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系統識別號 U0026-2608201310104500
論文名稱(中文) 疏水性修飾幾丁聚醣做為皮膚輸送藥物載體之研究
論文名稱(英文) Hydrophobically Modified Glycol Chitosan Gel as Drug Carrier for Skin Delivery
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 101
學期 2
出版年 102
研究生(中文) 王博駿
研究生(英文) Po-Chun Wang
學號 tb8951010
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-蔡瑞真
召集委員-駱雨利
口試委員-許漢銘
口試委員-林鴻儒
口試委員-簡偉明
中文關鍵字 乙二醇幾丁聚醣  分子量  維他命C磷酸鎂鹽  薑黃素  皮膚滲透性  皮膚滯留量 
英文關鍵字 glycol chitosan  molecular weight  magnesium ascorbyl phosphate  curucmin  skin permeability  skin deposition 
學科別分類
中文摘要 皮膚傳遞方法比注射或口服給藥有更多優勢,因為它可以避免肝臟首渡代謝效應,而且可以提供病患簡單而方便的給藥途徑。乙二醇幾丁聚醣是一種幾丁聚醣的水溶性衍生物,具有生物相容性、生物分解性、無毒性等特性,然而乙二醇幾丁聚醣的親水性限制了它在皮膚製劑上的應用。本研究之目的在以palmitic和 lauric acid修飾乙二醇幾丁聚醣形成具有兩性聚合物GCP 和GCL (palmitoyl glycol chitosan和lauroyl glycol chitosan),提供做為皮膚輸送系統的藥物載體。
本研究進行:(1) 評估GCP/GCL之物化特性並探討對於親水性化妝品成分維他命C磷酸鎂鹽 (MAP)在皮膚上的應用;(2) 製備低分子量兩性乙二醇幾丁聚醣,並評估其物化特性,比較高低分子量兩性乙二醇幾丁聚醣(GCP/GCL/LMWGCP/LMWGCL)對不同親水性/親脂性、不同分子量藥物皮膚滲透性之影響; (3) 探討以兩性幾丁聚醣做為載體輸送薑黃素在皮膚細胞株之效率,並以最適條件之兩性幾丁聚醣做為載體,於活體動物模式經由皮膚投與薑黃素,評估抗皮膚腫瘤之效果。
結果:GCP/GCL凝膠對於MAP有延遲釋放的功能,而在皮膚上則有促進穿透及增加藥物滯留在皮膚的能力。在高低分子量兩性乙二醇幾丁聚醣對不同親水性/親脂性、不同分子量藥物皮膚滲透性之影響方面,GCP對於兩性藥物hydrocortisone及大分子藥物PEG4000有促進穿透的效果,GCL則對親水性藥物ALA有促進效果,而LMWGCP/LMWGCL兩者對所有藥物皆有促進穿透之效果,其中以LMWGCP的效果最佳。而藥物在皮膚滯留量方面,LMWGCP對於不同性質藥物的皮膚滯留也比LMWGCL較佳,但在親脂性藥物方面則以LMWGCL呈現較佳效果。以LMWGCP評估對hydrocortisone之效應呈現濃度依賴性,濃度越高藥物皮膚滲透性與滯留量都會提高。低分子量兩性幾丁聚醣會影響角質層結構造成藥物容易滲透及滯留,但又不會造成皮膚刺激性反應,因此LMWGCP具有做為藥物輸送載體的最佳潛力,因此選擇LMWGCP評估做為薑黃素藥物輸送載體之可行性。研究結果發現LMWGCP促進皮膚癌細胞(SCC 25)攝入薑黃素的量較正常細胞(HaCaT) 為高,同時LMWGCP也會降低薑黃素抑制癌細胞生長的IC50濃度,但對正常細胞則不影響。LMWGCP會增加薑黃素的溶解度,導致皮膚累積量增加,但穿透量並無增加,表示LMWGCP-薑黃素之組合得應用於局部療法,在活體動物試驗中亦證實LMWGCP-薑黃素組合顯著抑制皮膚腫瘤之生長。
結論:低分子量架接palmitic acid與lauric acid之兩性乙二醇幾丁聚醣應用於皮膚藥物傳輸上,相較於高分子量聚合物具有較佳的促進皮膚穿透及藥物滯留效果,其中以LMWGCP對於大多數不同性質藥物的效應最佳。皮膚塗抹LMWGCP與薑黃素的組合可以明顯抑制皮膚腫瘤的生長,因此具有未來應用於皮膚癌治療的發展性。
英文摘要 A skin delivery method has many advantages over injection or oral administration because it can avoid first-pass hepatic metabolism and provides patients with an easier and more convenient route for drug administration. Glycol chitosan (GC) is a water-soluble derivative of chitosan that has biocompatibility, biodegradability, and non-toxic properties. However the hydrophilicity hinder the usage of GC in the field of skin engineering. In order to increase the application of GC, we aimed to hydrophobically modify GC with palmitic/lauric acid to form polymeric amphiphiles consisting of both hydrophilic and hydrophobic properties, and to explore their applications in skin delivery. Specifically, the studies were designed to (1) evaluate the application of lauroyl/palmitoyl glycol chitosan (GCL/GCP) in gel form for skin delivery of the hydrophilic cosmetic ingredient, magnesium ascorbyl phosphate (MAP); (2) to prepare and characterize low molecular weight GC (LMWGC) and hydrophobically modified to form LMWGCP and LMWGCL, and their effects on skin permeability and deposition of drugs with different physicochemical properties were systematically determined and compared with high molecular weights amphiphilic gels; and (3) to investigate the effects of the optimized amphiphilc GC on the uptake of the lipophilic curcumin into skin cells, and to demonstrate its antitumor effect by topical application of the optimized curcumin/polymer combination in vivo.
Results: GCL/GCP in either water or 10% ethanol vehicles increased the skin penetration and skin deposition of MAP in comparison with commercial gels, while sustained its release from the polymer gels, suggesting both GCL and GCP can be applied as delivery vehicles to improve percutaneous absorption of MAP. LMWGCP gel most effectively increased the skin permeability of 5-aminolevulinic acid (log KO/W = -0.14), hydrocortisone (log KO/W = 1.28), and PEG 4000, but not for estradiol (log KO/W = 3.84). In addition, LMWGCP gel increased drug deposition into the epidermal and dermal layers, whereas LMWGCL gel increased deposition of selected compounds into the dermal layer only. The low molecular weight polymers showed higher capacity to solubilize both amphiphilic and lipophilic molecules than normal molecular weight polymers, and were able to interact with intercellular lipid in the deeper layers of the SC, resulting in membrane fluidization and increased permeability without inducing skin irritation. Low molecular weights amphiphilic GC displayed various effects on the skin delivery of compounds and LMWGCP was identified with potential application in transdermal and topical drug delivery. LMWGCP was then selected as vehicle for skin delivery of curcumin. LMWGCP enhanced the uptake of curcumin into squamous cell carcinoma cells (SCC25) and reduced its IC50 for cytotoxic effect, but not for normal cell line (HaCaT). Solubility of curcumin was increased by LMWGCP, resulting in elevated skin deposition but not skin penetration, indicating its potential application in topical therapy. It was then demonstrated in animals in vivo that topical application of curcumin in 5% LMWGCP gel for seven days significantly reduced tumor size in comparison to 10% ethanol and mineral oil-based curcumin formulations.
Conclusion: In comparison with GCP/GCL, LMWGCP/LMWGCL displayed more pronounced effects on skin permeability and deposition for a range of compounds with different physicochemical properties, which was optimal with LMWGCP. Topical application of curcumin with LMWGCP demonstrated significant antitumor effects, and warranted future development for the treatment of skin cancers.
論文目次 中文摘要 I
Abstract III
Acknowledgment VI
Contents VIII
Figure of Contents XII
Table of Contents XV
Abbreviations XVI
Chapter 1- Literature Review 1
1.1. Amphiphilic Glycol Chitosan 1
1.2. Skin Structure, Function and Permeability 4
1.3. Skin Delivery 9
1.4. Objective 10
Chapter 2- Lauroyl/Palmitoyl Glycol Chitosan for Skin Delivery of MAP 12
2.1 Introduction 12
2.1.1. Magnesium L-Ascorbic acid-2-Phosphate (MAP) 12
2.2. Experimental Methods 14
2.2.1. Materials 14
2.2.2. Animals 14
2.2.3. Synthesis of Lauroyl/Palmitoyl Glycol Chitosan 14
2.2.4. Physicochemical Characterization of the Synthesized Polymers 15
2.2.5. Preparation of MAP-Containing GCL/GCP Gels 16
2.2.6. In Vitro Release/Skin Permeation Studies 17
2.2.7. HPLC Assay of MAP 18
2.3. Results and Discussion 20
2.3.1. Characterization of Synthesized Lauroyl/Palmitoyl Glycol Chitosan 20
2.3.2. MAP Release Test 26
2.3.3. In Vitro Skin Permeation and Deposition of MAP 30
2.3.4. Comparison with Carbopol and HPMC Gels 35
2.4. Conclusions 36
Chapter 3- Lauroyl/Palmitoyl Glycol Chitosan Gels of Two Molecular Weights as Skin Delivery Vehicles 37
3.1. Introduction 37
3.2. Experimental Methods 39
3.2.1. Materials 39
3.2.2. Animals 39
3.2.3. Synthesis of Low Molecular Weight Polymers 39
3.2.4. Physicochemical Characterization of the Synthesized Polymers 40
3.2.5. In Vitro Skin Permeation and Deposition Analyses 40
3.2.6. Measurement of Drug Solubility in the Polymer Gels 42
3.2.7. ATR-FTIR Evaluation of Polymer Effects on SC Morphology 43
3.2.8. Assessment of Skin Irritation 44
3.3. Results and Discussion 45
3.3.1. Physicochemical Characteristics of Polymers 45
3.3.2. Effects of the Polymer Gels on the Skin Permeability of the Model Compounds 48
3.3.3. Skin Deposition of Model Compounds from LMWGCP/LMWGCL Gels 52
3.3.4. Effects of Polymer Concentration on Skin Permeability and Deposition of Hydrocortisone 54
3.3.5. Drug Solubility in Polymer Gels 56
3.3.6. Effects of Polymers on SC Morphology as Evaluated Using ATR-FTIR 57
3.3.7. Skin Irritation Response to the Various Polymer Treatments 61
3.4. Conclusions 63
Chapter 4- Topical Delivery of Curcumin with Palmitoyl Glycol Chitosan for the Treatment of Skin Cancer 64
4.1. Introduction 64
4.1.1. Skin Cancer 64
4.1.2. Curcumin 65
4.1.3. Rationale of Curcumin-Amphiphilic Glycol Chitosan 71
4.2. Experimental Methods 73
4.2.1. Materials 73
4.2.2. Cells Lines 73
4.2.3. Animals 73
4.2.4. Cytotoxitic and Cell Uptake of Curcumin 74
4.2.5. In Vitro Skin Deposition Studies 75
4.2.6. Curcumin Solubility in Polymer Gels 77
4.2.7. In Vivo Studies 77
4.2.8. Antitumor Effect 78
4.3. Results and Discussion 79
4.3.1. Cytotoxicity and Cellular Uptake of Curcumin 79
4.3.2. In Vitro Skin Deposition of Curcumin 83
4.3.3. Curcumin Solubility in Polymer Gels 88
4.3.4. In Vivo Skin Absorption and Antitumor Effect 90
4.4. Conclusions 93
Chapter 5- Summary 94
References 97
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