KR20090002946A - Thermo-sensitive polymer hydrogels having interpenetrating polymer network structure, preparation method thereof and injectable drug delivery system comprising the same - Google Patents
Thermo-sensitive polymer hydrogels having interpenetrating polymer network structure, preparation method thereof and injectable drug delivery system comprising the same Download PDFInfo
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Abstract
Description
도 1은 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔 내 P(NIPAAm)과 P(VPAc)의 조성비에 따른 저임계 용액온도(LCST)를 나타낸 도이다.1 is a view showing a low critical solution temperature (LCST) according to the composition ratio of P (NIPAAm) and P (VPAc) in the P (NIPAAm-co-VPAc) hydrogel of the present invention.
도 2는 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔 내에서 약물의 방출거동을 나타낸 도이다.Figure 2 is a diagram showing the release behavior of the drug in the P (NIPAAm-co-VPAc) hydrogel of the present invention.
본 발명은 상호침투성 가교구조를 갖는 온도감응성 고분자 하이드로겔, 이의 제조방법 및 이를 포함하는 주사제형 약물전달체에 관한 것이다.The present invention relates to a temperature sensitive polymer hydrogel having an interpenetrating crosslinked structure, a method for preparing the same, and an injectable drug carrier comprising the same.
하이드로겔(hydrogel)의 대표적인 특징은 물에 팽윤할 수 있는 친수성 고분자의 망상구조로서 많은 양의 물을 함유할 수 있다는 것이다. 하이드로겔의 3차원적인 망상구조는 공유결합, 수소결합, 반데르발스(Van der Waals) 결합 또는 물리적 응집 등 여러 요인에 의해 형성될 수 있다. 또한, 여러 가지 고분자 하이드로겔 은 온도, pH, 용매의 조성, 이온의 농도, 전기장, 광도, 화학물질 등과 같은 외부 자극에 대하여 민감하게 반응하여 연속적 또는 불연속적으로 함수율 등의 물성변화를 나타내게 된다.A typical feature of hydrogels is the network structure of hydrophilic polymers that can swell in water and can contain large amounts of water. The three-dimensional network structure of the hydrogel may be formed by various factors such as covalent bonds, hydrogen bonds, Van der Waals bonds, or physical aggregation. In addition, various polymer hydrogels react sensitively to external stimuli such as temperature, pH, composition of solvent, ion concentration, electric field, light intensity, chemicals, etc., and exhibit changes in physical properties such as water content continuously or discontinuously.
일반적으로 물에 용해 또는 팽윤될 수 있는 친수성 그룹을 고분자에 도입하게 되면 그 고분자는 물에 의해 용해 또는 팽윤될 수 있으며, 온도 증가에 따라 물에 대한 용해성은 증가하게 된다. 그러나 친수성과 소수성 부분으로 구성된 고분자는 온도 증가에 따라 물에 대한 용해성이 감소하는 저임계 용액온도(Lower Critical Solution Temperature; LCST)를 갖게 된다. 친수성과 소수성 부분으로 구성된 고분자는 낮은 온도에서 고분자의 친수기와 물분자 사이의 수소결합력이 우세하여 물에 용해되나, 온도를 증가시키면 고분자 소수기 부분의 결합력이 수소 결합력보다 우세하게 되므로 고분자의 소수기 부분의 응집이 일어나게 된다. 일반적으로 고분자에서 소수기 부분의 증가는 LCST를 낮추게 되므로, 친수기와 소수기의 분자사슬의 조절을 통해 LCST를 변화시킬 수 있다.In general, when a hydrophilic group capable of dissolving or swelling in water is introduced into a polymer, the polymer may be dissolved or swelled by water, and the solubility in water increases with increasing temperature. However, polymers composed of hydrophilic and hydrophobic moieties have a lower critical solution temperature (LCST) that decreases in solubility in water with increasing temperature. The polymer composed of hydrophilic and hydrophobic moieties dissolves in water because the hydrogen bonding force between the hydrophilic group and the water molecule of the polymer is predominant at low temperature, but as the temperature increases, the bonding force of the hydrophobic group of the polymer is superior to the hydrogen bonding force. Coagulation will occur. In general, since the increase of the hydrophobic group in the polymer lowers the LCST, the LCST can be changed by controlling the molecular chain of the hydrophilic group and the hydrophobic group.
폴리(N-이소프로필아크릴아미드) [Poly(N-isopropylacrylamide); PNIPAAm]는 약 32℃ 부근의 온도에서 LCST를 나타내며, 32℃ 이하에서는 물에 녹지만 32℃ 이상에서는 침전하는 경향을 보인다. 또한, 부틸메타아크릴레이트, 폴리에틸렌글리콜, 폴리프로필렌글리콜 등과 같은 공중합 고분자는 다양한 온도 범위에서 졸-겔 변화를 나타낸다. 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 (PEO-PPO-PEO)의 공중합체 또한 졸-겔 변화를 보이는 고분자로서, 많은 공중합체가 Pluronic, Poloxamer, Tetronic 등의 상품명으로 사용되고 있다. 또한 소수기 부분 에 생분해성 고분자 사슬로서 폴리(락트산/글리콜산) [poly(lactic acid/glycolic acid)], 폴리(카프로락톤) [poly(caprolactone)] 등을 도입한 고분자들에 관한 연구도 보고되고 있으나 온도에 대한 감응성은 PNIPAAm에 비해 현저하게 떨어진다.Poly (N-isopropylacrylamide) [Poly (N-isopropylacrylamide); PNIPAAm] shows LCST at a temperature around 32 ° C. and dissolves in water below 32 ° C., but tends to precipitate above 32 ° C. In addition, copolymerized polymers such as butyl methacrylate, polyethylene glycol, polypropylene glycol, and the like exhibit sol-gel changes over various temperature ranges. Copolymer of polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) is also a polymer exhibiting a sol-gel change, and many copolymers are used under trade names such as Pluronic, Poloxamer, and Tetronic. In addition, studies have been made on polymers incorporating poly (lactic acid / glycolic acid) [poly (lactic acid / glycolic acid)] and poly (caprolactone) [poly (caprolactone)] as biodegradable polymer chains. However, temperature sensitivity is significantly lower than that of PNIPAAm.
따라서, 대표적인 온도감응성 고분자인 PNIPAAm으로 이루어진 하이드로겔은 32℃ 부근에서 LCST를 갖고 있기 때문에, 이를 자극응답성 약물전달체로서 사용하고자 하는 연구가 많이 진행되어 왔다. 그러나 PNIPAAm 만으로 이루어진 하이드로겔의 경우 32℃ 이상의 온도에서는 소수성 특성이 상당히 증가하여 빠르게 응축하는 특성을 나타낸다.Therefore, since a hydrogel made of PNIPAAm, which is a typical temperature sensitive polymer, has LCST at around 32 ° C, many studies have been conducted to use it as a stimulant-responsive drug carrier. However, in the case of hydrogel consisting of PNIPAAm alone, the hydrophobic property increases considerably at a temperature of 32 ° C. or higher, thereby rapidly condensing.
이에, 본 발명자들은 높은 함수율을 유지하여 빠르게 응축하는 것을 방지할 수 있는 하이드로겔에 대하여 연구하던 중, 가교도를 낮추어 약하게 가교된 온도 감응성이 우수한 폴리(N-이소프로필아크릴아미드) [PNIPAAm]와 친수성 고분자인 폴리(비닐 포스폰산) [poly(vinyl phosphonic acid); P(VPAc)]으로 이루어진 P(NIPAAm-co-VPAc) 하이드로겔을 제조하였으며, 상기 P(NIPAAm-co-VPAc) 하이드로겔이 실온에서는 주사제형으로 인체에 주입할 수 있는 액체와 같은 물성을 나타내지만, LCST 이상의 온도인 체온 37℃에서는 기계적인 물성이 증가하면서 높은 함수율을 유지하여 하이드로겔이 빠르게 응축하는 것을 방지하여 지속적인 약물방출을 나타내는 것을 확인하고, 본 발명을 완성하였다.Therefore, while the present inventors are studying a hydrogel that can maintain a high water content and prevent rapid condensation, the present invention has a low crosslinking degree and has a weakly crosslinked temperature sensitivity and excellent hydrophilicity with poly (N-isopropylacrylamide) [PNIPAAm]. Polymer poly (vinyl phosphonic acid) [poly (vinyl phosphonic acid); P (VPAc)] was prepared P (NIPAAm-co-VPAc) hydrogel, and the P (NIPAAm-co-VPAc) hydrogel does not exhibit the same physical properties as the liquid that can be injected into the human body at room temperature. However, at a body temperature of 37 ° C., which is a temperature higher than LCST, the mechanical properties are increased while maintaining a high moisture content to prevent the hydrogel from condensing rapidly, thereby confirming the continuous drug release and completing the present invention.
본 발명은 상호침투성 가교구조를 갖는 온도감응성 고분자 하이드로겔, 이의 제조방법 및 이를 포함하는 주사제형 약물전달체를 제공하고자 한다.The present invention is to provide a thermosensitive polymer hydrogel having an interpenetrating crosslinked structure, a preparation method thereof, and an injectable drug carrier comprising the same.
본 발명은 폴리(N-이소프로필아크릴아미드) [poly(N-isopropylacrylamide); PNIPAAm]와 폴리(비닐 포스폰산) [poly(vinyl phosphonic acid); P(VPAc)]으로 이루어지며, 상호침투성 가교구조를 갖는 온도감응성 고분자[P(NIPAAm-co-VPAc)] 하이드로겔을 제공한다.The present invention is poly (N-isopropylacrylamide) [poly (N-isopropylacrylamide); PNIPAAm] and poly (vinyl phosphonic acid); P (VPAc)], and provides a thermosensitive polymer [P (NIPAAm-co-VPAc)] hydrogel having an interpenetrating crosslinking structure.
상기 고분자[P(NIPAAm-co-VPAc)] 하이드로겔은 PNIPAAm와 PVPAc이 90:10 내지 99:1로 이루어지며, 33~36℃의 저임계 용액온도(LCST)를 갖는 것을 특징으로 한다.The polymer [P (NIPAAm-co-VPAc)] hydrogel is composed of PNIPAAm and PVPAc 90:10 to 99: 1, characterized in that it has a low critical solution temperature (LCST) of 33 ~ 36 ℃.
상호침투성 가교구조(interpenetrating polymer network; IPN)는 분자규모에서 적어도 부분적으로 교차되나 공유결합이 아니며 화학결합이 깨지기 전까지는 분리되지 않는 2개 이상의 그물구조를 갖는 고분자를 말하는 것으로, 2개로 제조된 고분자의 혼합물과는 다르다. IPN의 종류는 중합방법과 형태에 따라 나뉘며, 이러한 IPN은 열경화성 수지를 대체할 수 있는 넓은 온도의 감쇄물질이나 보강된 탄성체를 형성하기도 하고, 어떤 종류의 IPN은 다른 고분자가 나타내기 힘든 연속적인 물리적, 기계적 성질을 나타낸다. 하이드로겔은 가교밀도가 낮은 친수성 가교 고분자로 평형상태에서 20~90%의 물을 포함하는 수화된 가교결합 중합체성 시스템이기 때문에 전형적으로 산소투과성이며 생체 상용성이다.Interpenetrating polymer network (IPN) refers to a polymer having two or more network structures that are at least partially cross-linked at the molecular scale but are not covalent and not separated until the chemical bond is broken. It is different from the mixture. The types of IPNs are divided according to the polymerization method and form, and these IPNs form a wide range of attenuating materials or reinforced elastomers to replace thermosetting resins, and some types of IPNs are continuous physical materials that are difficult for other polymers to exhibit. , Mechanical properties. Hydrogels are hydrophilic crosslinked polymers with low crosslinking density and are typically oxygen permeable and biocompatible because they are hydrated crosslinked polymeric systems containing 20-90% water at equilibrium.
또한, 본 발명은 상호침투성 가교구조를 갖는 온도감응성 고분자[P(NIPAAm-co-VPAc)] 하이드로겔의 제조방법을 제공한다.The present invention also provides a method for preparing a thermosensitive polymer [P (NIPAAm-co-VPAc)] hydrogel having an interpenetrating crosslinking structure.
본 발명의 제조방법은 폴리(N-이소프로필아크릴아미드) [PNIPAAm]와 폴리(비닐 포스폰산) [P(VPAc)]을 모노머로 사용하고, 가교제로 폴리에틸렌글리콜 디메타아크릴레이트(PEG dimethacrylate), 개시제로 APS(ammomium peroxydisulfate) 및 가속제로 TEMED(N,N,N',N'-tetramethylethylenediamine)를 사용하여 실온에서 24시간 방치하여 라디칼 중합반응 및 가교반응을 동시에 진행시켜 상호침투성 가교구조를 갖는 온도감응성 고분자[P(NIPAAm-co-VPAc)] 하이드로겔을 제조하며, 하기 반응식 1로 표시된다.In the production method of the present invention, poly (N-isopropylacrylamide) [PNIPAAm] and poly (vinyl phosphonic acid) [P (VPAc)] are used as monomers, and polyethylene glycol dimethacrylate (PEG dimethacrylate), APS (ammomium peroxydisulfate) as an initiator and TEMED (N, N, N ', N'-tetramethylethylenediamine) were used for 24 hours at room temperature to proceed radical polymerization and crosslinking at the same time to have an interpenetrating crosslinking structure. A sensitive polymer [P (NIPAAm-co-VPAc)] hydrogel was prepared, and is represented by Scheme 1 below.
상기 반응식 1에서, n은 1~1000의 정수이다.In Reaction Scheme 1, n is an integer of 1 to 1000.
본 발명의 제조방법은 두 가지 모노머 NIPAAm : VPAc의 공급 몰비를 90:10 내지 99:1로 변화시키면서 고분자[P(NIPAAm-co-VPAc)] 하이드로겔을 제조한다.The preparation method of the present invention prepares a polymer [P (NIPAAm-co-VPAc)] hydrogel while changing the molar ratio of two monomers NIPAAm: VPAc from 90:10 to 99: 1.
구체적으로, 상기와 같이 두 가지 모노머 NIPAAm : VPAc의 공급 몰비를 변화시킨 공중합체에, 가교제인 폴리에틸렌글리콜 디메타아크릴레이트(PEG dimethacrylate)의 공급 몰비를 전체 모노머 몰비에 대해 0.0015~1.5000 mol%로 변화시켜 넣고, 개시제인 APS(ammomium peroxydisulfate)를 전체 모노머 몰비에 대해 0.8 mol%, 가속제인 TEMED(N,N,N',N'-tetramethylethylenediamine)를 전체 모노머 몰비에 대해 8 mol%를 첨가하여 고르게 섞어준다. 상기 반응 혼합물을 실온에서 24시간 방치하여 라디칼 중합반응 및 가교반응을 동시에 진행시켜 상호침투성 가교구조를 갖는 온도감응성 고분자 하이드로겔[P(NIPAAm-co-VPAc)]을 제조한다.Specifically, in the copolymer having a change in the molar ratio of the two monomers NIPAAm: VPAc as described above, the supply molar ratio of the crosslinking agent polyethylene glycol dimethacrylate (PEG dimethacrylate) is changed to 0.0015 ~ 1.5000 mol% relative to the total monomer molar ratio. APS (ammomium peroxydisulfate) as an initiator is added and mixed evenly by adding 0.8 mol% to the total monomer molar ratio and TEMED (N, N, N ', N'-tetramethylethylenediamine) as the accelerator to 8 mol% relative to the total monomer molar ratio. give. The reaction mixture was allowed to stand at room temperature for 24 hours to simultaneously undergo radical polymerization and crosslinking to prepare a temperature sensitive polymer hydrogel [P (NIPAAm-co-VPAc)] having an interpenetrating crosslinking structure.
상기 제조방법에 따라 제조된 P(NIPAAm-co-VPAc) 하이드로겔은 실온(22℃)과 37℃에서 90% 이상의 함수율을 나타낸다. 또한, P(NIPAAm-co-VPAc) 하이드로겔 내 P(VPAc)의 공급 몰비가 증가함에 따라 LCST가 점차로 증가한다. 비록, P(NIPAAm-co-VPAc) 하이드로겔 내에서 NIPAAm에 대한 VPAc의 공급 몰비가 증가할수록 고분자 하이드로겔의 LCST와 함수율을 증가시킬 수 있으나, VPAc의 공급 몰비가 10 mol%를 초과하면 P(NIPAAm-co-VPAc) 하이드로겔은 온도에 대한 감응성이 떨어지게 된다.P (NIPAAm-co-VPAc) hydrogel prepared according to the above production method has a water content of 90% or more at room temperature (22 ℃) and 37 ℃. In addition, LCST gradually increases as the feed molar ratio of P (VPAc) in the P (NIPAAm-co-VPAc) hydrogel increases. Although, as the feed molar ratio of VPAc to NIPAAm in P (NIPAAm-co-VPAc) hydrogel increases, the LCST and water content of the polymer hydrogel can be increased, but if the feed molar ratio of VPAc exceeds 10 mol%, P ( NIPAAm-co-VPAc) hydrogels are less sensitive to temperature.
따라서, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔은 P(NIPAAm)과 P(VPAc)의 조성비에 따라 33~36℃로 LCST를 조절하여, 실온에서는 주사제형으로 인체에 주입할 수 있는 액체와 같은 물성을 나타내며, 인체의 체온인 37℃에서는 실온에서보다 어느 정도 함수율이 감소하지만 폴리(N-이소프로필아크릴아미드) [PNIPAAm]만으로 이루어진 하이드로겔처럼 급격한 함수율의 감소는 나타내지 않고 90% 이상의 함수율을 유지한다.Therefore, the P (NIPAAm-co-VPAc) hydrogel of the present invention is adjusted to LCST at 33 ~ 36 ℃ according to the composition ratio of P (NIPAAm) and P (VPAc), can be injected into the human body in the form of an injection at room temperature It has the same physical properties as the liquid, and its water content decreases to a certain extent at room temperature of 37 ° C., but it does not show a rapid decrease in moisture content like hydrogels composed of poly (N-isopropylacrylamide) [PNIPAAm] alone. Maintain moisture content.
또한, 본 발명은 상호침투성 가교구조를 갖는 온도감응성 고분자 하이드로겔 내에 약물을 담지한 주사제형 약물전달체를 제공한다.The present invention also provides an injectable drug carrier in which a drug is carried in a thermosensitive polymer hydrogel having an interpenetrating crosslinking structure.
본 발명의 제조방법에 따라 제조된 하이드로겔을 냉동건조한 후, 약물 수용액에 담가 용액확산(solution diffusion) 방법에 의해 약물이 담지된 하이드로겔을 제조한다.After freeze-drying the hydrogel prepared according to the preparation method of the present invention, a hydrogel in which the drug is loaded is prepared by a solution diffusion method by immersing in a drug aqueous solution.
본 발명에서 사용한 약물로는 소혈청알부민(bovin serum albumin; BSA)을 사용하였으나, 상기 약물은 특정 약제나 분류에 의해 제한되지 않으며, 투여에 적합한 화학적 또는 생물학적 물질 또는 화합물, 예를 들어 단백질, 펩타이드, 합성화합물, 추출물, 핵산, 골다공치료제, 항생제, 항암제, 소염진통제, 항바이러스제, 항균제, 호르몬 등 일 수 있다. 단백질 및 펩타이드 약물로는 소, 돼지, 양 등의 동물 성장 호르몬, 인간 성장 호르몬(hGH), 백혈구 성장 인자(G-CSF), 상피세포 성장 인자(EGF), 골 형성 단백질(BMP), 적혈구 증강제(EPO), 인터페론(INF), 인슐린, 글루카곤, 옥트레오타이드, 칼시토닌, 데카펩틸, 난포자극 호르몬 등의 합성 동족물, 변형물 및 그의 약리학적으로 활성 단편, 모노크로날 항체 및 가용성 백신 중에서 선택되는 펩타이드 및 단백질을 예시할 수 있다. 핵산으로는 DNA, RNA, 올리고뉴클레오티드 등으로 이루어진 군에서 선택되는 핵산을 예시할 수 있다. 골다공 치료제는 비스포스네이트 등을 예시할 수 있다. 항생제로는 테트라사이클린, 미노사이클린, 독시사이클린, 오플록사신, 레보플록사신, 시프로플록사신, 클라리스로마이신, 에리쓰로마이신, 세파클러, 세포탁심, 이미페넴, 페니실린, 겐타마이신, 스트렙토마이신, 반코마이신 등의 유도체 및 혼합물에서 선택되는 항생제를 예시할 수 있다. 항암제로는 메토트렉세이트, 카보플라틴, 탁솔, 시스플라틴, 5-플루오로우라실, 독소루비신, 에트포사이드,파클리탁셀, 캄토테신, 사이토신 아라비노스 등의 유도체 및 혼합물에서 선택되는 항암제를 예시할 수 있다. 소염 진통제로는 인도메타신, 이부프로펜, 케토프로펜, 피록시캄, 플루비프로펜, 디클로페낙 등의 유도체 및 혼합물에서 선택되는 것들을 예시할 수 있다. 항바이러스제로는 아시콜로버, 로바빈 등의 유도체 및 혼합물에서 선택되는 항바이러스제를 예시할 수 있다. 항균제로는 케토코나졸, 이트라코나졸, 플루코나졸, 암포테리신-B, 그리세오풀빈 등의 유도체 및 혼합물에서 선택되는 항균제를 예시할 수 있다.Bovin serum albumin (BSA) was used as the drug used in the present invention, but the drug is not limited by a specific drug or classification, and is suitable for administration of a chemical or biological substance or compound, for example, a protein or a peptide. , Synthetic compounds, extracts, nucleic acids, osteoporosis, antibiotics, anticancer agents, anti-inflammatory drugs, antiviral agents, antibacterial agents, hormones and the like. Protein and peptide drugs include animal growth hormones such as cattle, pigs, sheep, human growth hormone (hGH), leukocyte growth factor (G-CSF), epithelial growth factor (EGF), bone morphogenetic protein (BMP), erythropoietin (EPO), interferon (INF), insulin, glucagon, octreotide, calcitonin, decapeptyl, synthetic homologs such as follicle stimulating hormones, variants and their pharmacologically active fragments, monoclonal antibodies and soluble vaccines Peptides and proteins can be exemplified. The nucleic acid can be exemplified a nucleic acid selected from the group consisting of DNA, RNA, oligonucleotide and the like. Osteoporosis therapeutics can be exemplified by bisphosphates and the like. Antibiotics include derivatives and mixtures of tetracycline, minocycline, doxycycline, opfloxacin, levofloxacin, ciprofloxacin, clarithromycin, erythromycin, sefacller, cefotaxime, imipenem, penicillin, gentamicin, streptomycin, vancomycin and the like. The antibiotic selected can be illustrated. Examples of the anticancer agent include an anticancer agent selected from derivatives and mixtures of methotrexate, carboplatin, taxol, cisplatin, 5-fluorouracil, doxorubicin, etoposide, paclitaxel, camptothecin, cytosine arabinose and the like. Anti-inflammatory analgesics can be exemplified by those selected from derivatives and mixtures of indomethacin, ibuprofen, ketoprofen, pyroxicam, flubiprofen, diclofenac and the like. The antiviral agent can be exemplified by an antiviral agent selected from derivatives and mixtures such as acicolober, lovabin and the like. The antimicrobial agent may be exemplified by an antimicrobial agent selected from derivatives and mixtures such as ketoconazole, itraconazole, fluconazole, amphotericin-B, griseofulvin and the like.
본 발명의 P(NIPAAm-co-VPAc) 하이드로겔에 담지된 약물은 그 자체로 약학적 활성을 나타낼 수도 있고, 또는 인체 내에서 생체 내 변화에 의해 활성 형태로 변환될 수도 있다.The drug supported on the P (NIPAAm-co-VPAc) hydrogel of the present invention may exhibit pharmaceutical activity by itself or may be converted into an active form by in vivo changes in the human body.
또한, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔에 담지된 약물은 임의로 희석제, 방출 지연제, 비활성 오일, 결합제 등의 당 기술 분야에서 다양한 부형제를 선택적으로 혼합할 수 있다.In addition, the drug supported on the P (NIPAAm-co-VPAc) hydrogel of the present invention may optionally mix various excipients in the art, such as diluents, release retardants, inert oils, binders and the like.
상기 약물이 담지된 P(NIPAAm-co-VPAc) 하이드로겔은 P(NIPAAm) 하이드로겔에 비해 65~92%의 높은 약물 담지율을 나타내며, P(NIPAAm-co-VPAc) 하이드로겔 내 의 P(VPAc) 함량비가 증가할수록 약물 담지율이 점차적으로 증가한다. 또한, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔로부터 약물의 방출은 초기의 빠른 방출거동 없이 일주일 이상 지속된다.The drug-supported P (NIPAAm-co-VPAc) hydrogel exhibited a higher drug loading rate of 65-92% compared to the P (NIPAAm) hydrogel, and the P (NIPAAm-co-VPAc) hydrogel contained P (NIPAAm-co-VPAc) hydrogel. As the VPAc) content ratio increases, the drug loading rate gradually increases. In addition, the release of the drug from the P (NIPAAm-co-VPAc) hydrogel of the present invention lasts more than a week without the initial rapid release behavior.
따라서, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔은 고분자의 조성비와 가교도를 조절하여 함수율과 하이드로겔 내에 담지된 약물의 방출속도를 제어할 수 있으므로, 주사제형 약물전달체로서 유용하게 사용될 수 있다.Therefore, the P (NIPAAm-co-VPAc) hydrogel of the present invention can control the water content and release rate of the drug supported in the hydrogel by controlling the composition ratio and the degree of crosslinking of the polymer, and thus can be usefully used as an injection drug delivery agent. have.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.
실시예Example 1~6 1-6 : 조성을 변화시킨 P( : P (change in composition) NIPAAmNIPAAm -- coco -- VPAcVPAc ) ) 하이드로겔의Hydrogel 제조 Produce
N-이소프로필아크릴아미드(NIPAAm)와 비닐 포스폰산(VPAc) 모노머의 공급 몰비를 하기 표 1과 같이 변화시키면서 (NIPAAm : VPAc = 90:10 내지 99:1) 온도감응성 고분자 하이드로겔을 제조하였다. 구체적으로, NIPAAm과 VPAc, 가교제로 폴리에틸렌글리콜 디메타아크릴레이트(PEG dimethacrylate) (전체 모노머 몰비에 대해 0.1500 mol%)를 플라스크 내에서 100 ㎖의 초순수에 녹인 후, 건조 질소 기체를 15분간 불어넣어 산소를 제거하였다. 여기에 개시제로 APS(ammomium peroxydisulfate) (전체 모노머 몰비에 대해 0.8 mol%)와 가속제로 TEMED (N,N,N',N'-tetramethylethylenediamine) (전체 모노머 몰비에 대해 8 mol%)를 첨가하였다. 상기 반응 혼합물을 30초 정도 고르게 섞어준 후, 실온에서 24시간 방치하여 라디칼 중합반응 및 가교반응을 동시에 진행시켜 P(NIPAAm-co-VPAc) 하이드로 겔을 제조하였다.A temperature-sensitive polymer hydrogel was prepared by varying the supply molar ratio of N-isopropylacrylamide (NIPAAm) and vinyl phosphonic acid (VPAc) monomer as shown in Table 1 below (NIPAAm: VPAc = 90:10 to 99: 1). Specifically, polyethylene glycol dimethacrylate (0.1500 mol% based on the total monomer molar ratio) is dissolved in 100 ml of ultrapure water in a flask using NIPAAm, VPAc, and a crosslinking agent, followed by blowing dry nitrogen gas for 15 minutes. Was removed. To this was added ampsium peroxydisulfate (APS) (0.8 mol% relative to the total monomer molar ratio) as initiator and TEMED (N, N, N ', N'-tetramethylethylenediamine) (8 mol% relative to the total monomer molar ratio) as accelerator. After the reaction mixture was evenly mixed for about 30 seconds, the mixture was left at room temperature for 24 hours to simultaneously undergo radical polymerization and crosslinking to prepare P (NIPAAm-co-VPAc) hydrogel.
실시예Example 7~9 7-9 : : 가교도를Degree of crosslinking 조절한 P( Adjusted P ( NIPAAmNIPAAm -- coco -- VPAcVPAc ) ) 하이드로겔의Hydrogel 제조 Produce
N-이소프로필아크릴아미드(NIPAAm)와 비닐 포스폰산(VPAc) 모노머의 공급 몰비를 97:3으로 일정하게 하고, 전체 모노머에 대한 가교제 폴리에틸렌글리콜 디메타아크릴레이트(PEG dimethacrylate)의 공급 몰비를 하기 표 1과 같이 0.0015~1.5000 mol% 범위로 변화시키면서 상기 실시예 1~6의 방법과 동일하게 하여 하이드로겔을 제조하였다.The supply molar ratio of the N-isopropylacrylamide (NIPAAm) and the vinyl phosphonic acid (VPAc) monomer was kept constant at 97: 3, and the supply molar ratio of the crosslinking agent polyethylene glycol dimethacrylate to the total monomers was shown in the following table. Hydrogel was prepared in the same manner as in Examples 1 to 6 while varying in the range of 0.0015 to 1.5000 mol%, as in Example 1.
비교예Comparative example 1 One : P( : P ( NIPAAmNIPAAm ) ) 하이드로겔의Hydrogel 제조 Produce
상기 실시예 1~6에서 비닐 포스폰산(VPAc) 모노머를 넣지 않고 N-이소프로필아크릴아미드(NIPAAm)만 주성분으로 사용한 것을 제외하고는, 상기 실시예 1~6의 방법과 동일하게 하여 하이드로겔을 제조하였다.Hydrogels were prepared in the same manner as in Examples 1 to 6, except that only N-isopropylacrylamide (NIPAAm) was used as a main component without adding the vinyl phosphonic acid (VPAc) monomer in Examples 1 to 6. Prepared.
실험예Experimental Example 1 One : 본 발명의 P( : P of the present invention NIPAAmNIPAAm -- coco -- VPAcVPAc ) ) 하이드로겔의Hydrogel 함수율 측정 Moisture content measurement
본 발명의 P(NIPAAm-co-VPAc) 하이드로겔의 온도 변화에 따른 함수율을 측정하기 위하여, 하기와 같은 실험을 수행하였다.In order to measure the moisture content according to the temperature change of the P (NIPAAm-co-VPAc) hydrogel of the present invention, the following experiment was performed.
상기 실시예 1 내지 9에서 제조한 P(NIPAAm-co-VPAc) 하이드로겔과 비교예 1에서 제조한 P(NIPAAm) 하이드로겔을 냉동건조시킨 후, 건조된 하이드로겔의 무게를 측정하였다. 상기 건조무게를 측정한 하이드로겔을 인산염 완충용액 10㎖에 침지시켜 실온(22℃)과 37℃에서 방치한 다음, 24시간 후 하이드로겔의 무게를 측정하였다. 하이드로겔의 함수율은 하이드로겔의 팽윤되기 전과 후의 무게를 기준으로 하여 하기 수학식 1에 의하여 계산하였다.After freeze-drying the P (NIPAAm-co-VPAc) hydrogel prepared in Examples 1 to 9 and the P (NIPAAm) hydrogel prepared in Comparative Example 1, the weight of the dried hydrogel was measured. The dried hydrogel was immersed in 10 ml of phosphate buffer solution and left at room temperature (22 ° C.) and 37 ° C., and the hydrogel was weighed after 24 hours. The water content of the hydrogel was calculated by the following Equation 1 based on the weight before and after the hydrogel was swollen.
결과는 표 2에 나타내었다.The results are shown in Table 2.
※ Ws : 팽윤된 하이드로겔의 무게, Wd : 건조된 하이드로겔의 무게※ W s : Weight of swollen hydrogel, W d : Weight of dried hydrogel
표 2에 나타난 바와 같이, 상기 실시예 1 내지 9 및 비교예 1에서 제조된 하이드로겔 모두 실온(22℃)에서는 90% 이상의 함수율을 나타내었다. 그러나 37℃에서는, 비교예 1에서 제조된 P(NIPAAm) 하이드로겔의 경우 60% 이하로 급격한 함수율의 감소를 나타낸 반면, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔의 경우 함수율이 실온에 비해 약간 감소하였으나 90% 이상의 함수율을 유지하였다.As shown in Table 2, all of the hydrogels prepared in Examples 1 to 9 and Comparative Example 1 exhibited a water content of 90% or more at room temperature (22 ° C). However, at 37 ° C., the P (NIPAAm) hydrogel prepared in Comparative Example 1 showed a rapid decrease in moisture content of 60% or less, whereas the water content of the P (NIPAAm-co-VPAc) hydrogel of the present invention was measured at room temperature. Although slightly reduced, the moisture content was maintained above 90%.
실험예Experimental Example 2 2 : 본 발명의 P( : P of the present invention NIPAAmNIPAAm -- coco -- VPAcVPAc ) ) 하이드로겔의Hydrogel 저임계Low threshold 용액온도 (LCST) 측정 Solution temperature (LCST) measurement
본 발명의 P(NIPAAm-co-VPAc) 하이드로겔의 저임계 용액온도를 측정하기 위하여, 하기와 같은 실험을 수행하였다.In order to measure the low critical solution temperature of the P (NIPAAm-co-VPAc) hydrogel of the present invention, the following experiment was performed.
상기 실시예 1 내지 9에서 제조한 P(NIPAAm-co-VPAc) 하이드로겔과 비교예 1에서 제조한 P(NIPAAm) 하이드로겔의 초기무게를 측정한 후, 상기 하이드로겔을 인산염 완충용액 10㎖에 침지시키고, 0.5℃씩 온도를 상승시키면서 각 온도에서 하이드로겔의 무게를 측정하였다(n=3).After measuring the initial weight of the P (NIPAAm-co-VPAc) hydrogel prepared in Examples 1 to 9 and P (NIPAAm) hydrogel prepared in Comparative Example 1, the hydrogel in 10 ml of phosphate buffer It was immersed and the weight of the hydrogel was measured at each temperature while increasing the temperature by 0.5 ℃ (n = 3).
결과는 도 1에 나타내었다.The results are shown in FIG.
도 1에 나타난 바와 같이, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔 내 P(VPAc)의 공급 몰비가 증가할수록 LCST가 점차로 증가하였다. 또한, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔 내 P(NIPAAm)과 P(VPAc)의 공급 몰비에 따라 33~36℃로 LCST를 조절할 수 있었다.As shown in FIG. 1, the LCST gradually increased as the feed molar ratio of P (VPAc) in the P (NIPAAm-co-VPAc) hydrogel of the present invention increased. In addition, LCST was adjusted to 33 ~ 36 ℃ according to the molar ratio of P (NIPAAm) and P (VPAc) in the P (NIPAAm-co-VPAc) hydrogel of the present invention.
실험예Experimental Example 3 3 : 본 발명의 P( : P of the present invention NIPAAmNIPAAm -- coco -- VPAcVPAc ) ) 하이드로겔Hydrogel 내의 약물 Drugs within 담지율Support rate 측정 Measure
본 발명의 P(NIPAAm-co-VPAc) 하이드로겔 내의 약물 담지율을 측정하기 위하여, 하기와 같은 실험을 수행하였다.In order to measure the drug loading in the P (NIPAAm-co-VPAc) hydrogel of the present invention, the following experiment was performed.
약 0.1g의 냉동건조된 상기 실시예 2 내지 6에서 제조한 P(NIPAAm-co-VPAc) 하이드로겔과 비교예 1에서 제조한 P(NIPAAm) 하이드로겔의 건조 무게를 측정한 후, 이를 소혈청알부민(bovin serum albumin; BSA) 수용액 50 ㎎/㎖에 24시간 동안 침지시켰다. 24시간 후, 약물 수용액 내에서 팽윤된 하이드로겔의 무게를 측정하였다. 농도를 알고 있는 약물 수용액과, 하이드로겔의 건조무게 및 팽윤무게를 기준으로 약물의 담지율을 측정하였다.After measuring the dry weight of the P (NIPAAm-co-VPAc) hydrogel prepared in Examples 2 to 6 and the P (NIPAAm) hydrogel prepared in Comparative Example 1, the freeze-dried bovine serum It was immersed in 50 mg / ㎖ of aqueous albumin (bovin serum albumin (BSA)) for 24 hours. After 24 hours, the swelled hydrogel was weighed in aqueous drug solution. The supporting ratio of the drug was measured based on the aqueous solution of the drug having a known concentration and the dry weight and swelling weight of the hydrogel.
결과는 표 3에 나타내었다.The results are shown in Table 3.
표 3에 나타난 바와 같이, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔은 P(NIPAAm) 하이드로겔에 비해 65~92%의 높은 약물 담지율을 나타내었으며, P(VPAc)의 함량비가 증가할수록 약물 담지율이 점차적으로 증가하였다.As shown in Table 3, the P (NIPAAm-co-VPAc) hydrogel of the present invention showed a higher drug loading rate of 65-92% compared to the P (NIPAAm) hydrogel, and the content ratio of P (VPAc) was increased. The drug loading rate gradually increased.
실험예Experimental Example 4 4 : 본 발명의 P( : P of the present invention NIPAAmNIPAAm -- coco -- VPAcVPAc ) ) 하이드로겔Hydrogel 내의 undergarment 약물방출거동Drug release behavior
본 발명의 P(NIPAAm-co-VPAc) 하이드로겔 내에서 약물의 방출거동을 측정하기 위하여, 하기와 같은 실험을 수행하였다.In order to measure the release behavior of the drug in the P (NIPAAm-co-VPAc) hydrogel of the present invention, the following experiment was performed.
상기 실험예 3과 동일한 방법으로 하여, 상기 실시예 3 및 5에서 제조한 P(NIPAAm-co-VPAc) 하이드로겔과 비교예 1에서 제조한 P(NIPAAm) 하이드로겔 내에 약물(소혈청알부민, BSA)을 도입하였다. 약물이 담지된 건조 하이드로겔 0.1g을 각각 인산염 완충용액(PBS, 0.1M, pH 7.4) 30㎖에 넣고, 37℃를 유지하면서 흔들어주었다. 일정시간마다 방출매질로부터 0.5~5 ㎖ 씩 취하고 새로운 방출매질을 채워넣으면서 자외선 분광기를 사용하여 물질의 흡광도를 측정하였다. 측정된 흡광도로 약물의 방출거동을 검토하였다.In the same manner as in Experimental Example 3, P (NIPAAm-co-VPAc) hydrogels prepared in Examples 3 and 5 and P (NIPAAm) hydrogels prepared in Comparative Example 1 (bovine serum albumin, BSA ) Was introduced. 0.1 g of the dry hydrogel loaded with the drug was put in 30 ml of phosphate buffer solution (PBS, 0.1M, pH 7.4), respectively, and shaken while maintaining 37 ° C. 0.5 to 5 ml of the release medium was taken at regular intervals, and the absorbance of the material was measured using an ultraviolet spectrometer while the new release medium was filled. The release behavior of the drug was examined with the measured absorbance.
결과는 도 2에 나타내었다.The results are shown in FIG.
도 2에 나타난 바와 같이, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔로부터 약물의 방출은 초기의 빠른 방출거동 없이 일주일 이상 지속됨을 확인할 수 있었다.As shown in Figure 2, it was confirmed that the release of the drug from the P (NIPAAm-co-VPAc) hydrogel of the present invention lasts for more than a week without the initial rapid release behavior.
본 발명에 따른 P(NIPAAm-co-VPAc) 하이드로겔은 P(NIPAAm)과 P(VPAc)의 조성비에 따라 33~36℃로 LCST를 조절하여, 실온에서는 주사제형으로 인체에 주입할 수 있는 액체와 같은 물성을 나타내며, 인체의 체온인 37℃에서는 어느 정도 기계적 물성을 증가시키면서 90% 이상의 높은 함수율을 유지한다. 또한, 본 발명의 P(NIPAAm-co-VPAc) 하이드로겔은 고분자의 조성비와 가교도를 조절하여 하이드로겔의 함수율과 LCST를 조절함으로써 하이드로겔 내에 담지된 약물의 방출속도를 제어 할 수 있으므로, 주사제형 약물전달체로서 유용하게 사용될 수 있다.P (NIPAAm-co-VPAc) hydrogel according to the present invention by adjusting the LCST to 33 ~ 36 ℃ according to the composition ratio of P (NIPAAm) and P (VPAc), a liquid that can be injected into the human body as an injection at room temperature It shows the same physical properties, and maintains a high water content of more than 90% while increasing the mechanical properties to some extent at 37 ℃, the body temperature of the human body. In addition, the P (NIPAAm-co-VPAc) hydrogel of the present invention can control the release rate of the drug supported in the hydrogel by controlling the moisture content and LCST of the hydrogel by controlling the composition ratio and the degree of crosslinking of the polymer. It can be usefully used as a drug carrier.
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