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논문 기본 정보

자료유형
학위논문
저자정보

Keum-Yong Seong (부산대학교, 부산대학교 대학원)

지도교수
양승윤
발행연도
2020
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부산대학교 논문은 저작권에 의해 보호받습니다.

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이 논문의 연구 히스토리 (2)

2020

Development of Biodegradable Microneedle Patches for Controlled Transdermal Drug Delivery
Keum-Yong Seong 바이오소재과학과 2020.01 학위논문

2016

Biodegradable Microneedle Patches for Tissue Adhesion and Controlled Drug Delivery
Keum-Yong Seong ,  Seung Yun Yang 한국고분자학회 학술대회 연구논문 초록집 2016.10 학술대회자료

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Microneedles (MNs) have recently been adopted for use as a painless and effective method of transdermal therapeutic delivery across skin in a minimally invasive manner. Depending on drug delivery mechanism, various MN designs and materials have been investigated. Among them, hydrogel-forming MNs by absorption of body fluids after insertion into the skin have been widely used to achieve prolonged drug release. This swellable MN system, mainly prepared by crosslinking of synthetic polymers, can easily control drug release kinetics by adjusting the crosslinking density. However, poor biocompatibility limits their use in the medical field. In addition, achieving precise dose control through MN-assisted transdermal drug delivery system presents considerable challenges. The main contribution of this thesis is proposing suitable MN materials and rationale MN structures to achieve controlled transdermal drug delivery. In pursuing this primary objective, natural biopolymers present in our body have been used to fabricate transdermal MN patches. This thesis is organized as follows:
Chapter I introduces the MN-based transdermal drug delivery system and presents the goal of this thesis (development of biodegradable MN system for controlled transdermal drug delivery).
In chapter 2, we present a new biodegradable MN system for delivering of therapeutics including chemical drugs and peptides through the transdermal route. The biodegradable swellable MNs made by crosslinked natural polymer (genipin-crosslinked gelatin, gelpin) showed a water-responsiveness following absorption of dermal interstitial fluid and demonstrated different release rate of encapsulated drugs through the dissolution and degradation of the crosslinked polymer network.
Charter 3 shows the swellable air-pocket MNs (sAP-MNs) prepared by gelpin, enabling shear-induced implantation inside skin following distal swelling of MN tips by absorbing the interstitial fluids. The gelpin-based sAP-MNs exhibited mechanical interlocking with the skin tissue after absorption of body fluids. The swollen MN tips interlocked at the interface between inserted tips and the un-inserted bottom part of MNs was easily broken. Since loaded drugs in the embedded MN tips can be released by passive diffusion through the swollen hydrogel networks, a long-term drug release was achieved. For immediate application of this embeddable MN system, sAP-MNs loading minoxidil (MXD) was applied to prevent hair loss. In addition, MXD-loaded sAP-MNs showed the potential to regrowth the hair in a preclinical model which could provide a minimally invasive treatment of hair loss.
In chapter 4, we exploited a biodegradable MN patch that delivers hyaluronate (HA)-antigen peptide conjugates for the treatment of melanoma. The conjugation of the antigenic peptide to HA prolonged the residence time of the peptide in skin tissue, which improved the antigen-specific immune response. Interestingly, the HA MN patch delivering HA-antigenic peptide conjugate for the treatment of melanoma improved antigen-specific cytotoxic T lymphocyte (CTL) responses.
Overall, these results show great promise for both sustained transdermal drug delivery and precise dose control in biomedical applications.

목차

Lists of Contents
List of Contents…………………………………………………………………i
List of Figures……………………………………………………………………v
List of Tables……………………………………………………………………xi
Abbreviations…………………………………………………………………xii
Abstract………………………………………………………………………xiv
Chapter I: Introduction
1.1. Skin anatomy…………………………………………………………………1
1.1.1. The epidermis………………………………………………………………………………1
1.1.2. The dermis…………………………………………………………………………………2
1.1.3. The hypodermis……………………………………………………………………………2
1.2. Transdermal drug delivery system……………………………………………3
1.2.1. Physical methods for enhanced transdermal drug delivery…………………………………4
1.2.2. Chemical methods for enhanced transdermal drug delivery…………………………………4
1.3. Microneedles (MNs)…………………………………………………………5
1.3.1. MNs as a tool for transdermal drug delivery………………………………………………5
1.3.2. Types of MNs………………………………………………………………………………5
1.3.2.1. Solid MNs…………………………………………………………………………6
1.3.2.2. Coated MNs………………………………………………………………………7
1.3.2.3. Dissolving MNs……………………………………………………………………7
1.3.2.4. Hollow MNs………………………………………………………………………7
1.3.2.5. Hydrogel-forming MNs……………………………………………………………8
1.4. Applications of MNs…………………………………………………………8
1.4.1. Drug delivery………………………………………………………………………………8
1.4.2. Vaccination…………………………………………………………………………………8
1.4.3. Diagnostics…………………………………………………………………………………9
1.4.4. Current clinical research in humans………………………………………………………10
1.5. Motivation and objectives…………………………………………………11
1.6. References…………………………………………………………………13
Chapter II: Biodegradable microneedles patches for controlled degradability and drug release
2.1. Introduction…………………………………………………………………20
2.2. Experimental………………………………………………………………22
2.2.1. Preparation of genipin-crosslinked gelatin films…………………………………………22
2.2.2. Evaluation of crosslinking density by ninhydrin assay……………………………………23
2.2.3. Swelling test of gelpin films………………………………………………………………23
2.2.4. Mechanical properties of gelpin hydrogels………………………………………………24
2.2.5. In vivo degradation tests……………………………………………………………………24
2.2.6. Fabrication of gelpin microneedle patches………………………………………………25
2.2.7. Measurement of fracture force……………………………………………………………25
2.2.8. Analysis of swelling behavior of gelpin microneedles……………………………………26
2.2.9. In vitro drug release test……………………………………………………………………26
2.2.10. In vivo application of gelpin MNs………………………………………………………26
2.3. Results and Discussion………………………………………………………27
2.3.1. Characterization of gelpin films depending on crosslinking density……………………27
2.3.2. In vivo biodegradability of gelpin films……………………………………………………30
2.3.3. Fabrication gelpin MNs……………………………………………………………………32
2.3.4. Mechanical properties of MNs with geometry and different genipin concentration………33
2.3.5. Water-responsiveness of the gelpin MNs…………………………………………………34
2.3.6. In vitro drug release test using a model drug………………………………………………36
2.3.7. In vivo application of gelpin MNs…………………………………………………………37
2.4. Conclusion…………………………………………………………………39
2.5. References…………………………………………………………………40
Chapter III: One-touch embeddable microneedles for hair loss treatment
3.1. Introduction…………………………………………………………………45
3.2. Experimental………………………………………………………………47
3.2.1. Preparation and characterisation of genipin-crosslinked fish gelatin films………………47
3.2.1.1. Preparation of genipin-crosslinked fish gelatin films……………………………47
3.2.1.2. Swelling tests of genipin-crosslinked fish gelatin films…………………………48
3.2.1.3. Analysis of mechanical properties…………………………………………………48
3.2.2. Preparation of air-pocket MNs (AP-MNs) with a genipin-crosslinked fish gelatin………48
3.2.3. Measurement of penetration forces of AP-MNs……………………………………………49
3.2.4. Measurement of fracture forces of AP-MNs………………………………………………49
3.2.5. In vitro swelling and embedding tests of AP-MNs…………………………………………49
3.2.6. Ex vivo embedding test……………………………………………………………………50
3.2.7. Simulation…………………………………………………………………………………50
3.2.8. In vivo microparticle infiltration test……………………………………………………50
3.2.9. Preparation of MXD-loaded AP-MNs and ex vivo drug release test using Franz diffusion cells…………………………………………………………………………………………51
3.2.10. Animals and care…………………………………………………………………………52
3.2.11. Efficacy test of MXD-loaded MNs with experiment animals……………………………52
3.2.12. Histological analysis………………………………………………………………………53
3.2.13. Western blot analysis……………………………………………………………………53
3.2.14. In vivo pharmacokinetics of MXD………………………………………………………54
3.2.15. Statistical analysis………………………………………………………………………55
3.3. Results and Discussion………………………………………………………55
3.3.1. Characterisation of genipin-crosslinked fish gelatin films…………………………………55
3.3.2. Fabrication and characterisation of AP-MNs………………………………………………58
3.3.3. Swelling and embedding behaviour of AP-MNs…………………………………………61
3.3.4. In vivo infiltration test……………………………………………………………………66
3.3.5. Ex vivo drug permeation test………………………………………………………………67
3.3.6. In vivo hair growth test……………………………………………………………………70
3.3.7. In vivo pharmacokinetics…………………………………………………………………74
3.4. Conclusions…………………………………………………………………76
3.5. References…………………………………………………………………77
Chapter IV: Delivering of Antigenic Peptide - Hyaluronate Conjugate using a Biodegradable Microneedle Patch for Cancer Immunotherapy
4.1. Introduction…………………………………………………………………83
4.2. Experimental………………………………………………………………84
4.2.1. Materials…………………………………………………………………………………84
4.2.2. Synthesis of multivalent HA ? antigenic peptide conjugate………………………………85
4.2.3. Fabrication and characterization of HA MN patches containing the conjugates…………86
4.2.4. Mechanical strength test of MNs…………………………………………………………86
4.2.5. Animal care………………………………………………………………………………87
4.2.6. Two-photon microscopy of MN-assisted transdermal delivery……………………………87
4.2.7. MN-assisted transdermal immunization……………………………………………………87
4.2.8. Tumor monitoring…………………………………………………………………………88
4.2.9. Statistical analysis…………………………………………………………………………88
4.3. Results and Discussion………………………………………………………89
4.3.1. Synthesis and characterization of multivalent HA ? antigenic peptide conjugate…………89
4.3.2. Fabrication and characterization of HA MN patch containing the conjugate………………92
4.3.3. In vivo MN-assisted transdermal delivery of HA?antigenic peptide conjugates…………95
4.3.4. MN-assisted transdermal immunization for prophylactic immunotherapy………………98
4.4. Conclusions………………………………………………………………101
4.5. References………………………………………………………………102
Summary………………………………………………………………………106
Abstract (In Korean)…………………………………………………………107
Curriculum Vitae……………………………………………………………109
Acknowledgement…………………………………………………………114

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