KR20090017310A - Poly(n-isopropylacrylamide)-immobilized monoolein cubic phase and the method for production of the said monoolein cubic phase - Google Patents
Poly(n-isopropylacrylamide)-immobilized monoolein cubic phase and the method for production of the said monoolein cubic phase Download PDFInfo
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- KR20090017310A KR20090017310A KR1020070081953A KR20070081953A KR20090017310A KR 20090017310 A KR20090017310 A KR 20090017310A KR 1020070081953 A KR1020070081953 A KR 1020070081953A KR 20070081953 A KR20070081953 A KR 20070081953A KR 20090017310 A KR20090017310 A KR 20090017310A
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6903—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Abstract
Description
본 발명은 모노올레인 큐빅상(monoolein cubic phase)에 관한 것으로, 좀 더 구체적으로 소수화된 폴리이소프로필아크릴아미드(Poly(N-isopropylacrylamide); PNIPAM)가 큐빅상 내부의 미세 수상채널에 고정화되어 제조된 모노올레인 큐빅상에 관한 것이다. The present invention relates to a monoolein cubic phase, more specifically, hydrophobized polyisopropylacrylamide (Poly ( N -isopropylacrylamide); PNIPAM) is prepared by immobilization on the fine water channel inside the cubic phase To a monooleic cubic phase.
팩킹 파라미터(packing parameter)가 1에 가까운 글리세롤 모노올레이트(glycerol monooleate; Monoolein 이하, '모노올레인'이라 함)는 수상에서 시스템의 온도, 모노올레인의 농도 그리고 수상의 함량이 적절하면 큐빅상을 형성하는데, 큐빅상은 조직화된 등방성 구조를 가지고 있어 투명하다. Glycerol monooleate (packing parameter close to 1) is called the Cubic Award if the temperature of the system, the concentration of monoolein and the water content in the water phase are appropriate. The cubic phase is transparent because it has an organized isotropic structure.
큐빅상을 구성하는 모노올레인은 인체에 대한 독성이 없어 생체에 사용하기 적합하고, 생분해성이다. 또한, 약물을 서서히 방출하는 서방성 거동을 보이고, 피 부와 점막에 대한 접착성이 우수하여, 주사(injection), 경피흡수(transdermal), 점막흡수 전달(trans-mucous membrane delivery)과 그 외 인체 내 약물전달 운반체로서 연구가 활발히 진행되고 있다 (Kim et al, 2004. Colloids and Surfaces B: Biointerfaces 36:161-166). The monoolein constituting the cubic phase is not toxic to the human body and is suitable for use in a living body and is biodegradable. In addition, it exhibits sustained-release behavior of slowly releasing drugs and has excellent adhesion to skin and mucous membranes, resulting in injection, transdermal, trans-mucous membrane delivery, and other human bodies. Research is actively underway as a drug delivery vehicle (Kim et al, 2004. Colloids and Surfaces B: Biointerfaces 36: 161-166).
큐빅상 내부에는 서로 교차하는 수상 채널(water channel)들이 있고 수상채널 주위에는 모노올레인 이중층 표면(bilayer surface)이 존재한다 (도 1). 이와 같이 큐빅상 내부에는 수상채널과 지질 매트릭스(lipid matrix)가 함께 존재하기 때문에 수용성 목적성분과 지용성 목적성분을 모두 포집(entrapment)할 수 있는 장점이 있다 (Lara et al, 2005. International journal of pharmaceutics 293:241-250). Inside the cubic phase there are water channels intersecting with each other and a monoolefin bilayer surface around the water channel (FIG. 1). As such, since the water channel and the lipid matrix exist together in the cubic phase, there is an advantage in that both water-soluble and fat-soluble target components can be trapped (Lara et al, 2005. International journal of pharmaceutics) 293: 241-250).
한편, 종래에 목적물질을 포집한 모노올레인 큐빅상에 관한 특허기술의 예로는, 대한민국특허공개공보 제10-1991-0009242호(공개일: 1991.06.28)에 '필수적으로 모노올레인 1 내지 99%와 소염제, 항미생물제, 항생제, 퍼옥사이드, 마취제 및 비타민으로 이루어진 그룹으로부터 선택되며 구강 질환 치료에 적합한 활성 약제 1 내지 90%로 이루어진, 구강 질환을 앓는 사람 또는 하등동물의 치근막낭 속에 또는 이의 주위에 주입하기에 적합한 조성물'이 개시되어 있다.On the other hand, as an example of the patent technology related to the monoolein cubic image trapping the target substance in the prior art, the Republic of Korea Patent Publication No. 10-1991-0009242 (published: June 28, 1991) 'Essentially monoolein 1 to 99% and 1 to 90% of active agents selected from the group consisting of anti-inflammatory agents, antimicrobials, antibiotics, peroxides, anesthetics and vitamins and suitable for the treatment of oral diseases, or in the periosteal sac of a person or lower animal with oral disease. Compositions suitable for infusion into the environment are disclosed.
그러나, 이 특허 발명에 개시된 모노올레인 큐빅상은 포집된 약물을 단순 확산에 의해 서서히 방출시키는 것에 관한 것일 뿐, 특정의 조건에서 선택적으로 내부에 포집된 목적성분을 선택적으로 방출하는 기술적 사상에 대해서는 전혀 언급되어 있지 않다. However, the monoolein cubic phase disclosed in this patent invention is only related to the slow release of the trapped drug by simple diffusion, and there is no idea of the technical idea of selectively releasing the target component selectively collected therein under specific conditions. Not mentioned.
이에 본 발명은 특정의 조건에서만 목적물질을 방출할 수 있는 모노올레인 큐빅상을 개발하여 제공하는데 그 목적이 있다. Accordingly, an object of the present invention is to develop and provide a monoolein cubic phase capable of releasing a target substance only under specific conditions.
상기 목적을 달성하기 위하여, 본 발명은 폴리이소프로필아크릴아미드(poly(N-isopropylacrylamide); PNIPAM)가 큐빅상 내부의 수상 채널에 고정화된 모노올레인(monoolein) 큐빅상(cubic phase)을 제공한다. In order to achieve the above object, the present invention provides a monooolein cubic phase in which poly (N-isopropylacrylamide; PNIPAM) is immobilized on an aqueous channel inside the cubic phase. .
폴리이소프로필아크릴아미드는 약 32℃에서 상전이 온도(lower critical solution temperature, LCST)를 나타내는 열 민감성 고분자인데, 상전이 온도 이하에서는 수용성이고 고분자 사슬이 팽윤되어 있지만, 상전이 온도 이상에서는 수 불용성이 되고 고분자 사슬이 수축한다. 이와 같은 특성을 갖는 폴리이소프로필아크릴아미드를 큐빅상의 수상채널에 고정화하면 시스템의 온도가 고분자의 상전이 온도보다 낮을 때에는 고분자 사슬이 팽윤되어 있기 때문에 수상채널이 폐쇄되고 그로 말미암아 목적성분이 비교적 적게 방출된다 (도 2A). 반면, 시스템의 온도가 상전이 온도보다 높을 때에는 폴리이소프로필아크릴아미드가 수축하기 때문에 수상채널이 열리고 그로 말미암아 목적성분의 방출속도가 급속히 증가한다 (도 2B).Polyisopropylacrylamide is a heat sensitive polymer that exhibits a lower critical solution temperature (LCST) at about 32 ° C. It is water-soluble below the phase transition temperature and swells the polymer chain, but is insoluble at the temperature above the phase transition temperature, It contracts. When immobilized polyisopropylacrylamide having such characteristics in the cubic phase water channel, the polymer chain is swollen when the temperature of the system is lower than the phase transition temperature of the polymer, so that the water channel is closed, thereby releasing relatively few target components. (FIG. 2A). On the other hand, when the temperature of the system is higher than the phase transition temperature, the polyisopropylacrylamide shrinks, so that the water channel opens, thereby rapidly increasing the release rate of the target component (FIG. 2B).
한편, 본 발명의 모노올레인 큐빅상에 있어서, 폴리이소프로필아크릴아미드는 당업계에 고정화 수단으로 알려진 다양한 방법을 통해 큐빅상 내부의 수상 채널 에 고정화될 수 있으나, 바람직하게는 고정화 물질로 소수성 앵커(hydrophobic anchor)가 결합된 것이 좋다. 이때, 더욱 바람직하게 상기 소수성 앵커는 모노알킬아크릴레이트(monoalkylacrylate) 또는 디알킬아크릴레이트(dialkylacrylate) 중 선택되는 어느 하나인 것이 좋다. 소수성 앵커는 큐빅상 내부의 수상 채널과 폴리이소프로필아크릴아미드 사이에 고정화 수단의 일종인 소수성 결합을 제공할 수 있는 물질로서, 소수성 앵커가 결합된 폴리이소프로필아크릴아미드는 큐빅상 내부의 수상 채널에 소수성 결합을 통해 고정화된다. On the other hand, in the monoolefin cubic phase of the present invention, polyisopropylacrylamide can be immobilized in the aqueous channel inside the cubic phase through various methods known in the art as immobilization means, but preferably a hydrophobic anchor as an immobilization material. (hydrophobic anchor) is preferably combined. At this time, more preferably, the hydrophobic anchor is any one selected from monoalkylacrylate or dialkylacrylate. A hydrophobic anchor is a substance capable of providing a hydrophobic bond, which is a kind of immobilization means, between the water channel and the polyisopropylacrylamide inside the cubic phase, and the polyisopropylacrylamide combined with the hydrophobic anchor is attached to the water channel inside the cubic phase. Immobilized via hydrophobic bonds.
한편, 본 발명은 큐빅상 내부의 수상 채널에 고정되도록 고정화 물질이 결합된 폴리이소프로필아크릴아미드와 수상 채널에 포집하려는 목적물질을 혼합하여 혼합액을 제조하는 단계; 및 상기 혼합액을 모노올레인 용융액에 첨가하고, 투명한 겔을 형성시키는 단계;를 포함하는 것을 특징으로 하는 모노올레인 큐빅상의 제조방법을 제공한다. On the other hand, the present invention comprises the steps of mixing the polyisopropyl acrylamide immobilized material to be fixed to the water channel in the cubic phase and the target material to be collected in the water channel to prepare a mixed solution; And adding the mixed solution to a monoolein melt, and forming a transparent gel.
상기 본 발명의 모노올레인 큐빅상 제조방법에 있어서, 바람직하게 모노올레인 용융액의 온도는 30~60℃인 것이 좋다. 이보다 낮은 온도에서는 모노올레인이 용융되지 않고, 이보다 높은 온도에서는 모노올레인이 산화되어 변성될 수 있기 때문이다. 이때, 상기 모노올레인 용융액의 온도는 더욱 바람직하게는 35~55℃, 가장 바람직하게는 40~50℃인 것이 좋다. 모노올레인은 불포화 탄화수소를 가지고 있는 모노글리세라이드(monoglyceride)이기 때문에 고온에서 화학적으로 산화되어 탄화수소사슬이 끊어질 수 있다. 따라서 모노올레인을 용융시킬 때는 갑작스런 온도 상 승을 막기 위해 중탕으로 용융시킬 필요가 있는 것이다. 이때, 바람직하게 상기 혼합액의 온도는 모노올레인 용융액의 온도와 동일한 것이 좋다. In the monoolefin cubic phase production method of the present invention, preferably, the temperature of the monoolefin melt is 30 to 60 ° C. This is because the monoolein is not melted at a lower temperature, and the monoolein may be oxidized and denatured at a higher temperature. At this time, the temperature of the molten monoolefin is more preferably 35 to 55 ℃, most preferably 40 to 50 ℃. Since monoolein is a monoglyceride containing unsaturated hydrocarbons, it can be chemically oxidized at high temperatures, thus breaking the hydrocarbon chain. Therefore, when melting monoolein, it needs to be melted in a bath to prevent sudden temperature rise. At this time, preferably the temperature of the mixed solution is the same as the temperature of the monoolein melt.
한편, 상기 본 발명의 모노올레인 큐빅상 제조방법에 있어서, 바람직하게 혼합액과 모노올레인 용융액의 비율은 무게비로서 3:2~1:3인 것이 좋다. 혼합액 함량이 용융액보다 낮으면 모노올레인이 완전히 용액화되지 않고, 그로 말미암아 큐빅상이 형성되지 않으며, 혼합액 함량이 용융액보다 높으면 혼합액의 함량이 과도하게 많아서 큐빅상에 혼합액이 모두 흡수되지 못하기 때문이다. 이때, 혼합액과 모노올레인 용융액의 비율은 더욱 바람직하게는 무게비로 1:1~1:2, 가장 바람직하게는 4:5~3:5인 것이 좋다. . On the other hand, in the monoolein cubic phase production method of the present invention, preferably the ratio of the mixed liquid and the monoolein melt is 3: 2 to 1: 3 by weight ratio. If the mixed liquid content is lower than the molten liquid, the monoolein is not completely liquefied, and thus, no cubic phase is formed, and if the mixed liquid content is higher than the molten liquid, the mixed liquid content is excessively high so that all of the mixed liquid cannot be absorbed in the cubic phase. . At this time, the ratio of the mixed solution and the monoolein melt is more preferably in the weight ratio of 1: 1 to 1: 2, most preferably 4: 5 to 3: 5. .
한편, 상기 본 발명의 모노올레인 큐빅상 제조방법에 있어서, 바람직하게 고정화 물질이 결합된 폴리이소프로필아크릴아미드의 농도는 혼합액 중 1~25%인 것이 좋다. 이보다 높은 농도에서는 용액의 점도가 너무 높아서 큐빅상이 제조되지 않고, 이보다 낮은 농도에서는 큐빅상이 적은 양의 폴리이소프로필아크릴아미드를 함유하여 본 발명에서 이루고자 하는 온도 민감성 방출 특성을 얻을 수 없기 때문이다. 이때, 더욱 바람직하게 상기 고정화 물질이 결합된 폴리이소프로필아크릴아미드의 농도는 혼합액 중 5~20%, 가장 바람직하게는 7~15%인 것이 좋다.On the other hand, in the monoolefin cubic phase production method of the present invention, preferably, the concentration of the polyisopropyl acrylamide to which the immobilization material is bound is preferably 1 to 25% in the mixed solution. This is because, at higher concentrations, the viscosity of the solution is so high that no cubic phase is produced, and at lower concentrations, the cubic phase contains a small amount of polyisopropylacrylamide, so that the temperature-sensitive release characteristic to be achieved in the present invention cannot be obtained. At this time, more preferably, the concentration of the polyisopropylacrylamide to which the immobilization material is bound is 5 to 20%, most preferably 7 to 15% in the mixed solution.
한편, 포집하려는 목적물질은 항암제, 항생제, 항진균제, 항박테리아제, 항산화제, 미백제, 소염제 등 다양한 소수성, 친수성 생리활성 성분이 사용될 수 있다. On the other hand, the target material to be collected may be used a variety of hydrophobic, hydrophilic bioactive components such as anticancer, antibiotic, antifungal, antibacterial, antioxidant, whitening, anti-inflammatory.
한편, 상기 본 발명의 모노올레인 큐빅상 제조방법에 있어서, 바람직하게 고 정화 물질이 결합된 폴리이소프로필아크릴아미드는 이소플로필아크릴아미드, 고정화 물질, 중합 개시제를 용매에 녹여 용액을 제조하는 단계; 상기 용액을 가열하면서 라디칼 중합을 시키는 단계;를 포함하는 과정으로부터 제조된 것이 좋다. On the other hand, in the monoolein cubic phase production method of the present invention, polyisopropyl acrylamide preferably is a high purification material is combined isoflophyl acrylamide, immobilized material, a polymerization initiator in a solvent to prepare a solution ; It is preferably prepared from the process comprising; step of radical polymerization while heating the solution.
이때, 상기 고정화 물질은 바람직하게 소수성 앵커인 것이 좋고, 더욱 바람직하게 소수성 앵커는 폴리이소프로필아크릴아미드와 소수성 앵커가 몰비율로 1000:1~20:1이 되도록 첨가되는 것이 좋다. 소수성 앵커의 함량이 낮으면 폴리이소프로필아크릴아미드의 소수화가 부족하고, 그로 말미암아 폴리이소프로필아크릴아미드가 큐빅상의 수상채널에 제대로 고정화되지 못하고, 소수성 앵커의 함량이 높으면 폴리이소프로필아크릴아미드의 열적인 수축 및 팽창 특성이 소실되기 때문이다. 이때, 더욱 더 바람직하게는 상기 소수성 앵커는 폴리이소프로필아크릴아미드와 소수성 앵커가 몰비율로 500:1~30:1, 가장 바람직하게는 200:1~50:1로 첨가되는 것이 좋다. 소수성 앵커는 큐빅상의 탄화수소 메트릭스에 삽입되기 때문에 폴리이소프로필아크릴아미드를 고정화시키는 역할을 한다. 소수성 앵커는 바람직하게 모노알킬아크릴레이트 또는 디알킬아크릴레이트 중 선택되는 어느 하나인 것이 좋고, 알킬아크릴레이트의 탄소수는 바람직하게 C12~C22인 것이 좋다. 이 범위보다 탄소수가 적거나 많으면 소수성 앵커 역할을 하지 못하기 때문이다. 이때, 상기 알킬아크릴레이트의 탄소수는 더욱 바람직하게 C14-C20, 가장 바람직하게 C16-C18인 것이 좋다. In this case, the immobilization material is preferably a hydrophobic anchor, more preferably the hydrophobic anchor is preferably added so that the polyisopropyl acrylamide and the hydrophobic anchor is in a molar ratio of 1000: 1 to 20: 1. If the content of hydrophobic anchor is low, the hydrophobization of polyisopropylacrylamide is insufficient. Therefore, the polyisopropylacrylamide is not properly immobilized in the water channel of the cubic phase. This is because shrinkage and expansion characteristics are lost. At this time, the hydrophobic anchor is more preferably polyisopropylacrylamide and hydrophobic anchor in a molar ratio of 500: 1 to 30: 1, most preferably 200: 1 to 50: 1. Hydrophobic anchors serve to immobilize polyisopropylacrylamide because they are inserted into the hydrocarbon matrix on the cubic phase. The hydrophobic anchor is preferably any one selected from monoalkyl acrylate or dialkyl acrylate, and the carbon number of the alkyl acrylate is preferably C 12 to C 22 . This is because if the carbon number is less or more than this range, it does not act as a hydrophobic anchor. In this case, the alkyl acrylate may be more preferably C 14 -C 20 , most preferably C 16 -C 18 .
한편, 상기 본 발명의 모노올레인 큐빅상 제조방법에 있어서, 중합 개시제는 바람직하게 이소플로필아크릴아미드와 중합 개시제가 몰비율로 100000:1~1000:1의 비율이 되도록 첨가되는 것이 좋다. 중합 개시제의 함량이 낮으면, 중합이 진행되지 않고, 중합 개시제의 함량이 높으면 고분자량의 폴리이소프로필아크릴아미드가 중합되지 않기 때문이다. 이때, 중합 개시제는 더욱 바람직하게 이소플로필아크릴아미드와 중합 개시제가 몰비율로 50000:1~5000:1, 가장 바람직하게 30000:1~10000:1로 첨가되는 것이 좋다. 중합 개시제는 당업계 알려진 것이라면 어느 것을 사용하여도 무방하나, 바람직하게는 아조비스이소부틸로니트릴(N, N'-azobisisobutyronitrile)인 것이 좋다. On the other hand, in the monoolefin cubic phase production method of the present invention, the polymerization initiator is preferably added so that isoflophyl acrylamide and the polymerization initiator are in a molar ratio of 100000: 1 to 1000: 1. This is because if the content of the polymerization initiator is low, the polymerization does not proceed, and if the content of the polymerization initiator is high, the high molecular weight polyisopropylacrylamide does not polymerize. At this time, the polymerization initiator more preferably isoflophyl acrylamide and the polymerization initiator are added in a molar ratio of 50000: 1 to 5000: 1, most preferably 30000: 1 to 10000: 1. Any polymerization initiator may be used as long as it is known in the art, but is preferably azobisisobutylonitrile (N, N'-azobisisobutyronitrile).
한편, 상기 본 발명의 모노올레인 큐빅상 제조방법에 있어서, 바람직하게 용매는 양용매인 것이 좋고, 더욱 바람직하게 디메틸포름아마이드(dimethylformamide), 디메틸설폭사이드(dimethylsulfoxide), 디옥산(dioxane) 중 선택되는 어느 하나인 것이 좋다. On the other hand, in the monoolefin cubic phase production method of the present invention, the solvent is preferably a good solvent, more preferably selected from dimethylformamide, dimethylsulfoxide, dioxane (dioxane) It is good to be either.
한편, 상기 본 발명의 모노올레인 큐빅상 제조방법에 있어서, 중합은 바람직하게 50~90℃의 온도로 수행하는 것이 좋다. 이보다 낮은 온도에서는 중합이 안 되고, 이보다 높은 온도에서는 중합된 고분자가 열분해 될 수 있기 때문이다. 이때, 중합 온도는 더욱 바람직하게 60~80℃, 가장 바람직하게 65~75℃인 것이 좋다. On the other hand, in the monoolefin cubic phase production method of the present invention, the polymerization is preferably carried out at a temperature of 50 ~ 90 ℃. This is because polymerization is not possible at lower temperatures, and polymerized polymers may be pyrolyzed at higher temperatures. At this time, the polymerization temperature is more preferably 60 ~ 80 ℃, most preferably 65 ~ 75 ℃.
한편, 본 발명에 있어서, '%농도'는 특별한 언급이 없으면 '중량%' 즉, 'w/w%'로 한다. On the other hand, in the present invention, '% concentration' is referred to as 'wt%', that is, 'w / w%' unless otherwise specified.
이상, 상기에서 살펴본 바와 같이 소수화된 폴리이소프로필아크릴아미드가 큐빅상의 미세 수상채널에 고정화되어 제조된 본 발명의 모노올레인 큐빅상은 폴리이소프로필아크릴아미드의 상전이 온도 이하에서는 포집된 목적성분을 비교적 적게 방출하고, 상전이 온도 이상에서는 포집된 목적성분을 비교적 많이 방출하는 효과를 발휘한다. As described above, the monoolein cubic phase of the present invention prepared by hydrophobizing polyisopropylacrylamide is immobilized on a fine water channel of the cubic phase has a relatively small amount of the target component collected at or below the phase transition temperature of the polyisopropylacrylamide. It releases, and at the phase transition temperature or more, it exhibits the effect of comparatively releasing the collected target component.
이하, 본 발명의 내용을 하기 실시예를 들어 더욱 상세히 설명하고자 한다. 다만, 본 발명의 권리범위가 하기 실시예에만 한정되는 것은 아니고, 그와 등가의 기술적 사상의 변형까지를 포함한다. Hereinafter, the content of the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited only to the following examples, but includes modifications of equivalent technical ideas.
실시예 1 : 소수화 폴리이소프로필아크릴아미드의 중합Example 1 Polymerization of Hydrophobized Polyisopropylacrylamide
소수화 폴리이소프로필아크릴아미드는 라디칼 중합법(radical polymerization)에 의해 중합되었다. 먼저, 이소프로필아크릴아미드(9.7×10-2 mol), 옥타데실아크릴레이트(octadecylacrylate, 5×10-4mol), 아조비스이소부틸로니트릴(5.5×10-5mol)를 40ml 디메틸설폭사이드(dimethylsulfoxide)에 용해시킨 후 75℃에서 8시간 동안 질소 기류 하에 반응시켰다. 반응 후, 이를 상온으로 식히고 과량의 디에틸 에테르(diethyl ether)에 반복 침전시킨 후, 뜨거운 물로 세척하고, 40℃에서 건조하였다. 도 3은 중합된 폴리이소프로필아크릴아미드의 온도에 따른 탁도 변화를 증류수에 녹인 후 관찰한 결과이다. 도 3에서 보는 바와 같이 약 32℃에서 상전이 하는 것을 확인할 수 있었다. Hydrophobized polyisopropylacrylamide was polymerized by radical polymerization. First, isopropylacrylamide (9.7 × 10 −2 mol), octadecylacrylate (5 × 10 −4 mol), and azobisisobutylonitrile (5.5 × 10 −5 mol) were added to 40 ml dimethyl sulfoxide ( dimethylsulfoxide) and reacted under nitrogen stream at 75 ° C. for 8 hours. After the reaction, it was cooled to room temperature, repeatedly precipitated in excess of diethyl ether, washed with hot water, and dried at 40 ° C. Figure 3 is the result of observation of the turbidity change according to the temperature of the polymerized polyisopropyl acrylamide dissolved in distilled water. As shown in Figure 3, it was confirmed that the phase change at about 32 ℃.
실시예 2, 3 : '목적성분만이 녹아 있는 용액'의 제조 및 '소수화 Examples 2 and 3: Preparation and 'Hydrogenation' of the solution in which only the target component is dissolved 폴리이소프로필아크릴아미드와With polyisopropylacrylamide 목적성분이 녹아 있는 용액'의 제조 Preparation of 'Soluble of the Desired Ingredient'
실시예 1에서 합성된 소수화 폴리이소프로필아크릴아미드와 목적성분으로 항염증제인 소디움 살리실레이트(sodium salicylate)를 표 1의 조성대로 증류수에 첨가하여 상온에서 완전히 녹을 때까지 교반하였다. Hydrophobized polyisopropylacrylamide synthesized in Example 1 and sodium salicylate, an anti-inflammatory agent as a target component, were added to the distilled water according to the composition of Table 1 and stirred until completely dissolved at room temperature.
(중량 %)(weight %)
실시예 4,5 : '소수화 Examples 4,5 '' dehydration 폴리이소프로필아크릴아미드와With polyisopropylacrylamide 목적성분을 함유한 Containing the target ingredient 큐빅상Cubic Award '의 제조 및 '목적성분만을 함유한 Manufacture and 'Contain only the Purpose Ingredients' 큐빅상Cubic Award ' 제조' Produce
모노올레인을 45℃ 중탕으로 용융시켰다, 여기에 실시예 2 또는 실시예 3에서 제조한 수용액을 모노 놀레인 용융액과 같은 온도로 가열한 후, 표 2의 조성대로 모노올레인 용융액에 첨가하였다. 그 후 투명해질 때까지 방치하였다. The monoolein was melted in a 45 ° C. hot water bath, where the aqueous solution prepared in Example 2 or Example 3 was heated to the same temperature as the mononole melt, and then added to the monoolein melt according to the composition of Table 2. It was then left to become transparent.
(중량 %)(weight %)
도 4는 실시예 5에서와 같은 방법으로 제조한 큐빅상 사진이다. 큐빅상의 전형적인 외관인 투명한 겔이 형성되었음을 확인할 수 있었다. 실시예 4의 외관도 투명한 겔이었고, 큐빅상이 형성되었음을 역시 확인할 수 있었다(미도시).Figure 4 is a cubic image photographed in the same manner as in Example 5. It was confirmed that a transparent gel was formed, which is a typical appearance of the cubic phase. The appearance of Example 4 was also a transparent gel, and it was also confirmed that a cubic phase was formed (not shown).
평가예Evaluation example 1. 온도에 따른 1.according to temperature 큐빅상의Cubic tops 방출특성 Emission characteristics
10 ml 시험관에 각각 담겨있는 실시예 4의 큐빅상 1g과, 실시예 5의 큐빅상 1g에 증류수 10 ml을 붓고 25℃와 37℃에서 시간에 따른 방출 %를 측정하였다. 큐빅상에서 증류수로 방출된 소디움 살리실레이트 양은 290 nm에서 흡광도를 측정하여 구하였고, 방출 %는 큐빅상에 함유되어 있는 소디움 살리실레이트의 총량에 대한 증류수로 방출되어 나온 양의 백분율이다. 10 g of distilled water was poured into 1 g of the cubic phase of Example 4 and 1 g of the cubic phase of Example 5 each contained in a 10 ml test tube, and the percentage of release over time was measured at 25 ° C and 37 ° C. The amount of sodium salicylate released from distilled water in the cubic phase was obtained by measuring absorbance at 290 nm, and the percentage of release is a percentage of the amount released in distilled water relative to the total amount of sodium salicylate contained in the cubic phase.
(방출 %)(Release %)
표 3에서와 같이 폴리이소프로필아크릴아미드을 함유하지 않은 큐빅상(실시예 4의 큐빅상)의 경우에는 25℃와 37℃에서 방출 %가 큰 차이가 없었다. 반면, 폴리이소프로필아크릴아미드을 함유한 큐빅상(실시예 5의 큐빅상)의 경우에는 25℃에서는 매우 낮은 방출 %를 보였지만 37℃에서는 25℃에 비해서 현저하게 높은 방출 %를 보였다. 이것은 폴리이소프로필아크릴아미드의 상전이 온도보다 낮은 온도인 25℃에서 폴리이소프로필아크릴아미드는 팽윤되어 있기 때문에 큐빅상의 채널을 막고 있고, 상전이 온도보다 높은 온도인 37℃에서는 폴리이소프로필아크릴아미드가 수축하여 큐빅상의 채널이 열리기 때문에 발생한 현상으로 추론할 수 있었다. As shown in Table 3, in the cubic phase containing no polyisopropylacrylamide (cubic phase of Example 4), the percent of release was not significantly different at 25 ° C and 37 ° C. On the other hand, the cubic phase containing the polyisopropylacrylamide (cubic phase of Example 5) showed a very low% release at 25 ° C., but a significantly higher%% at 37 ° C. compared to 25 ° C. This is because the polyisopropylacrylamide is swollen at 25 ° C, which is lower than the phase transition temperature of the polyisopropylacrylamide, thereby blocking the channel of the cubic phase. It could be inferred as a phenomenon that occurred because the channel on the cubic was opened.
도 1은 모노올레인 큐빅상의 모식도이다.1 is a schematic diagram of a monooleic cubic phase.
도 2는 폴리이소프로필아크릴아미드를 함유한 모노올레인 큐빅상의 수상 채널을 나타낸다. A도는 고분자의 상전이 온도보다 낮은 온도에서 수상채널이 고분자의 팽윤에 의해서 막혀 있는 상태를 나타내고, B도는 고분자의 상전이 온도보다 높은 온도에서 수상채널이 고분자의 수축에 의해서 열려 있는 상태를 나타낸다. 2 shows an aqueous channel of a monooleic cubic phase containing polyisopropylacrylamide. A shows the state in which the water channel is blocked by the swelling of the polymer at a temperature lower than the phase transition temperature of the polymer, and B shows the state in which the water channel is opened due to shrinkage of the polymer at a temperature higher than the phase of the polymer.
도 3은 폴리이소프로필아크릴아미드 수용액의 온도에 따른 탁도 변화를 관찰 한 결과이다.3 is a result of observing the change in turbidity according to the temperature of the polyisopropyl acrylamide aqueous solution.
도 4는 폴리이소프로필아크릴아미드과 소디움 살리실레이트(목적물질)를 함유한 모노올레인 큐빅상의 사진이다.4 is a photograph of a monoolein cubic phase containing polyisopropylacrylamide and sodium salicylate (target material).
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101360315B1 (en) * | 2012-06-26 | 2014-02-12 | 강원대학교산학협력단 | magnetic cubic phase nanoparticles and method for preparing the same |
| CN107286290A (en) * | 2017-05-26 | 2017-10-24 | 奎克化学（中国）有限公司 | A kind of Self-cleaning type antirust oil for metal base |
| KR20180121103A (en) * | 2017-04-28 | 2018-11-07 | 강원대학교산학협력단 | Monoolein cubic phase with glucose concentration-dependent release characteristics |
| KR20190005037A (en) * | 2017-07-05 | 2019-01-15 | 강원대학교산학협력단 | Reduction-responsive Lipid Nanostructures Crosslinked by Disulfide Linkage and Methods Thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101340586B1 (en) | 2011-12-12 | 2013-12-11 | 강원대학교산학협력단 | Photo-responsive cubic phase composition and method for preparing thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6638621B2 (en) | 2000-08-16 | 2003-10-28 | Lyotropic Therapeutics, Inc. | Coated particles, methods of making and using |
| FR2809957B1 (en) | 2000-06-08 | 2002-10-04 | Oreal | USE OF CUBIC GEL PARTICLES AS AN ANTI-POLLUTION AGENT, ESPECIALLY IN A COSMETIC COMPOSITION |
| EP1408932A4 (en) * | 2001-06-23 | 2009-02-25 | Lyotropic Therapeutics Inc | Particles with improved solubilization capacity |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101360315B1 (en) * | 2012-06-26 | 2014-02-12 | 강원대학교산학협력단 | magnetic cubic phase nanoparticles and method for preparing the same |
| KR20180121103A (en) * | 2017-04-28 | 2018-11-07 | 강원대학교산학협력단 | Monoolein cubic phase with glucose concentration-dependent release characteristics |
| CN107286290A (en) * | 2017-05-26 | 2017-10-24 | 奎克化学（中国）有限公司 | A kind of Self-cleaning type antirust oil for metal base |
| KR20190005037A (en) * | 2017-07-05 | 2019-01-15 | 강원대학교산학협력단 | Reduction-responsive Lipid Nanostructures Crosslinked by Disulfide Linkage and Methods Thereof |
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| KR100891545B1 (en) | 2009-04-03 |
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