로리드 및 히드로클로로티아지드 (모두레틱), 스피로놀락톤 (알닥톤), 스피로놀락톤 및 히드로클로로티아지드 (알닥타지드), 트리암테렌 (디레니움), 트리암테렌 및 히드로클로로티아지드 (디아지드, 맥스지드)를 포함하지만 이들에 한정되지 않는 이뇨제의 전달을 제공한다.
일부 구체예에서, 본 발명은 알데스류킨, 알렘투주맙, 알리트레티노인, 알로푸리놀, 알트레타민, 아미포스틴, 아나그렐리드, 아나스트로졸, 삼산화비소, 아스파라기나아제, 벡사로텐, 비칼루타미드, 블레오마이신, 부술판, 칼루스테론, 카페시타빈, 카르보플라틴, 카르무스틴, 셀레콕시브, 클로람부실, 시스플라틴, 클라드리빈, 시클로포스파미드, 시타라빈, 다카르바진, 닥티노마이신, 다베포에틴 알파, 다우노루비신, 다우노마이신, 덱스라족세인, 도세탁셀, 독소루비신, 에포에틴 알파, 에스트라무스틴, 에토포시드, 에토포시드 인산염, 엑세메스테인, 필그라스팀, 플록수리딘, 플루다라빈, 플루타미드, 풀베스트란트, 젬시타빈, 겜투주맙 오조가미신, 고세렐린 아세트산염, 히드록시요소, 이브리투모맙 티욱세탄, 이다루비신, 이포스파미드, 이마티닙 메실레이트, 인터페론 알파-2a, 인터페론 알파-2b, 이리노테칸, 레플루노미드, 레트로졸, 류코보린, 레바미솔, 로무스틴, 메클로레타민 (질소 머스타드), 메게스트롤 아세트산염, 멜팔란, 메르캅토푸린, 메스나, 메토트렉사트, 메톡살렌, 미토마이신 C, 미토탄, 미톡산트론, 미코페놀레이트 모페틸, 난드롤론 펜프로피오네이트, 닐루타미드, 노페투모맙, 오프렐베킨, 옥살리플라틴, 파클리탁셀, 파미드로네이트, 페가데마제, 페가스파르가제, 페그필그라스팀, 펜토스타틴, 피포브로만, 플리카마이신, 포르피머 나트륨, 프로카르바진, 퀴나크린, 라스부리카제 리툭시맙, 사르그라모스팀, 스트렙토조신, 타크롤리무스, 타목시펜, 테모졸로미드, 테니포시드, 테스톨락톤, 티오구아닌, 티오테파, 토포테칸, 토레미펜, 토시투모맙, 트라스투주맙, 트레티노인, 우라실 머스타드, 발루비신, 빈블라스틴, 빈크리스틴, 비노렐빈, 그리고 졸레드로네이트를 포함하지만 이들에 한정되지 않는 항암제의 전달을 제공한다.
다른 구체예에서, 생리활성 작용제는 siRNA이다. 본 발명의 RNAi 구조체는 염기쌍을 이루어 dsRNA RNA 영역을 형성하는 RNA를 발현하는 유전자(들)이다. 이들 RNA는 동일한 분자 또는 상이한 분자의 일부일 수 있다. 바람직한 구체예에서, RNAi 구조체는 루프 서열에 의해 분리된 2개의 상보성 서열을 인코딩하는 핵산 서열에 작동가능하게 연결된 프로모터를 포함한다. 이들 상보성 영역은 루프 서열에 의해 분리된 표적 RNA 서열에 상응한다. RNAi 구조체가 발현될 때, 결과의 RNA 분자의 상보성 영역은 서로 대합하여 이중 가닥 RNA 영역을 형성한다. 본 발명은 임의의 특정 길이의 루프 서열에 한정되지 않는다. 일부 바람직한 구체예에서, 루프 서열은 길이에서 약 4개 내지 약 20개 뉴클레오티드의 범위이다. 더욱 바람직한 구체예에서, 루프 서열은 길이에서 약 6개 내지 약 12개 뉴클레오티드이다. 다른 바람직한 구체예에서, dsRNA 영역은 길이에서 약 19개 내지 약 23개이다.
다른 구체예에서, dsRNA는 벡터로부터 2개의 별개의 가닥으로서 전사된 RNA로부터 형성된다. 다른 구체예에서, dsRNA를 형성하는데 이용되는 DNA의 2개의 가닥은 동일한 또는 2개의 상이한 이중나선에 속할 수 있는데, 여기서 이들은 각각 최소한 부분적으로 상보성 서열의 DNA 가닥을 형성한다. dsRNA가 이에 따라서 생산될 때, 전사되는 DNA 서열은 2개의 프로모터와 측면에서 접하는데, 이들 중에서 하나는 가닥 중에서 하나의 전사를 제어하고, 그리고 다른 하나는 상보성 가닥의 전사를 제어한다. 이들 2개의 프로모터는 동일하거나 상이할 수 있다. 일부 구체예에서, 각 단부에서 프로모터 서열이 제공되는 DNA 이중나선은 규정된 길이의 RNA를 직접적으로 산출할 수 있고, 그리고 쌍으로 연결되어 dsRNA를 형성할 수 있다. 가령, 본원에서 참조로서 편입되는 U.S. 특허 번호 5,795,715를 참조한다. RNA 이중나선 형성은 세포 내측 또는 외측에서 시작될 수 있다.
처리 후 결과의 siRNA는 2개의 평활 말단, 1개의 평활 말단 및 오버행을 갖는 1개의 단부, 또는 오버행을 갖는 2개의 단부를 포함할 수 있는 것으로 인식될 것이다. 일부 구체예에서, 오버행을 갖는 단부 또는 단부들은 1개 또는 2개 뉴클레오티드의 오버행을 포함한다. 무제한적 실례로서, 길이에서 23개 뉴클레오티드의 siRNA는 각 단부에서 2개 뉴클레오티드 오버행을 갖는 2개의 19mer을 포함한다. 다른 무제한적 실례로서, 길이에서 21개 뉴클레오티드의 siRNA는 각 단부에서 단일 뉴클레오티드 오버행을 갖는 2개의 19mer을 포함한다. 또 다른 무제한적 실례로서, 길이에서 22개 뉴클레오티드의 siRNA는 어느 단부에서도 오버행이 없는 2개의 22mer을 포함한다.
저해는 RNA의 이중나선 영역에 상응하는 뉴클레오티드 서열이 유전적 저해를 위해 표적화된다는 점에서 서열-특이적이다. 표적 유전자의 일부와 동일한 뉴클레오티드 서열을 내포하는 RNA 분자가 저해를 위해 선호된다. 표적 서열에 비하여 삽입, 결실 및 단일 점 돌연변이를 갖는 RNA 서열 역시 저해에 효과적인 것으로 밝혀졌다. 따라서, 서열 동일성은 당해 분야에서 공지된 서열 비교 및 정렬 알고리즘에 의해 (Gribskov and Devereux, Sequence Analysis Primer, Stockton Press, 1991 및 그 안에 인용된 참고문헌을 참조한다), 그리고 예로서, 디폴트 파라미터를 이용한 BESTFIT 소프트웨어 프로그램 (가령, University of Wisconsin Genetic Computing Group)에서 실행된 바와 같은 Smith-Waterman 알고리즘에 의해 뉴클레오티드 서열 사이에 차이 퍼센트를 계산함으로써 최적화될 수 있다. 저해성 RNA 및 표적 유전자의 일부 사이에 90%보다 큰 서열 동일성, 또는 심지어 100% 서열 동일성이 선호된다. 대안으로, RNA의 이중나선 영역은 표적 유전자 전사체의 일부와 혼성화할 수 있는 뉴클레오티드 서열로서 기능적으로 규정될 수 있다.
이용될 수 있는 dsRNA의 길이에는 상한선이 없다. 가령, dsRNA는 유전자의 약 21개 염기쌍 (bp)으로부터 유전자의 전장 또는 그 이상까지의 범위에서 변할 수 있다. 한 구체예에서, 본 발명의 방법에서 이용되는 dsRNA는 길이에서 약 1000 bp이다. 다른 구체예에서, dsRNA는 길이에서 약 500 bp이다. 또 다른 구체예에서, dsRNA는 길이에서 약 22 bp이다. 일부 바람직한 구체예에서, RNAi를 매개하는 서열은 약 21 내지 약 23개 뉴클레오티드이다. 본 발명의 단리된 iRNA는 표적 RNA의 분해를 매개한다.
본 발명의 이중 가닥 RNA는 이것이 표적 RNA에 대한 RNAi를 매개하는 능력을 가질 만큼 충분히 자연 RNA와 유사하기만 하면 된다. 한 구체예에서, 본 발명은 자신의 서열이 상응하는 특정한 mRNA의 개열을 주도하는, 변하는 길이의 RNA 분자에 관계한다. 이들 서열이 완벽하게 상응할 필요는 않지만, 상응은 상기 RNA가 표적 mRNA의 RNAi 개열을 주도할 수 있게 할 만큼 충분해야 한다. 특정한 구체예에서, 본 발명의 RNA 분자는 3' 히드록실 기를 포함한다.
E. 의료 장치
일부 구체예에서, 본 발명은 바람직하게는, 생리활성 화합물 (가령, 항균성 은 화합물, 항균성 갈륨 화합물, 또는 진통 화합물)을 포함하는, 전술된 바와 같은 원하는 크기와 모양의 자립형(freestanding) 마이크로시트를 제공한다. 마이크로시트는 바람직하게는, 기재 물질을 원하는 크기와 모양으로 절단하고 마이크로시트를 기재로부터 벗겨냄으로써 원하는 크기와 모양에서 제공될 수 있다. 마이크로시트는 이후, 생물학적 표면, 예를 들면, 상처, 또는 의학적 표면, 예를 들면, 의료 장치, 예를 들면, 상처 덮개의 표면에 적용될 수 있다.
일부 구체예에서, 마이크로시트는 매트릭스 물질의 첨가에 의한 기능화와 양립하는 상처 드레싱 또는 생물학적 상처 드레싱을 변형하는데 이용된다. 마이크로시트의 첨가에 의해 변형될 수 있는 상업적으로 가용한 상처 드레싱의 실례는 Biobrane™, 거즈, 접착 테이프, 붕대, 예를 들면, Band-Aids®, 그리고 COMPEEL®, DUODERM™, TAGADERM™ 및 OPSITE®를 포함하지만 이들에 한정되지 않는 다른 상업적으로 가용한 상처 드레싱을 포함하지만 이들에 한정되지 않는다. 일부 구체예에서, 본 발명은 중합체 다중층을 원하는 표면, 예를 들면, 연한 표면으로 이전하기 위한 방법을 제공한다. 이런 연한 표면은 피부, 상처 기부, 조직, 인공 피부 조직을 포함하는 인공 조직, 예를 들면, 기관형적으로 배양된 피부 조직, Apligraf®, Dermagraft®, Oasis®, Transcyte®, Cryoskin® 및 Myskin®, 인공 조직 매트릭스, 생체분자를 포함하는 겔, 상처 드레싱, 그리고 생물학적 상처 드레싱을 포함하지만 이들에 한정되지 않는다. 일부 구체예에서, 원하는 표면은 중합체 다중층, 예를 들면, 지지체에서 뒷받침된 중합체 다중층과 접촉되고, 그리고 중합체 다중층의 지지체로부터 원하는 표면으로의 전달을 달성하기 위해 압력이 적용된다. 일부 구체예에서, 압력은 약 10 내지 약 500 kPa이다. 일부 구체예에서, 전달은 용액의 실제적인 또는 완전한 부재에서 수행된다. 이런 건성 전달 과정은 생물학적 성분의 활성에 영향을 줄 수 있는 종류를 내포하는 수성 용액에 원하는 표면의 생물학적 성분의 노출을 수반하지 않는다. 일부 구체예에서, 전달은 가스상을 통해 수행된다. 일부 구체예에서, 전달은 습도가 100%의 포화도보다 낮은 환경에서 수행된다. 일부 구체예에서, 전달은 액체수의 부재에서 수행된다.
따라서, 일부 구체예에서, 본 발명은 상처에 정향된 표면을 갖는 지지체 물질을 포함하는 상처 드레싱을 제공하는데, 여기서 상처에 정향된 표면은 본 발명의 마이크로시트 물질로 변형된다. 상처에 적용될 때, 매트릭스 물질로 변형된 지지체 물질의 표면은 상처 기부와 접촉된다.
일부 구체예에서, 지지체는 생물학적 상처 드레싱이다. 일부 구체예에서, 생물학적 상처 드레싱은 예로서, 상처 표면과 접촉하여 배치될 수 있는 세포 (가령, 각질세포 또는 섬유모세포 및 이들의 조합) 및/또는 한 가지 또는 그 이상의 생체분자 또는 생체분자의 단편을 포함하거나, 이들로 코팅되거나, 또는 이들을 통합하는 유형의 상처 드레싱이다. 생체분자는 한 가지 또는 그 이상의 생체분자를 포함하는 인공 조직 매트릭스의 형태에서 제공될 수 있다. 이런 생체분자의 실례는 콜라겐, 글리코사미노글리칸, 히알루론산, 라미닌, 비트로넥틴, 섬유결합소, 케라틴, 항균성 폴리펩티드, 그리고 이들의 조합을 포함하지만 이들에 한정되지 않는다. 적합한 생물학적 상처 드레싱의 실례는 BIOBRANE™, Integra™, Apligraf®, Dermagraft®, Oasis®, Transcyte®, Cryoskin® 및 Myskin®을 포함하지만 이들에 한정되지 않는다.
일부 구체예에서, 마이크로시트는 지지체 물질, 예를 들면, 직물, 바람직하게는 중합성 직물, 예를 들면, 나일론 직물에서 뒷받침된 탄성중합체 필름 (가령, 실리콘 필름)으로 구축된 생합성적 상처 드레싱을 변형하는데 이용된다. 일부 구체예에서, 직물은 최소한 부분적으로, 필름 (가령, BioBrane™) 내로 묻힌다. 일부 구체예에서, 탄성중합체 필름은 한 가지 또는 그 이상의 생체재료, 예를 들면, 콜라겐, 케라틴, 섬유결합소, 비트로넥틴, 라미닌, 그리고 이들의 조합으로 코팅된다. 따라서, 직물은 생체재료 (가령, 콜라겐)이 결합된, 바람직하게는 화학적으로 결합된 복잡한 3-D 구조를 상처 기부에 제공한다. 일부 바람직한 구체예에서, 상처에 제공된 표면은 전술된 바와 같은 마이크로시트 물질로 더욱 변형된다. 일부 바람직한 구체예에서, 마이크로시트 물질은 바람직하게는, 은 나노입자, 원소성 은 및 은 내포 화합물, 예를 들면, 은 술파디아진 및/또는 갈륨 이온 및 관련된 화합물 중에서 한 가지 또는 그 이상에서 선택되고, 그리고 바람직하게는, 전술된 농도 범위에서 포함되는 생리활성 작용제를 포함하는 고분자전해질 막이다. 일부 구체예에서, 마이크로시트는 나노규모 또는 마이크로규모 입자를 더욱 포함한다.
일부 구체예에서, 마이크로시트는 바람직하게는, 상처에 접촉할 흡수성 패드 의 표면상에서, 상처에 유착을 예방하는 물질 (다시 말하면, 비유착성 물질)로 처리되거나 또는 코팅되는, 또는 비유착성 물질, 예를 들면, Teflon®의 층을 포함하는, 접착성 부분 (가령, 접착성 스트립) 및 흡수성 물질을 포함하는 접착성 붕대를 변형하는데 이용된다. 일부 구체예에서, 지지체 물질은 바람직하게는, 상처에 접촉할 흡수성 패드의 표면상에서, 상처에 유착을 예방하는 물질 (다시 말하면, 비유착성 물질)로 처리되거나 또는 코팅되는, 또는 비유착성 물질, 예를 들면, Teflon® 또는 다른 적합한 물질의 층을 포함하는 흡수성 패드 (가령, 거즈 패드 또는 중합체 거품)이다. 일부 구체예에서, 비접착성 물질 또는 층은 통기성이다. 일부 구체예에서, 상처 드레싱은 겔-형성 작용제, 예를 들면, 수성콜로이드, 예를 들면, 나트륨 카르복시메틸셀룰로오스를 포함한다. 일부 구체예에서, 흡수성 패드 또는 겔-형성 작용제는 방수성 및/또는 통기성인 물질에 부착된다. 실례는 반투성 폴리우레탄 필름을 포함하지만 이들에 한정되지 않는다. 방수성 및/또는 통기성 물질은 붕대를 개체의 피부에 접착하기 위한 접착성 물질을 더욱 포함할 수 있다. 방수성 및/또는 통기성 물질은 바람직하게는, 접착성 붕대 또는 패드의 외측 표면을 형성한다, 다시 말하면, 상처에 접촉하는 매트릭스를 포함하는 표면의 정반대 표면이다. 이런 접착성 붕대 및 흡수성 패드의 실례는 상처 드레싱의 Band-Aid® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 Nexcare® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 Kendall Curity Tefla® 라인으로부터 접착성 붕대 및 비접착성 패드, 상처 드레싱의 Tegaderm® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 Steri-Strip® 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 COMFEEL® 라인, 접착성 붕대와 패드, 상처 드레싱의 Duoderm® 라인, 접착성 붕대와 패드, 상처 드레싱의 TEGADERM™ 라인, 접착성 붕대와 패드, 상처 드레싱의 OPSITE® 라인, 접착성 붕대와 패드, 상처 드레싱의 Allevyn™ 라인으로부터 접착성 붕대와 패드, 상처 드레싱의 Duoderm® 라인으로부터 접착성 붕대와 패드, 그리고 상처 드레싱의 Xeroform® 라인으로부터 접착성 붕대와 패드를 포함하지만 이들에 한정되지 않는다.
일부 구체예에서, 나노규모 중합체 매트릭스가 의료 장치, 예를 들면, 외과적 그물망을 변형하는데 이용된다. 아래에 설명된 바와 같은 매트릭스의 첨가에 의해 변형될 수 있는 상업적으로 가용한 외과용 그물망의 실례는 폴리프로필렌, 폴리에스테르, 폴리테트라플루오로에틸렌 그물망, 또는 흡수성 바이오메쉬, 또는 ULTRAPRO™ 그물망, PROCEED™ 그물망, PROLENE™ 폴리프로필렌 그물망, Ethicon Physiomesh™, MERSILENE™ 폴리에스테르 그물망, PARIETEX™ 그물망, DOLPHIN™ 폴리프로필렌 그물망, GORE INFINIT™ 그물망, PERFIX™, KUGEL™, 3DMAX™, BARD™, VISILEX™, XENMATRIX™, ALLOMAX™, SURGISIS BIODESIGN™ 및 TIGR MATRIX™을 포함하지만 이들에 한정되지 않는 생물학적 그물망 (바이오메쉬)을 포함하지만 이들에 한정되지 않는다.
G. 매트릭스의 이용
일부 구체예에서, 전술된 바와 같은 마이크로시트는 상처 수축에 의해 계측될 때, 상처 치유가 가속되도록 하는 조건 하에 상처에 적용된다. 본 발명의 일부 구체예에서, 한 가지 또는 그 이상의 생리활성 작용제를 내포하는 마이크로시트는 상처 또는 조직으로 이전 후, 희생 중합체 층이 나노규모 중합체 층의 위에 놓이도록 상처 또는 조직으로 이전된다. 일부 구체예에서, 상처 드레싱은 희생 중합체 층이 수성 액체에서 용해되거나 또는 부분적으로 용해되기 전 또는 용해된 후, 희생 중합체 층의 위에 배치된다. 일부 구체예에서, 희생 층이 상처에서 완전하게 용해되고, 그리고 PEM이 상처 조직 및 상처 위에 배치된 일차/이차 상처 드레싱과 직접적으로 접촉하도록, 한 가지 또는 그 이상의 생리활성 작용제 및 분해가능한 희생 두 번째 중합체 층을 내포하는 PEM으로 만들어진 나노규모 중합체 매트릭스가 상처 또는 조직 표면으로 이전된다. 일부 구체예에서, 일차 드레싱은 생물학적 드레싱이고, 그리고 나노규모 중합체 매트릭스는 상처 기부에서 생물학적 드레싱의 통합을 방해하지 않는다.
일부 구체예에서, 마이크로시트는 바람직하게는, 마이크로시트가 무균 패키지 내에 들어있는 키트로서 제공된다. 일부 구체예에서, 키트에서 제공되는 마이크로시트는 적어도 하나의 생리활성 작용제를 포함한다. 다른 구체예에서, 키트는 생리활성 작용제 및 상처에 적용에 앞서, 생리활성 작용제를 매트릭스에 적용하는 것으로부터 사용설명서를 포함한다.
전술된 바와 같은, 한 가지 또는 그 이상의 생리활성 작용제를 갖는 마이크로시트는 모든 유형의 상처에 적용될 수 있다. 게다가, 한 가지 또는 그 이상의 생리활성 작용제를 갖는 상처 조절제는 손상된 피부, 점막, 체강, 그리고 뼈, 조직 등의 속면에 적용될 수 있다. 한 가지 또는 그 이상의 생리활성 작용제를 갖는 마이크로시트는 자상, 찰과상, 궤양, 외과적 절개 부위, 화상과 같은 상처에서, 그리고 다른 유형의 조직 손상을 치료하는데 이용될 수 있다. 본 발명의 일부 구체예에서, 마이크로시트는 상처 치유를 증강한다. 본 발명은 상처 치유가 다양한 방식으로 증강될 수 있는 것으로 예기한다. 일부 구체예에서, 이들 조성물과 방법은 기능 및 미용술에 가장 우호적이도록 상처의 구축을 최소화한다. 일부 구체예에서, 이들 조성물과 방법은 기능 및 미용술에 가장 우호적이도록 상처 구축을 증진한다. 일부 구체예에서, 이들 조성물과 방법은 혈관화를 증진한다. 일부 구체예에서, 이들 조성물과 방법은 혈관화를 저해한다. 일부 구체예에서, 이들 조성물과 방법은 섬유형성을 증진한다. 일부 구체예에서, 이들 조성물과 방법은 섬유형성을 저해한다. 일부 구체예에서, 이들 조성물과 방법은 상피 덮음을 증진한다. 일부 구체예에서, 이들 조성물과 방법은 상피 덮음을 저해한다. 일부 구체예에서, 본 발명의 조성물과 방법은 상처 환경에서 또는 상처의 바로 인근에서 세포의 한 가지 또는 그 이상의 성질을 조정한다. 조정되는, 예를 들면, 증가되거나 또는 감소되는 성질은 유착, 이주, 증식, 분화, 세포외 기질 분비, 식균작용, MMP 활성, 수축, 그리고 이들의 조합을 포함하지만 이들에 한정되지 않는다. 본 발명의 마이크로시트는 예로서, 층을 보호하거나 또는 추가 흡습을 제공하는 것이 바람직하면, 이차 드레싱 또는 붕대로 덮일 수 있다.
실험
아래의 실시예는 본원에서 청구된 화합물, 조성물, 물품, 장치 및/또는 방법이 어떻게 만들어지고 평가되는 지에 관한 완전한 개시와 설명을 당업자에게 제공하기 위해 본 발명을 더욱 예시하는 역할을 하고, 그리고 발명의 범위를 제한하는 것으로 의도되지 않는다. 이들 실시예는 발명의 범위를 제한하는 것으로 의도되지 않는다.
실시예 1
A. 코팅 및 박리
재료.
1. pH = 6.8 - 7.2에서 다가양이온 (폴리알릴아민 염산염, PAH)의 20 mM 용액.
2. pH = 2.1 - 2.3에서 다가음이온 (폴리아크릴산, PAA)의 20 mM 용액.
3. 활성제 (질산은)의 10 mM 용액.
4. 환원제 (수소화붕소나트륨)의 1 mM 용액.
5. 중량 기초에서 폴리비닐 알코올의 21% 수성 용액.
6. 고분자전해질 다중층을 적층하기 위한 기재로서 박리 층으로 피복된 두께 1 - 10 mil (1 mil = 1/1000 인치)의 가요성 중합성 시트.
절차.
1. 각 항온처리 단계 후 헹굼 및 건조에 의해 매개된, 각각 6 분 동안 PAH 및 PAA의 수성 용액에서 기재를 항온처리함에 의한 층상 어셈블리를 통해 PAH 및 PAA의 10개 이중층을 포함하는 고분자전해질 다중층을 코팅한다.
2. 다음에 의해, 은을 고분자전해질 다중층 코팅 내로 부하한다:
a. 기재에서 뒷받침된 고분자전해질 다중층을 질산은 용액에서 30 분 동안 항온처리, 그 이후에 물로 헹굼 및 건조.
수소화붕소나트륨 용액에서 1 분 동안 항온처리, 그 이후에 헹굼.
b. (a.)를 반복
c. 기재에서 뒷받침된 고분자전해질 다중층을 질산은 용액에서 30 분 동안 항온처리, 그 이후에 물로 헹굼 및 건조.
3. 기재에서 뒷받침된 은 부하된 고분자전해질 다중층 위에 20 μm (건조 두께) PVA 필름을 주조한다.
4. 코팅을 기재로부터 벗겨냄으로써 자립형 필름을 획득한다.
결과.
각 기재는 다음의 예/아니오 검사에 근거하여 평가되었고, 그리고 결과는 아래의 표에서 기록된다:
1. 시각적 검사에 근거하여, 고분자전해질 다중층 코팅은 절차 단계 # 1의 완결 후 기재로부터 부분적으로 또는 완전하게 분리되었는가?
2. 시각적 검사에 근거하여, 고분자전해질 다중층 코팅은 절차 단계 # 2의 완결 후 기재로부터 부분적으로 또는 완전하게 분리되었는가?
3. 시각적 검사에 근거하여, 고분자전해질 다중층 코팅은 절차 단계 # 4의 완결 후 기재로부터 PVA 코팅으로 완전하게 이전되었는가?
*검사 방법 가용하지 않음
**Saint Gobain 검사 #125 습성 확산 박리
B. 과정
재료
1. pH = 6.8 - 7.2에서 다가양이온 (폴리알릴아민 염산염, PAH, 150 kDa)의 20 mM 용액. (달리 언급되지 않으면)
2. pH = 2.1 - 2.3에서 다가음이온 (폴리아크릴산, PAA, 100 kDa)의 20 mM 용액. (달리 언급되지 않으면)
3. 활성제 (질산은)의 S mM 용액.
4. 환원제 (수소화붕소나트륨)의 R mM 용액.
5. 폴리비닐 알코올의 21.25% 수성 용액.
6. 고분자전해질 다중층을 적층하기 위한 기재로서 박리 층으로 피복된 가요성 중합성 시트.
절차
1. 각 항온처리 단계 후 헹굼 및 건조에 의해 매개된, 각각 X s (또는 분) 동안 PAH 및 PAA의 수성 용액에서 기재를 항온처리함에 의한 층상 어셈블리를 통해 PAH 및 PAA의 N 이중층을 포함하는 고분자전해질 다중층을 코팅한다.
2. 다음에 의해, 은을 고분자전해질 다중층 코팅 내로 부하한다:
a. 기재에서 뒷받침된 고분자전해질 다중층을 질산은 용액에서
Y s (또는 분) 동안 항온처리, 그 이후에 물로 헹굼 및 건조.
수소화붕소나트륨 용액에서 1 분 동안 항온처리, 그 이후에 헹굼.
b. (a.)를 n회 반복
c. 기재에서 뒷받침된 고분자전해질 다중층을 질산은 용액에서
Y s (또는 분) 분 동안 항온처리, 그 이후에 물로 헹굼 및 건조.
3. 필름으로부터 은을 질산 내로 추출하고, 그리고 유도성으로 연계된 플라즈마 - 광학적 방출 분광법 (ICP-OES)을 이용하여 추출물을 분석함으로써 필름에서 은 부하를 계측한다.
결과
1. Y = 30 분, N = 10, n = 2, R = 1 mM
표: 고분자전해질 다중층에서 은 부하 (μg/cm2):
2. X = 6 분, n = 2, R = 1 mM
표: 고분자전해질 다중층에서 은 부하 (μg/cm2):
3. X = 6 분,
표: 고분자전해질 다중층에서 은 부하 (μg/cm2):
4. X = 6 분, Y = 60 분, N = 10, n = 2, S = 10 mM, R = 1 mM, Mw PAH = 150 kDa
표: 고분자전해질 다중층에서 은 부하 (μg/cm2):
상기 명세서에서 열거된 모든 간행물과 특허는 본원에서 전체적으로 참조로서 편입된다. 본 발명의 설명된 방법 및 시스템의 다양한 변형과 변이는 발명의 범위와 사상으로부터 벗어나지 않으면서 당업자에게 명백할 것이다. 비록 본 발명이 특정한 바람직한 구체예와 관련하여 설명되긴 했지만, 청구된 바와 같은 발명은 이런 특정한 구체예에 부당하게 한정되지 않는 것으로 이해될 것이다. 실제로, 당업자에게 명백한, 본 발명을 실시하기 위한 설명된 방식의 다양한 변경은 하기 청구항의 범위 내에 있는 것으로 의도된다.
SEQUENCE LISTING
<110> Imbed Biosciences Inc.
<120> METHODS AND COMPOSITIONS FOR WOUND HEALING
<130> IMBED-34937/WO-1/ORD
<150> US 62/368,646
<151> 2016-07-29
<160> 95
<170> PatentIn version 3.5
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Ser Trp Leu Ser Lys Thr Ala Lys Lys Leu Glu Asn Ser Ala Lys Lys
1 5 10 15
Arg Ile Ser Glu Gly Ile Ala Ile Ala Ile Gln Gly Gly Pro Arg
20 25 30
<210> 13
<211> 13
<212> PRT
<213> Bos Taurus
<400> 13
Ile Leu Pro Trp Lys Trp Pro Trp Trp Pro Trp Arg Arg
1 5 10
<210> 14
<211> 34
<212> PRT
<213> Lactococcus lactis
<400> 14
Ile Thr Ser Ile Ser Leu Cys Thr Pro Gly Cys Lys Thr Gly Ala Leu
1 5 10 15
Met Gly Cys Asn Met Lys Thr Ala Thr Cys His Cys Ser Ile His Val
20 25 30
Ser Lys
<210> 15
<211> 20
<212> PRT
<213> Rana catesbeiana
<400> 15
Phe Leu Gly Gly Leu Ile Lys Ile Val Pro Ala Met Ile Cys Ala Val
1 5 10 15
Thr Lys Lys Cys
20
<210> 16
<211> 25
<212> PRT
<213> Bos Taurus
<400> 16
Phe Lys Cys Arg Arg Trp Gln Trp Arg Met Lys Lys Leu Gly Ala Pro
1 5 10 15
Ser Ile Thr Cys Val Arg Arg Ala Phe
20 25
<210> 17
<211> 19
<212> PRT
<213> Sus scrofa
<220>
<221> misc_feature
<222> (19)..(19)
<223> Xaa can be any naturally occurring amino acid
<400> 17
Arg Gly Gly Arg Leu Cys Tyr Cys Arg Arg Arg Phe Cys Val Cys Val
1 5 10 15
Gly Arg Xaa
<210> 18
<211> 16
<212> PRT
<213> Sus scrofa
<400> 18
Gly Gly Arg Leu Cys Tyr Cys Arg Arg Arg Phe Cys Ile Cys Val Gly
1 5 10 15
<210> 19
<211> 51
<212> PRT
<213> Homo sapiens
<400> 19
Met Lys Phe Phe Val Phe Ala Leu Ile Leu Ala Leu Met Leu Ser Met
1 5 10 15
Thr Gly Ala Asp Ser His Ala Lys Arg His His Gly Tyr Lys Arg Lys
20 25 30
Phe His Glu Lys His His Ser His Arg Gly Tyr Arg Ser Asn Tyr Leu
35 40 45
Tyr Asp Asn
50
<210> 20
<211> 38
<212> PRT
<213> Macaca fascicularis
<400> 20
Asp Ser His Glu Glu Arg His His Gly Arg His Gly His His Lys Tyr
1 5 10 15
Gly Arg Lys Phe His Glu Lys His His Ser His Arg Gly Tyr Arg Ser
20 25 30
Asn Tyr Leu Tyr Asp Asn
35
<210> 21
<211> 33
<212> PRT
<213> Phyllomedusa sauvagei
<400> 21
Ala Leu Trp Lys Thr Met Leu Lys Lys Leu Gly Thr Met Ala Leu His
1 5 10 15
Ala Gly Lys Ala Ala Leu Gly Ala Ala Ala Asp Thr Ile Ser Gln Thr
20 25 30
Gln
<210> 22
<211> 34
<212> PRT
<213> Phyllomedusa sauvagei
<400> 22
Ala Leu Trp Phe Thr Met Leu Lys Lys Leu Gly Thr Met Ala Leu His
1 5 10 15
Ala Gly Lys Ala Ala Leu Gly Ala Ala Ala Asn Thr Ile Ser Gln Gly
20 25 30
Thr Gln
<210> 23
<211> 30
<212> PRT
<213> Phyllomedusa sauvagei
<400> 23
Ala Leu Trp Lys Asn Met Leu Lys Gly Ile Gly Lys Leu Ala Gly Lys
1 5 10 15
Ala Ala Leu Gly Ala Val Lys Lys Leu Val Gly Ala Glu Ser
20 25 30
<210> 24
<211> 21
<212> PRT
<213> Misgurnus anguillicaudatus
<400> 24
Arg Gln Arg Val Glu Glu Leu Ser Lys Phe Ser Lys Lys Gly Ala Ala
1 5 10 15
Ala Arg Arg Arg Lys
20
<210> 25
<211> 27
<212> PRT
<213> Apis mellifera
<400> 25
Gly Ile Gly Ala Val Leu Lys Val Leu Thr Thr Gly Leu Pro Ala Leu
1 5 10 15
Ile Ser Trp Ile Ser Arg Lys Lys Arg Gln Gln
20 25
<210> 26
<211> 33
<212> PRT
<213> Pardachirus pavoninus
<400> 26
Gly Phe Phe Ala Leu Ile Pro Lys Ile Ile Ser Ser Pro Leu Phe Lys
1 5 10 15
Thr Leu Leu Ser Ala Val Gly Ser Ala Leu Ser Ser Ser Gly Glu Gln
20 25 30
Glu
<210> 27
<211> 33
<212> PRT
<213> Pardachirus pavoninus
<400> 27
Gly Phe Phe Ala Leu Ile Pro Lys Ile Ile Ser Ser Pro Ile Phe Lys
1 5 10 15
Thr Leu Leu Ser Ala Val Gly Ser Ala Leu Ser Ser Ser Gly Gly Gln
20 25 30
Glu
<210> 28
<211> 176
<212> PRT
<213> Bos Taurus
<400> 28
Met Glu Thr Gln Arg Ala Ser Leu Ser Leu Gly Arg Cys Ser Leu Trp
1 5 10 15
Leu Leu Leu Leu Gly Leu Val Leu Pro Ser Ala Ser Ala Gln Ala Leu
20 25 30
Ser Tyr Arg Glu Ala Val Leu Arg Ala Val Asp Gln Phe Asn Glu Arg
35 40 45
Ser Ser Glu Ala Asn Leu Tyr Arg Leu Leu Glu Leu Asp Pro Thr Pro
50 55 60
Asn Asp Asp Leu Asp Pro Gly Thr Arg Lys Pro Val Ser Phe Arg Val
65 70 75 80
Lys Glu Thr Asp Cys Pro Arg Thr Ser Gln Gln Pro Leu Glu Gln Cys
85 90 95
Asp Phe Lys Glu Asn Gly Leu Val Lys Gln Cys Val Gly Thr Val Thr
100 105 110
Leu Asp Pro Ser Asn Asp Gln Phe Asp Ile Asn Cys Asn Glu Leu Gln
115 120 125
Ser Val Arg Phe Arg Pro Pro Ile Arg Arg Pro Pro Ile Arg Pro Pro
130 135 140
Phe Tyr Pro Pro Phe Arg Pro Pro Ile Arg Pro Pro Ile Phe Pro Pro
145 150 155 160
Ile Arg Pro Pro Phe Arg Pro Pro Leu Gly Pro Phe Pro Gly Arg Arg
165 170 175
<210> 29
<211> 155
<212> PRT
<213> Bos Taurus
<400> 29
Met Glu Thr Pro Arg Ala Ser Leu Ser Leu Gly Arg Trp Ser Leu Trp
1 5 10 15
Leu Leu Leu Leu Gly Leu Ala Leu Pro Ser Ala Ser Ala Gln Ala Leu
20 25 30
Ser Tyr Arg Glu Ala Val Leu Arg Ala Val Asp Gln Leu Asn Glu Gln
35 40 45
Ser Ser Glu Pro Asn Ile Tyr Arg Leu Leu Glu Leu Asp Gln Pro Pro
50 55 60
Gln Asp Asp Glu Asp Pro Asp Ser Pro Lys Arg Val Ser Phe Arg Val
65 70 75 80
Lys Glu Thr Val Cys Ser Arg Thr Thr Gln Gln Pro Pro Glu Gln Cys
85 90 95
Asp Phe Lys Glu Asn Gly Leu Leu Lys Arg Cys Glu Gly Thr Val Thr
100 105 110
Leu Asp Gln Val Arg Gly Asn Phe Asp Ile Thr Cys Asn Asn His Gln
115 120 125
Ser Ile Arg Ile Thr Lys Gln Pro Trp Ala Pro Pro Gln Ala Ala Arg
130 135 140
Leu Cys Arg Ile Val Val Ile Arg Val Cys Arg
145 150 155
<210> 30
<211> 29
<212> PRT
<213> Ceratitis capitata
<400> 30
Ser Ile Gly Ser Ala Leu Lys Lys Ala Leu Pro Val Ala Lys Lys Ile
1 5 10 15
Gly Lys Ile Ala Leu Pro Ile Ala Lys Ala Ala Leu Pro
20 25
<210> 31
<211> 29
<212> PRT
<213> Ceratitis capitata
<400> 31
Ser Ile Gly Ser Ala Phe Lys Lys Ala Leu Pro Val Ala Lys Lys Ile
1 5 10 15
Gly Lys Ala Ala Leu Pro Ile Ala Lys Ala Ala Leu Pro
20 25
<210> 32
<211> 170
<212> PRT
<213> Homo sapiens
<400> 32
Met Lys Thr Gln Arg Asn Gly His Ser Leu Gly Arg Trp Ser Leu Val
1 5 10 15
Leu Leu Leu Leu Gly Leu Val Met Pro Leu Ala Ile Ile Ala Gln Val
20 25 30
Leu Ser Tyr Lys Glu Ala Val Leu Arg Ala Ile Asp Gly Ile Asn Gln
35 40 45
Arg Ser Ser Asp Ala Asn Leu Tyr Arg Leu Leu Asp Leu Asp Pro Arg
50 55 60
Pro Thr Met Asp Gly Asp Pro Asp Thr Pro Lys Pro Val Ser Phe Thr
65 70 75 80
Val Lys Glu Thr Val Cys Pro Arg Thr Thr Gln Gln Ser Pro Glu Asp
85 90 95
Cys Asp Phe Lys Lys Asp Gly Leu Val Lys Arg Cys Met Gly Thr Val
100 105 110
Thr Leu Asn Gln Ala Arg Gly Ser Phe Asp Ile Ser Cys Asp Lys Asp
115 120 125
Asn Lys Arg Phe Ala Leu Leu Gly Asp Phe Phe Arg Lys Ser Lys Glu
130 135 140
Lys Ile Gly Lys Glu Phe Lys Arg Ile Val Gln Arg Ile Lys Asp Phe
145 150 155 160
Leu Arg Asn Leu Val Pro Arg Thr Glu Ser
165 170
<210> 33
<211> 170
<212> PRT
<213> Equus caballus
<400> 33
Met Glu Thr Gln Arg Asn Thr Arg Cys Leu Gly Arg Trp Ser Pro Leu
1 5 10 15
Leu Leu Leu Leu Gly Leu Val Ile Pro Pro Ala Thr Thr Gln Ala Leu
20 25 30
Ser Tyr Lys Glu Ala Val Leu Arg Ala Val Asp Gly Leu Asn Gln Arg
35 40 45
Ser Ser Asp Glu Asn Leu Tyr Arg Leu Leu Glu Leu Asp Pro Leu Pro
50 55 60
Lys Gly Asp Lys Asp Ser Asp Thr Pro Lys Pro Val Ser Phe Met Val
65 70 75 80
Lys Glu Thr Val Cys Pro Arg Ile Met Lys Gln Thr Pro Glu Gln Cys
85 90 95
Asp Phe Lys Glu Asn Gly Leu Val Lys Gln Cys Val Gly Thr Val Ile
100 105 110
Leu Asp Pro Val Lys Asp Tyr Phe Asp Ala Ser Cys Asp Glu Pro Gln
115 120 125
Arg Val Lys Arg Phe His Ser Val Gly Ser Leu Ile Gln Arg His Gln
130 135 140
Gln Met Ile Arg Asp Lys Ser Glu Ala Thr Arg His Gly Ile Arg Ile
145 150 155 160
Ile Thr Arg Pro Lys Leu Leu Leu Ala Ser
165 170
<210> 34
<211> 159
<212> PRT
<213> Bos Taurus
<400> 34
Met Glu Thr Gln Arg Ala Ser Leu Ser Leu Gly Arg Trp Ser Leu Trp
1 5 10 15
Leu Leu Leu Leu Gly Leu Ala Leu Pro Ser Ala Ser Ala Gln Ala Leu
20 25 30
Ser Tyr Arg Glu Ala Val Leu Arg Ala Val Asp Gln Leu Asn Glu Lys
35 40 45
Ser Ser Glu Ala Asn Leu Tyr Arg Leu Leu Glu Leu Asp Pro Pro Pro
50 55 60
Lys Glu Asp Asp Glu Asn Pro Asn Ile Pro Lys Pro Val Ser Phe Arg
65 70 75 80
Val Lys Glu Thr Val Cys Pro Arg Thr Ser Gln Gln Ser Pro Glu Gln
85 90 95
Cys Asp Phe Lys Glu Asn Gly Leu Leu Lys Glu Cys Val Gly Thr Val
100 105 110
Thr Leu Asp Gln Val Gly Ser Asn Phe Asp Ile Thr Cys Ala Val Pro
115 120 125
Gln Ser Val Gly Gly Leu Arg Ser Leu Gly Arg Lys Ile Leu Arg Ala
130 135 140
Trp Lys Lys Tyr Gly Pro Ile Ile Val Pro Ile Ile Arg Ile Gly
145 150 155
<210> 35
<211> 156
<212> PRT
<213> Equus caballus
<400> 35
Met Glu Thr Gln Arg Asn Thr Arg Cys Leu Gly Arg Trp Ser Pro Leu
1 5 10 15
Leu Leu Leu Leu Gly Leu Val Ile Pro Pro Ala Thr Thr Gln Ala Leu
20 25 30
Ser Tyr Lys Glu Ala Val Leu Arg Ala Val Asp Gly Leu Asn Gln Arg
35 40 45
Ser Ser Asp Glu Asn Leu Tyr Arg Leu Leu Glu Leu Asp Pro Leu Pro
50 55 60
Lys Gly Asp Lys Asp Ser Asp Thr Pro Lys Pro Val Ser Phe Met Val
65 70 75 80
Lys Glu Thr Val Cys Pro Arg Ile Met Lys Gln Thr Pro Glu Gln Cys
85 90 95
Asp Phe Lys Glu Asn Gly Leu Val Lys Gln Cys Val Gly Thr Val Ile
100 105 110
Leu Gly Pro Val Lys Asp His Phe Asp Val Ser Cys Gly Glu Pro Gln
115 120 125
Arg Val Lys Arg Phe Gly Arg Leu Ala Lys Ser Phe Leu Arg Met Arg
130 135 140
Ile Leu Leu Pro Arg Arg Lys Ile Leu Leu Ala Ser
145 150 155
<210> 36
<211> 160
<212> PRT
<213> Ovis aries
<400> 36
Met Glu Thr Gln Arg Ala Ser Leu Ser Leu Gly Arg Cys Ser Leu Trp
1 5 10 15
Leu Leu Leu Leu Gly Leu Ala Leu Pro Ser Ala Ser Ala Gln Val Leu
20 25 30
Ser Tyr Arg Glu Ala Val Leu Arg Ala Ala Asp Gln Leu Asn Glu Lys
35 40 45
Ser Ser Glu Ala Asn Leu Tyr Arg Leu Leu Glu Leu Asp Pro Pro Pro
50 55 60
Lys Gln Asp Asp Glu Asn Ser Asn Ile Pro Lys Pro Val Ser Phe Arg
65 70 75 80
Val Lys Glu Thr Val Cys Pro Arg Thr Ser Gln Gln Pro Ala Glu Gln
85 90 95
Cys Asp Phe Lys Glu Asn Gly Leu Leu Lys Glu Cys Val Gly Thr Val
100 105 110
Thr Leu Asp Gln Val Arg Asn Asn Phe Asp Ile Thr Cys Ala Glu Pro
115 120 125
Gln Ser Val Arg Gly Leu Arg Arg Leu Gly Arg Lys Ile Ala His Gly
130 135 140
Val Lys Lys Tyr Gly Pro Thr Val Leu Arg Ile Ile Arg Ile Ala Gly
145 150 155 160
<210> 37
<211> 12
<212> PRT
<213> Bos Taurus
<400> 37
Arg Leu Cys Arg Ile Val Val Ile Arg Val Cys Arg
1 5 10
<210> 38
<211> 30
<212> PRT
<213> Homo sapiens
<400> 38
Ala Cys Tyr Cys Arg Ile Pro Ala Cys Ile Ala Gly Glu Arg Arg Tyr
1 5 10 15
Gly Thr Cys Ile Tyr Gln Gly Arg Leu Trp Ala Phe Cys Cys
20 25 30
<210> 39
<211> 29
<212> PRT
<213> Homo sapiens
<400> 39
Cys Tyr Cys Arg Ile Pro Ala Cys Ile Ala Gly Glu Arg Arg Tyr Gly
1 5 10 15
Thr Cys Ile Tyr Gln Gly Arg Leu Trp Ala Phe Cys Cys
20 25
<210> 40
<211> 30
<212> PRT
<213> Homo sapiens
<400> 40
Asp Cys Tyr Cys Arg Ile Pro Ala Cys Ile Ala Gly Glu Arg Arg Tyr
1 5 10 15
Gly Thr Cys Ile Tyr Gln Gly Arg Leu Trp Ala Phe Cys Cys
20 25 30
<210> 41
<211> 33
<212> PRT
<213> Homo sapiens
<400> 41
Val Cys Ser Cys Arg Leu Val Phe Cys Arg Arg Thr Glu Leu Arg Val
1 5 10 15
Gly Asn Cys Leu Ile Gly Gly Val Ser Phe Thr Tyr Cys Cys Thr Arg
20 25 30
Val
<210> 42
<211> 33
<212> PRT
<213> Oryctolagus cuniculus
<400> 42
Val Val Cys Ala Cys Arg Arg Ala Leu Cys Leu Pro Arg Glu Arg Arg
1 5 10 15
Ala Gly Phe Cys Arg Ile Arg Gly Arg Ile His Pro Leu Cys Cys Arg
20 25 30
Arg
<210> 43
<211> 33
<212> PRT
<213> Oryctolagus cuniculus
<400> 43
Val Val Cys Ala Cys Arg Arg Ala Leu Cys Leu Pro Leu Glu Arg Arg
1 5 10 15
Ala Gly Phe Cys Arg Ile Arg Gly Arg Ile His Pro Leu Cys Cys Arg
20 25 30
Arg
<210> 44
<211> 34
<212> PRT
<213> Oryctolagus cuniculus
<400> 44
Gly Ile Cys Ala Cys Arg Arg Arg Phe Cys Pro Asn Ser Glu Arg Phe
1 5 10 15
Ser Gly Tyr Cys Arg Val Asn Gly Ala Arg Tyr Val Arg Cys Cys Ser
20 25 30
Arg Arg
<210> 45
<211> 34
<212> PRT
<213> Oryctolagus cuniculus
<400> 45
Gly Arg Cys Val Cys Arg Lys Gln Leu Leu Cys Ser Tyr Arg Glu Arg
1 5 10 15
Arg Ile Gly Asp Cys Lys Ile Arg Gly Val Arg Phe Pro Phe Cys Cys
20 25 30
Pro Arg
<210> 46
<211> 34
<212> PRT
<213> Oryctolagus cuniculus
<400> 46
Val Ser Cys Thr Cys Arg Arg Phe Ser Cys Gly Phe Gly Glu Arg Ala
1 5 10 15
Ser Gly Ser Cys Thr Val Asn Gly Gly Val Arg His Thr Leu Cys Cys
20 25 30
Arg Arg
<210> 47
<211> 33
<212> PRT
<213> Oryctolagus cuniculus
<400> 47
Val Phe Cys Thr Cys Arg Gly Phe Leu Cys Gly Ser Gly Glu Arg Ala
1 5 10 15
Ser Gly Ser Cys Thr Ile Asn Gly Val Arg His Thr Leu Cys Cys Arg
20 25 30
Arg
<210> 48
<211> 32
<212> PRT
<213> Rattus norvegicus
<400> 48
Val Thr Cys Tyr Cys Arg Arg Thr Arg Cys Gly Phe Arg Glu Arg Leu
1 5 10 15
Ser Gly Ala Cys Gly Tyr Arg Gly Arg Ile Tyr Arg Leu Cys Cys Arg
20 25 30
<210> 49
<211> 30
<212> PRT
<213> Rattus norvegicus
<400> 49
Cys Ser Cys Arg Tyr Ser Ser Cys Arg Phe Gly Glu Arg Leu Leu Ser
1 5 10 15
Gly Ala Cys Arg Leu Asn Gly Arg Ile Tyr Arg Leu Cys Cys
20 25 30
<210> 50
<211> 31
<212> PRT
<213> Rattus norvegicus
<400> 50
Ala Cys Thr Cys Arg Ile Gly Ala Cys Val Ser Gly Glu Arg Leu Thr
1 5 10 15
Gly Ala Cys Gly Leu Asn Gly Arg Ile Tyr Arg Leu Cys Cys Arg
20 25 30
<210> 51
<211> 31
<212> PRT
<213> Guinea pig
<400> 51
Arg Arg Cys Ile Cys Thr Thr Arg Thr Cys Arg Phe Pro Tyr Arg Arg
1 5 10 15
Leu Gly Thr Cys Ile Phe Gln Asn Arg Val Tyr Thr Phe Cys Cys
20 25 30
<210> 52
<211> 67
<212> PRT
<213> Homo sapiens
<400> 52
Met Arg Ile His Tyr Leu Leu Phe Ala Leu Leu Phe Leu Phe Leu Val
1 5 10 15
Pro Val Pro Gly His Gly Gly Ile Ile Asn Thr Leu Gln Lys Tyr Tyr
20 25 30
Cys Arg Val Arg Gly Gly Arg Cys Ala Val Leu Ser Cys Leu Pro Lys
35 40 45
Glu Glu Gln Ile Gly Lys Cys Ser Thr Arg Gly Arg Lys Cys Cys Arg
50 55 60
Arg Lys Lys
65
<210> 53
<211> 18
<212> PRT
<213> Macaca mulatta
<400> 53
Arg Cys Ile Cys Thr Arg Gly Phe Cys Arg Cys Leu Cys Arg Arg Gly
1 5 10 15
Val Cys
<210> 54
<211> 78
<212> PRT
<213> Helianthus annuus
<400> 54
Met Lys Ser Ser Met Lys Met Phe Ala Ala Leu Leu Leu Val Val Met
1 5 10 15
Cys Leu Leu Ala Asn Glu Met Gly Gly Pro Leu Val Val Glu Ala Arg
20 25 30
Thr Cys Glu Ser Gln Ser His Lys Phe Lys Gly Thr Cys Leu Ser Asp
35 40 45
Thr Asn Cys Ala Asn Val Cys His Ser Glu Arg Phe Ser Gly Gly Lys
50 55 60
Cys Arg Gly Phe Arg Arg Arg Cys Phe Cys Thr Thr His Cys
65 70 75
<210> 55
<211> 78
<212> PRT
<213> Helianthus annuus
<400> 55
Met Lys Ser Ser Met Lys Met Phe Ala Ala Leu Leu Leu Val Val Met
1 5 10 15
Cys Leu Leu Ala Asn Glu Met Gly Gly Pro Leu Val Val Glu Ala Arg
20 25 30
Thr Cys Glu Ser Gln Ser His Lys Phe Lys Gly Thr Cys Leu Ser Asp
35 40 45
Thr Asn Cys Ala Asn Val Cys His Ser Glu Arg Phe Ser Gly Gly Lys
50 55 60
Cys Arg Gly Phe Arg Arg Arg Cys Phe Cys Thr Thr His Cys
65 70 75
<210> 56
<211> 30
<212> PRT
<213> Macaca mulatta
<400> 56
Ala Cys Tyr Cys Arg Ile Pro Ala Cys Leu Ala Gly Glu Arg Arg Tyr
1 5 10 15
Gly Thr Cys Phe Tyr Met Gly Arg Val Trp Ala Phe Cys Cys
20 25 30
<210> 57
<211> 37
<212> PRT
<213> Androctonus australis hector
<400> 57
Gly Phe Gly Cys Pro Phe Asn Gln Gly Ala Cys His Arg His Cys Arg
1 5 10 15
Ser Ile Arg Arg Arg Gly Gly Tyr Cys Ala Gly Leu Phe Lys Gln Thr
20 25 30
Cys Thr Cys Tyr Arg
35
<210> 58
<211> 38
<212> PRT
<213> Mytilus galloprovincialis
<220>
<221> misc_feature
<222> (28)..(28)
<223> Xaa can be any naturally occurring amino acid
<400> 58
Gly Phe Gly Cys Pro Asn Asn Tyr Gln Cys His Arg His Cys Lys Ser
1 5 10 15
Ile Pro Gly Arg Cys Gly Gly Tyr Cys Gly Gly Xaa His Arg Leu Arg
20 25 30
Cys Thr Cys Tyr Arg Cys
35
<210> 59
<211> 54
<212> PRT
<213> Heuchera sanguinea
<400> 59
Asp Gly Val Lys Leu Cys Asp Val Pro Ser Gly Thr Trp Ser Gly His
1 5 10 15
Cys Gly Ser Ser Ser Lys Cys Ser Gln Gln Cys Lys Asp Arg Glu His
20 25 30
Phe Ala Tyr Gly Gly Ala Cys His Tyr Gln Phe Pro Ser Val Lys Cys
35 40 45
Phe Cys Lys Arg Gln Cys
50
<210> 60
<211> 49
<212> PRT
<213> Clitoria ternatea
<400> 60
Asn Leu Cys Glu Arg Ala Ser Leu Thr Trp Thr Gly Asn Cys Gly Asn
1 5 10 15
Thr Gly His Cys Asp Thr Gln Cys Arg Asn Trp Glu Ser Ala Lys His
20 25 30
Gly Ala Cys His Lys Arg Gly Asn Trp Lys Cys Phe Cys Tyr Phe Asn
35 40 45
Cys
<210> 61
<211> 91
<212> PRT
<213> Mus musculus
<400> 61
Met Lys Lys Leu Val Leu Leu Phe Ala Leu Val Leu Leu Ala Phe Gln
1 5 10 15
Val Gln Ala Asp Ser Ile Gln Asn Thr Asp Glu Glu Thr Lys Thr Glu
20 25 30
Glu Gln Pro Gly Glu Lys Asp Gln Ala Val Ser Val Ser Phe Gly Asp
35 40 45
Pro Gln Gly Ser Ala Leu Gln Asp Ala Ala Leu Gly Trp Gly Arg Arg
50 55 60
Cys Pro Gln Cys Pro Arg Cys Pro Ser Cys Pro Ser Cys Pro Arg Cys
65 70 75 80
Pro Arg Cys Pro Arg Cys Lys Cys Asn Pro Lys
85 90
<210> 62
<211> 40
<212> PRT
<213> Bos Taurus
<400> 62
Gln Gly Val Arg Asn Phe Val Thr Cys Arg Ile Asn Arg Gly Phe Cys
1 5 10 15
Val Pro Ile Arg Cys Pro Gly His Arg Arg Gln Ile Gly Thr Cys Leu
20 25 30
Gly Pro Gln Ile Lys Cys Cys Arg
35 40
<210> 63
<211> 40
<212> PRT
<213> Bos Taurus
<400> 63
Gln Gly Val Arg Asn Phe Val Thr Cys Arg Ile Asn Arg Gly Phe Cys
1 5 10 15
Val Pro Ile Arg Cys Pro Gly His Arg Arg Gln Ile Gly Thr Cys Leu
20 25 30
Gly Pro Arg Ile Lys Cys Cys Arg
35 40
<210> 64
<211> 42
<212> PRT
<213> Bos Taurus
<400> 64
Gln Gly Val Arg Asn His Val Thr Cys Arg Ile Tyr Gly Gly Phe Cys
1 5 10 15
Val Pro Ile Arg Cys Pro Gly Arg Thr Arg Gln Ile Gly Thr Cys Phe
20 25 30
Gly Arg Pro Val Lys Cys Cys Arg Arg Trp
35 40
<210> 65
<211> 40
<212> PRT
<213> Bos Taurus
<400> 65
Gln Val Val Arg Asn Pro Gln Ser Cys Arg Trp Asn Met Gly Val Cys
1 5 10 15
Ile Pro Ile Ser Cys Pro Gly Asn Met Arg Gln Ile Gly Thr Cys Phe
20 25 30
Gly Pro Arg Val Pro Cys Cys Arg
35 40
<210> 66
<211> 41
<212> PRT
<213> Bos Taurus
<400> 66
Gln Arg Val Arg Asn Pro Gln Ser Cys Arg Trp Asn Met Gly Val Cys
1 5 10 15
Ile Pro Phe Leu Cys Arg Val Gly Met Arg Gln Ile Gly Thr Cys Phe
20 25 30
Gly Pro Arg Val Pro Cys Cys Arg Arg
35 40
<210> 67
<211> 42
<212> PRT
<213> Bos Taurus
<400> 67
Gln Gly Val Arg Asn His Val Thr Cys Arg Ile Asn Arg Gly Phe Cys
1 5 10 15
Val Pro Ile Arg Cys Pro Gly Arg Thr Arg Gln Ile Gly Thr Cys Phe
20 25 30
Gly Pro Arg Ile Lys Cys Cys Arg Ser Trp
35 40
<210> 68
<211> 40
<212> PRT
<213> Bos Taurus
<400> 68
Gln Gly Val Arg Ser Tyr Leu Ser Cys Trp Gly Asn Arg Gly Ile Cys
1 5 10 15
Leu Leu Asn Arg Cys Pro Gly Arg Met Arg Gln Ile Gly Thr Cys Leu
20 25 30
Ala Pro Arg Val Lys Cys Cys Arg
35 40
<210> 69
<211> 42
<212> PRT
<213> Bos Taurus
<400> 69
Ser Gly Ile Ser Gly Pro Leu Ser Cys Gly Arg Asn Gly Gly Val Cys
1 5 10 15
Ile Pro Ile Arg Cys Pro Val Pro Met Arg Gln Ile Gly Thr Cys Phe
20 25 30
Gly Arg Pro Val Lys Cys Cys Arg Ser Trp
35 40
<210> 70
<211> 38
<212> PRT
<213> Bos Taurus
<400> 70
Asp Phe Ala Ser Cys His Thr Asn Gly Gly Ile Cys Leu Pro Asn Arg
1 5 10 15
Cys Pro Gly His Met Ile Gln Ile Gly Ile Cys Phe Arg Pro Arg Val
20 25 30
Lys Cys Cys Arg Ser Trp
35
<210> 71
<211> 74
<212> PRT
<213> Zophobas atratus
<400> 71
Ser Leu Gln Gly Gly Ala Pro Asn Phe Pro Gln Pro Ser Gln Gln Asn
1 5 10 15
Gly Gly Trp Gln Val Ser Pro Asp Leu Gly Arg Asp Asp Lys Gly Asn
20 25 30
Thr Arg Gly Gln Ile Glu Ile Gln Asn Lys Gly Lys Asp His Asp Phe
35 40 45
Asn Ala Gly Trp Gly Lys Val Ile Arg Gly Pro Asn Lys Ala Lys Pro
50 55 60
Thr Trp His Val Gly Gly Thr Tyr Arg Arg
65 70
<210> 72
<211> 67
<212> PRT
<213> Homo sapiens
<400> 72
Met Arg Ile His Tyr Leu Leu Phe Ala Leu Leu Phe Leu Phe Leu Val
1 5 10 15
Pro Val Pro Gly His Gly Gly Ile Ile Asn Thr Leu Gln Lys Tyr Tyr
20 25 30
Cys Arg Val Arg Gly Gly Arg Cys Ala Val Leu Ser Cys Leu Pro Lys
35 40 45
Glu Glu Gln Ile Gly Lys Cys Ser Thr Arg Gly Arg Lys Cys Cys Arg
50 55 60
Arg Lys Lys
65
<210> 73
<211> 40
<212> PRT
<213> Aedes aegypti
<400> 73
Ala Thr Cys Asp Leu Leu Ser Gly Phe Gly Val Gly Asp Ser Ala Cys
1 5 10 15
Ala Ala His Cys Ile Ala Arg Gly Asn Arg Gly Gly Tyr Cys Asn Ser
20 25 30
Lys Lys Val Cys Val Cys Arg Asn
35 40
<210> 74
<211> 35
<212> PRT
<213> Mytilus edulis
<220>
<221> misc_feature
<222> (28)..(28)
<223> Xaa can be any naturally occurring amino acid
<400> 74
Gly Phe Gly Cys Pro Asn Asp Tyr Pro Cys His Arg His Cys Lys Ser
1 5 10 15
Ile Pro Gly Arg Tyr Gly Gly Tyr Cys Gly Gly Xaa His Arg Leu Arg
20 25 30
Cys Thr Cys
35
<210> 75
<211> 40
<212> PRT
<213> Sarcophaga peregrine
<400> 75
Ala Thr Cys Asp Leu Leu Ser Gly Ile Gly Val Gln His Ser Ala Cys
1 5 10 15
Ala Leu His Cys Val Phe Arg Gly Asn Arg Gly Gly Tyr Cys Thr Gly
20 25 30
Lys Gly Ile Cys Val Cys Arg Asn
35 40
<210> 76
<211> 95
<212> PRT
<213> Oryctolagus cuniculus
<400> 76
Met Arg Thr Leu Ala Leu Leu Ala Ala Ile Leu Leu Val Ala Leu Gln
1 5 10 15
Ala Gln Ala Glu His Val Ser Val Ser Ile Asp Glu Val Val Asp Gln
20 25 30
Gln Pro Pro Gln Ala Glu Asp Gln Asp Val Ala Ile Tyr Val Lys Glu
35 40 45
His Glu Ser Ser Ala Leu Glu Ala Leu Gly Val Lys Ala Gly Val Val
50 55 60
Cys Ala Cys Arg Arg Ala Leu Cys Leu Pro Arg Glu Arg Arg Ala Gly
65 70 75 80
Phe Cys Arg Ile Arg Gly Arg Ile His Pro Leu Cys Cys Arg Arg
85 90 95
<210> 77
<211> 92
<212> PRT
<213> Mus musculus
<400> 77
Met Lys Pro Leu Val Leu Leu Ser Ala Leu Val Leu Leu Ser Phe Gln
1 5 10 15
Val Gln Ala Asp Pro Ile Gln Asn Thr Asp Glu Glu Thr Lys Thr Glu
20 25 30
Glu Gln Ser Gly Glu Glu Asp Gln Ala Val Ser Val Ser Phe Gly Asp
35 40 45
Arg Glu Gly Ala Ser Leu Gln Glu Glu Ser Leu Arg Asp Leu Val Cys
50 55 60
Tyr Cys Arg Thr Arg Gly Cys Lys Arg Arg Glu Arg Met Asn Gly Thr
65 70 75 80
Cys Arg Lys Gly His Leu Met Tyr Thr Leu Cys Cys
85 90
<210> 78
<211> 93
<212> PRT
<213> Mus musculus
<400> 78
Met Lys Thr Phe Val Leu Leu Ser Ala Leu Val Leu Leu Ala Phe Gln
1 5 10 15
Val Gln Ala Asp Pro Ile His Lys Thr Asp Glu Glu Thr Asn Thr Glu
20 25 30
Glu Gln Pro Gly Glu Glu Asp Gln Ala Val Ser Ile Ser Phe Gly Gly
35 40 45
Gln Glu Gly Ser Ala Leu His Glu Glu Leu Ser Lys Lys Leu Ile Cys
50 55 60
Tyr Cys Arg Ile Arg Gly Cys Lys Arg Arg Glu Arg Val Phe Gly Thr
65 70 75 80
Cys Arg Asn Leu Phe Leu Thr Phe Val Phe Cys Cys Ser
85 90
<210> 79
<211> 35
<212> PRT
<213> Mus musculus
<400> 79
Leu Arg Asp Leu Val Cys Tyr Cys Arg Ala Arg Gly Cys Lys Gly Arg
1 5 10 15
Glu Arg Met Asn Gly Thr Cys Arg Lys Gly His Leu Leu Tyr Met Leu
20 25 30
Cys Cys Arg
35
<210> 80
<211> 43
<212> PRT
<213> Pyrrhocoris apterus
<400> 80
Ala Thr Cys Asp Ile Leu Ser Phe Gln Ser Gln Trp Val Thr Pro Asn
1 5 10 15
His Ala Gly Cys Ala Leu His Cys Val Ile Lys Gly Tyr Lys Gly Gly
20 25 30
Gln Cys Lys Ile Thr Val Cys His Cys Arg Arg
35 40
<210> 81
<211> 32
<212> PRT
<213> Rattus norvegicus
<400> 81
Val Thr Cys Tyr Cys Arg Ser Thr Arg Cys Gly Phe Arg Glu Arg Leu
1 5 10 15
Ser Gly Ala Cys Gly Tyr Arg Gly Arg Ile Tyr Arg Leu Cys Cys Arg
20 25 30
<210> 82
<211> 31
<212> PRT
<213> Rattus norvegicus
<400> 82
Val Thr Cys Ser Cys Arg Thr Ser Ser Cys Arg Phe Gly Glu Arg Leu
1 5 10 15
Ser Gly Ala Cys Arg Leu Asn Gly Arg Ile Tyr Arg Leu Cys Cys
20 25 30
<210> 83
<211> 34
<212> PRT
<213> Oryctolagus cuniculus
<400> 83
Gly Ile Cys Ala Cys Arg Arg Arg Phe Cys Leu Asn Phe Glu Gln Phe
1 5 10 15
Ser Gly Tyr Cys Arg Val Asn Gly Ala Arg Tyr Val Arg Cys Cys Ser
20 25 30
Arg Arg
<210> 84
<211> 64
<212> PRT
<213> Pan troglodytes
<400> 84
Met Arg Val Leu Tyr Leu Leu Phe Ser Phe Leu Phe Ile Phe Leu Met
1 5 10 15
Pro Leu Pro Gly Val Phe Gly Gly Ile Ser Asp Pro Val Thr Cys Leu
20 25 30
Lys Ser Gly Ala Ile Cys His Pro Val Phe Cys Pro Arg Arg Tyr Lys
35 40 45
Gln Ile Gly Thr Cys Gly Leu Pro Gly Thr Lys Cys Cys Lys Lys Pro
50 55 60
<210> 85
<211> 64
<212> PRT
<213> Homo sapiens
<400> 85
Met Arg Val Leu Tyr Leu Leu Phe Ser Phe Leu Phe Ile Phe Leu Met
1 5 10 15
Pro Leu Pro Gly Val Phe Gly Gly Ile Gly Asp Pro Val Thr Cys Leu
20 25 30
Lys Ser Gly Ala Ile Cys His Pro Val Phe Cys Pro Arg Arg Tyr Lys
35 40 45
Gln Ile Gly Thr Cys Gly Leu Pro Gly Thr Lys Cys Cys Lys Lys Pro
50 55 60
<210> 86
<211> 68
<212> PRT
<213> Homo sapiens
<400> 86
Met Arg Thr Ser Tyr Leu Leu Leu Phe Thr Leu Cys Leu Leu Leu Ser
1 5 10 15
Glu Met Ala Ser Gly Gly Asn Phe Leu Thr Gly Leu Gly His Arg Ser
20 25 30
Asp His Tyr Asn Cys Val Ser Ser Gly Gly Gln Cys Leu Tyr Ser Ala
35 40 45
Cys Pro Ile Phe Thr Lys Ile Gln Gly Thr Cys Tyr Arg Gly Lys Ala
50 55 60
Lys Cys Cys Lys
65
<210> 87
<211> 64
<212> PRT
<213> Capra hircus
<400> 87
Met Arg Leu His His Leu Leu Leu Val Leu Phe Phe Leu Val Leu Ser
1 5 10 15
Ala Gly Ser Gly Phe Thr Gln Gly Ile Arg Ser Arg Arg Ser Cys His
20 25 30
Arg Asn Lys Gly Val Cys Ala Leu Thr Arg Cys Pro Arg Asn Met Arg
35 40 45
Gln Ile Gly Thr Cys Phe Gly Pro Pro Val Lys Cys Cys Arg Lys Lys
50 55 60
<210> 88
<211> 64
<212> PRT
<213> Capra hircus
<400> 88
Met Arg Leu His His Leu Leu Leu Ala Leu Phe Phe Leu Val Leu Ser
1 5 10 15
Ala Gly Ser Gly Phe Thr Gln Gly Ile Ile Asn His Arg Ser Cys Tyr
20 25 30
Arg Asn Lys Gly Val Cys Ala Pro Ala Arg Cys Pro Arg Asn Met Arg
35 40 45
Gln Ile Gly Thr Cys His Gly Pro Pro Val Lys Cys Cys Arg Lys Lys
50 55 60
<210> 89
<211> 96
<212> PRT
<213> Macaca mulatta
<400> 89
Met Arg Thr Leu Val Ile Leu Ala Ala Ile Leu Leu Val Ala Leu Gln
1 5 10 15
Ala Gln Ala Glu Pro Leu Gln Ala Arg Thr Asp Glu Ala Thr Ala Ala
20 25 30
Gln Glu Gln Ile Pro Thr Asp Asn Pro Glu Val Val Val Ser Leu Ala
35 40 45
Trp Asp Glu Ser Leu Ala Pro Lys Asp Ser Val Pro Gly Leu Arg Lys
50 55 60
Asn Met Ala Cys Tyr Cys Arg Ile Pro Ala Cys Leu Ala Gly Glu Arg
65 70 75 80
Arg Tyr Gly Thr Cys Phe Tyr Arg Arg Arg Val Trp Ala Phe Cys Cys
85 90 95
<210> 90
<211> 96
<212> PRT
<213> Macaca mulatta
<400> 90
Met Arg Thr Leu Val Ile Leu Ala Ala Ile Leu Leu Val Ala Leu Gln
1 5 10 15
Ala Gln Ala Glu Pro Leu Gln Ala Arg Thr Asp Glu Ala Thr Ala Ala
20 25 30
Gln Glu Gln Ile Pro Thr Asp Asn Pro Glu Val Val Val Ser Leu Ala
35 40 45
Trp Asp Glu Ser Leu Ala Pro Lys Asp Ser Val Pro Gly Leu Arg Lys
50 55 60
Asn Met Ala Cys Tyr Cys Arg Ile Pro Ala Cys Leu Ala Gly Glu Arg
65 70 75 80
Arg Tyr Gly Thr Cys Phe Tyr Leu Gly Arg Val Trp Ala Phe Cys Cys
85 90 95
<210> 91
<211> 33
<212> PRT
<213> Mesocricetus auratus
<400> 91
Val Thr Cys Phe Cys Arg Arg Arg Gly Cys Ala Ser Arg Glu Arg His
1 5 10 15
Ile Gly Tyr Cys Arg Phe Gly Asn Thr Ile Tyr Arg Leu Cys Cys Arg
20 25 30
Arg
<210> 92
<211> 31
<212> PRT
<213> Mesocricetus auratus
<400> 92
Cys Phe Cys Lys Arg Pro Val Cys Asp Ser Gly Glu Thr Gln Ile Gly
1 5 10 15
Tyr Cys Arg Leu Gly Asn Thr Phe Tyr Arg Leu Cys Cys Arg Gln
20 25 30
<210> 93
<211> 39
<212> PRT
<213> Gallus gallus
<400> 93
Gly Arg Lys Ser Asp Cys Phe Arg Lys Asn Gly Phe Cys Ala Phe Leu
1 5 10 15
Lys Cys Pro Tyr Leu Thr Leu Ile Ser Gly Lys Cys Ser Arg Phe His
20 25 30
Leu Cys Cys Lys Arg Ile Trp
35
<210> 94
<211> 43
<212> PRT
<213> Allomyrina dichotoma
<400> 94
Val Thr Cys Asp Leu Leu Ser Phe Glu Ala Lys Gly Phe Ala Ala Asn
1 5 10 15
His Ser Leu Cys Ala Ala His Cys Leu Ala Ile Gly Arg Arg Gly Gly
20 25 30
Ser Cys Glu Arg Gly Val Cys Ile Cys Arg Arg
35 40
<210> 95
<211> 31
<212> PRT
<213> Cavia porcellus
<400> 95
Arg Arg Cys Ile Cys Thr Thr Arg Thr Cys Arg Phe Pro Tyr Arg Arg
1 5 10 15
Leu Gly Thr Cys Ile Phe Gln Asn Arg Val Tyr Thr Phe Cys Cys
20 25 30
Claims (11)
- 다음을 포함하는 물품:
0.65 제곱 미터보다 큰 전체 표면적을 갖고, 실리콘(silicone) 코팅, 폴리디메틸 실록산 (PDMS) 코팅, 탄화플로오로 코팅, 폴리아크릴레이트 코팅, 폴리스티렌 코팅, 폴리스티렌아크릴 코팅, 크롬 스테아르산염 복합체 코팅, 및 폴리올레핀 코팅으로 이루어진 군에서 선택된 이형 코팅된 표면(release coated surface)을 포함하는 저 표면에너지 표면을 갖는, 가요성 기재(flexible substrate);
상기 저 표면에너지 표면에 인접하고 이와 접촉하는 나노규모 중합체 다중층으로서, 상기 나노규모 중합체 다중층은 0.5 nm 내지 10,000 nm의 두께를 가지는 것인, 나노규모 중합체 다중층; 및
상기 나노규모 중합체 다중층에 인접하고 이와 접촉하는 제2 희생 중합체층으로서, 상기 나노규모 중합체 다중층이 상기 가요성 기재의 저 표면에너지 표면 및 제2 희생 중합체층 사이에 위치하도록 제2 희생 중합체층이 위치하고, 제2 희생 중합체층은 분해가능하거나(dissolvable) 또는 생분해성(biodegradable)인, 제2 희생 중합체층.
- 청구항 1에 있어서, 상기 나노규모 중합체 다중층은 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질의 교호 층들을 포함하는 것인, 물품.
- 청구항 2에 있어서, 상기 적어도 하나의 양으로 하전된 고분자전해질은 폴리(알릴아민 염산염) (PAH), 폴리-리신 (PLL), 폴리(에틸렌 이민) (PEI), 폴리(히스티딘), 폴리(N,N-디메틸 아미노아크릴레이트), 폴리(N,N,N-트리메틸아미노아크릴레이트 염화물), 폴리(메티아크릴아미도프로필트리메틸 염화암모늄), 및 키토산을 포함한 천연 또는 합성 폴리사카라이드로 이루어진 군에서 선택되거나,
상기 적어도 하나의 음으로 하전된 고분자전해질은 폴리(아크릴산) (PAA), 폴리(스티렌술포네이트) (PSS), 알긴산염, 히알루론산, 헤파린, 헤파란 황산염, 콘드로이틴 황산염, 덱스트란 황산염, 폴리(메타크릴산), 산화된 셀룰로오스, 카르복시메틸 셀룰로오스, 폴리아스파르트산, 및 폴리글루탐산으로 이루어진 군에서 선택되는 것을 특징으로 하는 물품.
- 청구항 2 또는 3에 있어서, 상기 나노규모 중합체 다중층은 분사 코팅, 침지 코팅, 담금 코팅, 스핀 코팅, 슬롯 다이 코팅, 잉크젯 코팅, 아닐록스 코팅, 스크린 코팅, 오프셋 인쇄 프린팅, 철판 인쇄 코팅, 그라비야 코팅, 로토그라비야 코팅, 리버스 롤 코팅, 미터링 (Meyer) 막대 코팅, 블레이드 코팅, 나이프 오버 롤 코팅, 에어 나이프 코팅, 커튼 코팅, 용융 압출 코팅, 용매 캐스팅, 및 이들의 임의의 조합으로 이루어진 군에서 선택되는 방법에 의해, 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질을 적용함으로써 형성되는 것을 특징으로 하는 물품.
- 청구항 1 내지 4 중 어느 한 항에 있어서, 상기 물품은 나노규모 중합체 다중층 내로 도입된 생리활성 작용제를 더 포함하고,
선택적으로 상기 생리활성 작용제는 나노규모 중합체 다중층의 3차원 구조 내에 산재되거나, 또는 중합체 다중층의 층들 내에 산재되고, 또는 상기 생리활성 작용제는 항균제, 항생물막 작용제, 성장 인자, 지혈 작용제, 생리활성 펩티드, 생리활성 폴리펩티드, 진통제, 국부 마취제, 오피오이드, 오피오이드 길항제 또는 혼합된 효현제/길항제, 항응고제, 항염증제, 및 약물 분자 또는 약물 화합물로 이루어진 군에서 선택되는 것을 특징으로 하는 물품.
- 청구항 1 내지 5 중 어느 한 항에 있어서, 상기 두 번째 중합체 층은 나노규모 다중층으로부터 생리활성 작용제의 방출을 1 내지 1000 배 감소시키고, 선택적으로 상기 두 번째 중합체 층은 폴리아크릴산 (PAA), 폴리비닐피롤리돈 (PVP), 카르복시메틸 셀룰로오스 (CMC), 히드록시프로필 셀룰로오스, 히드록시프로필 메틸셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 히드록시에틸 셀룰로오스 (HEC), 알긴산염, 폴리비닐아세테이트 (PVAc), 폴리유산 (PLA), 폴리유산-코-글리콜산 (PLGA), 폴리글리콜산, 또는 폴리무수물을 포함하는 것을 특징으로 하는 물품.
- 다음을 포함하는, 물품의 제조 공정:
a) 0.1 제곱 미터보다 큰 표면적을 갖고, 실리콘(silicone) 코팅, 폴리디메틸 실록산 (PDMS) 코팅, 탄화플루오로 코팅, 폴리아크릴레이트 코팅, 폴리스티렌 코팅, 폴리스티렌아크릴 코팅, 크롬 스테아르산염 복합체 코팅(chromium sterate complex coating) 및 폴리올레핀 코팅으로 이루어진 군에서 선택된 이형 코팅을 포함하는, 가요성 기재(flexible substrate)를 제공하는 단계;
b) 롤투롤(roll to roll) 코팅 방법에 의해, 적어도 하나의 양으로 하전된 고분자전해질 및 적어도 하나의 음으로 하전된 고분자전해질의 교호 층을 적층하여, 저 표면에너지 표면 상에 약 0.5 nm 내지 10,000 nm 두께의 나노규모 중합체 다충층을 형성하는 단계;
c) 생리활성 작용제를 상기 나노규모 중합체 다중층 내로 도입하여 생리활성 나노규모 중합체 다중층을 제공하는 단계;
d) 상기 나노규모 중합체 다중층이 상기 가요성 기재의 저 표면에너지 표면 및 제2 희생 중합체층 사이에 위치하도록 제2 희생 중합체층을 상기 나노규모 중합체 다중층 상에 형성 또는 적층하는 단계로서, 이때 제2 희생 중합체층은 분해가능하거나(dissolvable) 또는 생분해성(biodegradable)인 것인, 단계; 및
e) 상기 나노규모 중합체 다중층을, 상기 가요성 기재의 저 표면에너지 표면으로부터 제2 중합체 층과 함께 박리하여 자립형(free standing) 마이크로시트를 제공하는 단계.
- 청구항 7에 있어서, 상기 롤투롤 코팅 방법은 제1 롤로부터 적어도 제2 롤로 상기 가요성 기재를 이동시키고, 상기 가요성 기재가 제1 롤과 제2 롤 사이로 이동되는 동안 상기 가요성 기재의 저 표면에너지 표면을 나노규모 중합체 층으로 코팅하는 것을 포함하는 것인, 물품의 제조 공정.
- 청구항 7에 있어서, 상기 적어도 하나의 양으로 하전된 고분자전해질은 폴리(알릴아민 염산염) (PAH), 폴리-리신 (PLL), 폴리(에틸렌 이민) (PEI), 폴리(히스티딘), 폴리(N,N-디메틸 아미노아크릴레이트), 폴리(N,N,N-트리메틸아미노아크릴레이트 염화물), 폴리(메티아크릴아미도프로필트리메틸 염화암모늄), 및 키토산을 포함한 천연 또는 합성 폴리사카라이드로 이루어진 군에서 선택되거나,
상기 적어도 하나의 음으로 하전된 고분자전해질은 폴리(아크릴산) (PAA), 폴리(스티렌술포네이트) (PSS), 알긴산염, 히알루론산, 헤파린, 헤파란 황산염, 콘드로이틴 황산염, 덱스트란 황산염, 폴리(메타크릴산), 산화된 셀룰로오스, 카르복시메틸 셀룰로오스, 폴리아스파르트산, 및 폴리글루탐산으로 이루어진 군에서 선택되는 것을 특징으로 하는, 물품의 제조 공정.
- 청구항 7 내지 9 중 어느 한 항에 있어서, 저 표면에너지 표면을 포함하는 가요성 기재의 표면적은 0.65 제곱 미터보다 큰 것을 특징으로 하는, 물품의 제조 공정.
- 청구항 7 내지 10 중 어느 한 항에 있어서, 나노규모 중합체 다중층의 코팅 동안 가요성 기재의 저 표면에너지 표면 상에서의 중합체 제제의 체류 시간은 헹굼에 앞서, 1 내지 600 초인 것을 특징으로 하는, 물품의 제조 공정.
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KR1020197006148A KR20190059266A (ko) | 2016-07-29 | 2017-07-28 | 상처 치유를 위한 방법 및 조성물 |
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US11541105B2 (en) | 2018-06-01 | 2023-01-03 | The Research Foundation For The State University Of New York | Compositions and methods for disrupting biofilm formation and maintenance |
US11793832B2 (en) | 2018-08-16 | 2023-10-24 | Nicholas L. Abbott | Methods and compositions for wound healing |
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CA3127982A1 (en) * | 2019-01-28 | 2020-08-06 | Core Scientific Creations Ltd. | Wound dressing compositions and methods |
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CN114853913A (zh) * | 2022-06-24 | 2022-08-05 | 五康生物科技股份有限公司 | 一种植物抗菌肽AFP1与芽孢杆菌分泌肽SPamyQ融合蛋白及应用 |
CN115975048A (zh) * | 2022-10-28 | 2023-04-18 | 山东龙昌动物保健品有限公司 | 一种含有杜仲叶提取物的抗菌复合制剂及其在食物防腐保鲜中的应用 |
CN115634305B (zh) * | 2022-12-16 | 2023-11-17 | 郑州大学第一附属医院 | 一种多功能静电纺复合纳米纤维材料及其制备方法和应用 |
KR102497294B1 (ko) * | 2022-12-23 | 2023-02-14 | 주식회사 코씨드바이오팜 | 신규 펩타이드를 유효성분으로 포함하는 피부 질환 예방 및 개선용 피부 외용제 조성물 |
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- 2017-07-28 WO PCT/US2017/044418 patent/WO2018023021A1/en unknown
- 2017-07-28 CN CN201780060329.9A patent/CN109843343A/zh active Pending
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EP4289910A3 (en) | 2024-03-13 |
KR20190059266A (ko) | 2019-05-30 |
WO2018023021A1 (en) | 2018-02-01 |
CN109843343A (zh) | 2019-06-04 |
EP4289910A2 (en) | 2023-12-13 |
EP3490622A4 (en) | 2020-04-29 |
US20240009342A1 (en) | 2024-01-11 |
EP3490622B1 (en) | 2023-09-06 |
EP3490622A1 (en) | 2019-06-05 |
KR20240025050A (ko) | 2024-02-26 |
KR102637746B1 (ko) | 2024-02-16 |
EP3490622C0 (en) | 2023-09-06 |
US20180028713A1 (en) | 2018-02-01 |
US11554194B2 (en) | 2023-01-17 |
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