Synthesis and characterization of stimuli-responsive hydrogels based on chitosan and synthetic polymers for drug delivery application
- Alternative Title
- 약물 전달 응용을 위한 키토산 및 합성 고분자에 기초한 자극 반응형 하이드로겔의 합성 및 특성화
- Abstract
- Nowadays, the application of renewable natural polymers is exploding in all fields, especially in the fields of biomedical materials, drug delivery systems, and diagnostic materials. However, it is difficult to achieve the desired properties for high performance biomaterial with using of only natural polymers, therefore modifying the structure of natural polymers or/and combining with synthetic polymers is necessary. Chitosan is one of natural polysaccharides that has been widely used in the preparation of biomedical materials and drug delivery system because of its special properties: biocompatibility, blood compatibility, tissue compatibility, nontoxicity with cell, muscoadhesive and high mechanical strength. However, as disadvantage that is mentioned above, the modification of the chitosan chain and combination with other synthetic polymers to optimize the advantages of chitosan have been more and more considered.
With the inspiration by chitosan and oral administration drug delivery systems, we prepared the novel dual pH-/thermal-responsive polyelectrolyte hydrogels based on the combination of norbornene-functionalized chitosan (CsNb) and poly(acrylic acid) (PAA) that synergized with chemical crosslink network with bistetrazine-poly(N-isopropyl acrylamide) (bisTz-PNIPAM). The polyionic (polyelectrolyte) network was formed by facile mixed of CsNb with PAA – the ammonium groups of CsNb and carboxylate of PAA created electrostatics interactions, in other side, the covalent bonds between CsNb and bisTz-PNIPAM was in-situ forming via inverse electron demand Diels-Alder reaction (iED-DA) between Nb and Tz groups.
The structure and properties of hydrogels were adjusted by changing the ratio of components in hydrogel compositions. The results shown that the drug release behavior was dual pH-/thermal-responsiveness and it depended on PAA amount and PNIPAM. The drug loading content was as a function of porous structure that generated by iED-DA reaction and the completely release was the key role of bisTz-PNIPAM crosslinker.
The combination of chitosan and synthetic polymers for preparation of multi stimuli responsive hydrogels has great potentials for application in oral administration drug delivery systems of diseases drug, insulin, proteins.
바이오의약품, 약물전달시스템, 진단물질 분야에서 재생 가능한 천연 중합체의 응용이 폭발적으로 증가하고 있다. 그러나 천연 중합체만을 사용해서는 고성능 바이오 소재에 대해 원하는 특성을 달성하기 어렵기 때문에 천연 중합체의 구조를 수정하거나 합성 중합체와 결합할 필요가 있다. 키토산은 생체적합성, 혈액적합성, 조직적합성, 세포와의 무독성, 근육질, 높은 기계적 강도라는 특수성 때문에 생물의약품 원료 조제 및 약물전달체계에 널리 사용되어 온 천연 다당류 중의 하나이다. 그러나 위에서 언급한 단점으로서 키토산의 장점을 최적화하기 위한 키토산 체인의 수정과 다른 합성 폴리머와의 결합이 점점 더 고려되어 왔다.
키토산과 경구 투여 약물 전달 시스템의 영감을 받아 bistetrazine-poly(N-isopropyl acrylamide)(bisTz-PNIPAM)과의 화학적 가교구조와 시너지 효과를 내는 노르보닌으로 기능화된 키토산(CsNb)과 poly(acrylic acid)(PAA)의 조합을 바탕으로 새로운 이중 pH/열 반응성의 polyelectrolyte 하이드로겔을 준비했다. Polyionic (polyelectrolyte) 가교구조는 CsNb과 PAA의 암모늄 그룹과 카복실산(carboxylate of PAA)의 혼합에 의해 형성되었다. 동시에, CsNb과 bisTz-PNIPAM 사이의 공유결합이 Inverse electron demand Diels-Alder reaction(iED-DA)을 통해 in-situ 방식으로 형성되었다.
하이드로겔 성분의 비율을 변경하여 하이드로겔의 구조와 성질을 조정하였다. 결과는 약물 방출 응답이 이중 pH/열 반응성이며 PAA와 PNIPAM의 함량에 의존한다는 것을 보여주었다. 약물 적재 함량은 iED-DA 반응에 의해 생성되는 다공성 구조의 함수로, 완전 방출은 bisTz-PNIPAM 가교제의 핵심 역할이었다.
키토산과 합성 고분자의 결합으로 여러 자극에 대한 반응성 하이드로겔은 약, 인슐린, 단백질의 경구 투여 약물 전달 시스템에 적용할 가능성이 크다.
- Issued Date
- 2021
- Awarded Date
- 2021. 2
- Type
- Dissertation
- Publisher
- 부경대학교
- Affiliation
- Pukyong National University Graduate School
- Department
- 대학원 스마트그린기술융합공학과
- Advisor
- Kwon Taek Lim
- Table Of Contents
- CHAPTER 1. GENERAL INTRODUCTION 1
1.1. Introduction about hydrogels for drug delivery systems. 1
1.2.Chitosan, chitosan-based hydrogels and application in pharmaceutical, medicine fields. 8
1.3.Smart materials based on stimuli-responsive polymers 13
1.3.1.Therrmo-responsive hydrogels 13
1.3.2.Poly (acrylic acid) (PAA) – based pH-responsive materials 15
1.3.3.The role of multi stimuli-responsive materials for specific DDS applications 15
1.4.The aim and outline of thesis 18
CHAPTER 2. SYNTHESIS OF PRECURSORS AND CHARACTERIZATIONS 19
SUMMARY OF CHAPTER 19
2.1. Introduction about “click” chemistry and its application in biomaterials fabrication. 20
2.2. Experiments 23
2.2.1. Materials 23
2.2.1. Functionalization of Chitosan by norbornene group 24
2.2.2. Synthesis of telechelic carboxylic Poly(N-Isopropyl acrylamide) (bisCOOH-PNIPAM) 25
2.2.3. Synthesis of tetrazine hydroxyl compound (Tz-OH) 26
2.2.4. Synthesis of telechelic tetrazine Poly(N-Isopropyl acrylamide) (bisTz-PNIPAM) 27
2.2.5. Characterizations 28
2.3. Results and discussions 28
2.3.1. Functionalization of Chitosan by norbornene group 28
2.3.2. Synthesis of telechelic carboxylic Poly(N-Isopropyl acrylamide) (bisCOOH-PNIPAM) 30
2.3.3. Synthesis of tetrazine hydroxyl compound (Tz-OH) 32
2.3.4. Synthesis of telechelic tetrazine Poly(N-Isopropyl acrylamide) (bisTz-PNIPAM) 34
CHAPTER 3. PREPARATION OF HYDROGELS, CHARACTERIZATIONS AND DRUG RELEASE PROFILES. 36
SUMMARY OF CHAPTER 36
3.1. Introduction 37
3.2. Experiments 39
3.2.1. Materials 39
3.2.2. Preparation of polyelectrolyte hydrogels 40
3.2.3. Characterization of hydrogels 41
3.2.4. Swelling properties 42
3.2.5. Drug loading to hydrogels 42
3.2.6. Release of the drug at different pH environments and temperatures 43
3.2.7. In vitro drug release studies 43
3.3. Results and discussions 43
3.3.1. Formation of polyelectrolyte network between polyanion and polyacation 44
3.3.2. FTIR spectra 45
3.3.3. X-ray diffraction analysis 47
3.3.4. Thermal properties 49
3.3.5. Morphological properties. 50
3.3.6. Swelling ratio 52
3.3.7. Drug loading content 54
3.3.8. Drug release at different pH environments. 56
3.3.9. Drug release at different temperatures 57
3.3.10. In vitro drug release in simulated GIT environment 58
3.4.CONCLUSION 59
4. REFERENCES 61
- Degree
- Master
- Appears in Collections:
- 대학원 > 스마트그린기술융합공학과
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