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MARC
논문명/저자명
Development of HM30181 mesylate-loaded microcapsules as novel P-glycoprotein inhibitor / Jin Cheul Kim 인기도
발행사항
서울 : 한양대학교 대학원, 2016.8
청구기호
TD 615 -16-283
형태사항
ix, 113 p. ; 26 cm
자료실
전자자료
제어번호
KDMT1201654311
주기사항
학위논문(박사) -- 한양대학교 대학원, Dept. of Pharmacy, 2016.8. 지도교수: Han-Gon Choi
원문

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Title Page

Contents

ABSTRACT 13

1. Introduction 15

1.1. P-glycoprotein 21

1.1.1. Overview 21

1.1.2. Drug interactions 24

1.1.3. Genetic factors 25

1.2. Paclitaxel 27

1.2.1. Physicochemical property 27

1.2.2. Action mechanism 32

1.3. Microcapsule 35

1.3.1. Overview 35

1.3.2. Features of microcapsule 35

1.3.3. Classification of microcapsule 36

1.3.4. Manufacturing techniques of microcapsule 38

1.3.5. Application of microencapsulation 49

1.3.6. Advantages of microencapsulation 51

2. Materials and methods 52

2.1. Materials 52

2.2. Solubility of HM30181M 53

2.3. Preparation of HM30181M-loaded microcapsule 53

2.4. Aqueous solubility of HM30181M in the microcapsules 58

2.5. Dissolution 58

2.6. Morphological physiognomies 59

2.7. Particle size 59

2.8. Structural aspects 59

2.9. Thermal characteristics 60

2.10. Pharmacokinetics 60

2.10.1. Animals 60

2.10.2. Dose administration and blood sampling 61

2.10.3. Sample preparation and HPLC-MS/MS conditions for paclitaxel and HM30181M analysis 62

2.10.4. Pharmacokinetic data and statistical analysis 63

3. Results and Discussion 65

4. Conclusion 101

Reference 102

국문요지 119

Table 1. Function of P-glycoprotein. 23

Table 2. Composition of HM30181M-loaded microcapsules prepared with various... 55

Table 3. Composition of HM30181M-loaded microcapsules prepared with... 56

Table 4. Composition of HM30181M-loaded microcapsules prepared with various... 57

Table 5. Pharmacokinetic parameters of HM30181M after oral administration of... 95

Table 6. Pharmacokinetic parameters of paclitaxel after oral administration of p... 99

Fig. 1. Action mechanism of P-glycoprotein inhibitor 19

Fig. 2. Chemical structure of HM30181M 20

Fig. 3. Tissue distribution of P-glycoprotein 22

Fig. 4. Chemical structure of paclitaxel 29

Fig. 5. Action mechanism of paclitaxel. Paclitaxel inhibits cellular replication... 34

Fig. 6. Classification of microcapsule 37

Fig. 7. Manufacturing techniques of microcapsule 39

Fig. 8. The process of micro-encapsulation by spray-drying 41

Fig. 9. Fluid-bed coater. 43

Fig. 10. Coating process in a perforated drum 46

Fig. 11. Solvent evaporation method 48

Fig. 12. Schematic representation of microencapsulation application 50

Fig. 13. Effect of hydrophilic polymers on the solubility of HM30181M. Each... 67

Fig. 14. Effect of surfactants on the solubility of HM30181M. Each value... 68

Fig. 15. Effect of oils on the solubility of HM30181M. Each value represents... 69

Fig. 16. Effect of solvents on the solubility of HM30181M. Each value... 70

Fig. 17. Effect of HPMC on the solubility of HM30181M in the microcapsule.... 72

Fig. 18. Effect of acidifying agents on the solubility of HM30181M in the... 74

Fig. 19. Effect of acidifying agents on the dissolution of HM30181M in the... 76

Fig. 20. Effect of the phosphoric acid concentration on the solubility of... 78

Fig. 21. Effect of the phosphoric acid concentration on the dissolution of... 80

Fig. 22. Comparative solubility of HM30181M in the physical mixture and... 82

Fig. 23. Comparative dissolution profile of HM30181M from the physical... 83

Fig. 24. Scanning electron micrographs (X1500) 85

Fig. 25. Particle size 86

Fig. 26. Differential scanning calorimetric thermograms 88

Fig. 27. Powder X-ray diffraction 89

Fig. 28. Differential scanning calorimetric thermograms after 3-months... 91

Fig. 29. Powder X-ray diffraction after 3-months storage 92

Fig. 30. Plasma concentration-time curves of HM30181M after oral... 96

Fig. 31. Plasma concentration-time curves of paclitaxel after oral... 100

초록보기 더보기

 본 연구의 목적은 P-glycoprotein 억제제로서의 HM30181 메실레이트 함유 마이크로캡슐을 개발하여 파크리탁셀의 경구 흡수를 증가시키기 위한 것이다. 본 연구에서는 HM30181 메실레이트의 용해도를 증가시키기 위하여 HM30181 메실레이트, 히프로멜로스(HPMC), 콜로이달 이산화규소를 인산과 함께 메틸렌클로라이드와 에탄올에 용해시킨 상태에서 고체분산체를 제조하여 마이크로캡슐로 제형화하였다. 제조한 마이크로캡슐에 대하여 현미경 사진, 입자 크기분포, 결정성 확인을 위한 DSC, XRD의 물리화학적 특성을 평가하였으며, HM30181 메실레이트 파우더와 마이크로캡슐이 경구 투여 파클리탁셀 생체이용율에 주는 영향을 실험쥐에서 비교하였다. HM30181 메실레이트 및 히프로멜로스, 콜로이달 이산화규소, 인산을 함유하는 마이크로캡슐은 각각의 질량비로서, 3:6:3:2의 비율로 제조시 HM30181 메실레이트 파우더보다 현저히 개선된 용해도 및 용출률을 보이는데 이는 구형의 모양과 작은 입자 크기를 통해 표면적이 극대화되고, 무정형 상태의 HM30181 메실레이트를 포함함으로서 가능하다. HM30181 메실레이트를 포함하는 마이크로캡슐은 HM30181 메실레이트의 흡수에 있어 1.7배 빠르며, 파클리탁셀의 흡수는 파클리탁셀 단독 투여보다 70배, HM30181 메실레이트 파우더와 동시 투여보다 2배 높은 흡수를 보였다.

따라서 본 연구에서 제조한 HM30181 메실레이트 함유 마이크로캡슐은 파클리탁셀의 경우 흡수율을 개선할 수 있는 P-glycoprotein 후보 제형이 됨을 확인하였다.

참고문헌 (81건) : 자료제공( 네이버학술정보 )더보기

참고문헌 목록에 대한 테이블로 번호, 참고문헌, 국회도서관 소장유무로 구성되어 있습니다.
번호 참고문헌 국회도서관 소장유무
1 Inhibition of Multidrug Transporter in Tumor Endothelial Cells Enhances Antiangiogenic Effects of Low-Dose Metronomic Paclitaxel 네이버 미소장
2 A phase II trial of Cremorphor EL-free paclitaxel (Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer. 네이버 미소장
3 2011. Microspheres as a Novel drug delivery system. International J of chem. Tech. 526- 534. 미소장
4 2015. Propagation of human iPS cells in alginate-based microcapsules prepared using reactions catalyzed by horseradish peroxidase... 미소장
5 Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. 네이버 미소장
6 Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice 네이버 미소장
7 Interaction of HM30181 with P-glycoprotein at the murine blood–brain barrier assessed with positron emission tomography 네이버 미소장
8 A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models 네이버 미소장
9 Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel. 네이버 미소장
10 Microencapsulation of 2-octylcyanoacrylate tissue adhesive for self-healing acrylic bone cement. 네이버 미소장
11 Preparation of microcapsules by complex coacervation of gum Arabic and chitosan 네이버 미소장
12 Effects of lipid vehicle and P-glycoprotein inhibition on the mesenteric lymphatic transport of paclitaxel in unconscious, lymph duct-cannulated rats. 네이버 미소장
13 Xanthone analogues as potent modulators of intestinal P-glycoprotein 네이버 미소장
14 2014. Controlled release of Lactobacillus rhamnosus biofilm probiotics from alginate-locust bean gum microcapsules. Carbohydr Polym.... 미소장
15 Preparation of cross-linked chitosan microspheres by spray drying: effect of cross-linking agent on the properties of spray dried microspheres. 네이버 미소장
16 Pharmacokinetic Study of Paclitaxel Concentration after Drug-Eluting Balloon Angioplasty in the Iliac Artery of Healthy and Atherosclerotic Rabbit Models 네이버 미소장
17 Development of a supersaturable SEDDS (S‐SEDDS) formulation of paclitaxel with improved oral bioavailability 네이버 미소장
18 Combined Delivery and Anti-Cancer Activity of Paclitaxel and Curcumin Using Polymeric Micelles. 네이버 미소장
19 Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation 네이버 미소장
20 Possibility of paclitaxel as an alternative radiosensitizer to 5-fluorouracil for colon cancer 네이버 미소장
21 Induction of multiple drug resistance in HMEC-1 endothelial cells after long-term exposure to sunitinib 네이버 미소장
22 A novel solid dispersion system for natural product-loaded medicine: silymarin-loaded solid dispersion with enhanced oral bioavailability and hepatoprotective activity. 네이버 미소장
23 Oral paclitaxel chemotherapy for brain tumors: Ideal combination treatment of paclitaxel and P-glycoprotein inhibitor 네이버 미소장
24 Response of brain specific microenvironment to P-glycoprotein inhibitor: an important factor determining therapeutic effect of P-glycoprotein inhibitor on brain metastatic tumors. 네이버 미소장
25 Unloading and reloading colloidal microcapsules with apolar solutions by controlled and reversible buckling. 네이버 미소장
26 Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein. 네이버 미소장
27 Comparison of a solid SMEDDS and solid dispersion for enhanced stability and bioavailability of clopidogrel napadisilate 네이버 미소장
28 Nanomedicine for treatment of cancer stem cells. 네이버 미소장
29 Novel fenofibric acid-loaded controlled release pellet bioequivalent to choline fenofibrate-loaded commercial product in beagle dogs 네이버 미소장
30 One-Step Generation of Multifunctional Polyelectrolyte Microcapsules via Nanoscale Interfacial Complexation in Emulsion (NICE). 네이버 미소장
31 Novel montelukast sodium-loaded clear oral solution prepared with hydroxypropyl-β-cyclodextrin as a solubilizer and stabilizer: enhanced stability and bioequivalence to commercial granules in rats 네이버 미소장
32 Mechanism of multidrug recognition by MDR1/ABCB1 네이버 미소장
33 Efficient delivery of therapeutic agents by using targeted albumin nanoparticles. 네이버 미소장
34 Pharmacokinetic drug interactions between apigenin, rutin and paclitaxel mediated by P-glycoprotein in rats 네이버 미소장
35 Albumin-bound paclitaxel in solid tumors: clinical development and future directions 네이버 미소장
36 Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel 네이버 미소장
37 Effects of silibinin, inhibitor of CYP3A4 and P-glycoprotein in vitro, on the pharmacokinetics of paclitaxel after oral and intravenous administration in rats. 네이버 미소장
38 A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer 소장
39 Phase I/II Study of Weekly Oraxol for the Second‐Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer 네이버 미소장
40 Nozzleless Fabrication of Oil-Core Biopolymeric Microcapsules by the Interfacial Gelation of Pickering Emulsion Templates. 네이버 미소장
41 Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense 네이버 미소장
42 Quercetin inhibits proliferation and increases sensitivity of ovarian cancer cells to cisplatin and paclitaxel. 네이버 미소장
43 Paclitaxel Loaded Nanoliposomes in Thermosensitive Hydrogel: A Dual Approach for Sustained and Localized Delivery. 네이버 미소장
44 2007. Real time observation of diffusion and bioaffinity binding processes in single polyelectrolyte-coated microcapsules: a... 미소장
45 Discovery of a marine-derived bis-indole alkaloid fascaplysin, as a new class of potent P-glycoprotein inducer and establishment of its structure-activity relationship. 네이버 미소장
46 Long-term cardiac safety and outcomes of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab with and without lapatinib in patients with early breast cancer. 네이버 미소장
47 1970. Microencapsulation techniques, application and problems. J.Soc.Cosmetic Chemists. 21, 85-98. 미소장
48 2014. Paclitaxel formulations: challenges and novel delivery options. Curr. Drug Deliv. 11(6), 666–686. 미소장
49 Oral microemulsions of paclitaxel: In situ and pharmacokinetic studies 네이버 미소장
50 Simultaneous determination of paclitaxel and a new P-glycoprotein inhibitor HM-30181 in rat plasma by liquid chromatography with tandem mass spectrometry 네이버 미소장
51 Effects of silymarin and formulation on the oral bioavailability of paclitaxel in rats 네이버 미소장
52 Oral delivery of paclitaxel nanocrystal (PNC) with a dual Pgp-CYP3A4 inhibitor: Preparation, characterization and antitumor activity 네이버 미소장
53 Hyaluronic acid-decorated poly(lactic-co-glycolic acid) nanoparticles for combined delivery of docetaxel and tanespimycin 네이버 미소장
54 Polypeptide-based Micelles for Delivery of Irinotecan: Physicochemical and In vivo Characterization. 네이버 미소장
55 Layer-by-layer coated lipid-polymer hybrid nanoparticles designed for use in anticancer drug delivery 네이버 미소장
56 Effect of hydroxypropylcellulose and Tween 80 on physicochemical properties and bioavailability of ezetimibe-loaded solid dispersion 네이버 미소장
57 Nanomedicine book review 네이버 미소장
58 Formation of multilayered biopolymer microcapsules and microparticles in a multiphase microfluidic flow. 네이버 미소장
59 2016. Turning the gun on cancer: Utilizing lysosomal P-glycoprotein as a new strategy to overcome multi-drug resistance. Free... 미소장
60 Development of docetaxel-loaded solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced chemotherapeutic effect 네이버 미소장
61 Enhanced oral bioavailability of paclitaxel by solid dispersion granulation. 네이버 미소장
62 Encapsulation of basic fibroblast growth factor by polyelectrolyte multilayer microcapsules and its controlled release for enhancing cell proliferation. 네이버 미소장
63 Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study. 네이버 미소장
64 Paclitaxel Inhibits Expression of Neuronal Nitric Oxide Synthase and Prevents Mitochondrial Dysfunction in Spinal Ventral Horn in Rats After C7 Spinal Root Avulsion. 네이버 미소장
65 Pharmacokinetic Interaction of Rifampicin with Oral Versus Intravenous Anticancer Drugs: Challenges, Dilemmas and Paradoxical Effects Due to Multiple Mechanisms. 네이버 미소장
66 Interfaces —Instructions to Authors 네이버 미소장
67 Vatalanib sensitizes ABCB1 and ABCG2-overexpressing multidrug resistant colon cancer cells to chemotherapy under hypoxia 네이버 미소장
68 Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal 네이버 미소장
69 Controlling the stability and size of double-emulsion-templated poly(lactic-co-glycolic) acid microcapsules. 네이버 미소장
70 Development of raloxifene-solid dispersion with improved oral bioavailability via spray-drying technique 소장
71 Nanomedicine book review 네이버 미소장
72 The effect of ABCB1 polymorphisms on the outcome of breast cancer treatment 네이버 미소장
73 Nanomedicine and the complement paradigm 네이버 미소장
74 Trantinterol, a Novel β~2-Adrenoceptor Agonist, Noncompetitively Inhibits P-Glycoprotein Function in Vitro and in Vivo 네이버 미소장
75 Hypersensitivity reaction studies of a polyethoxylated castor oil-free, liposome-based alternative paclitaxel formulation 네이버 미소장
76 Effects of cytochrome P450 3A (CYP3A) and the drug transporters P‐glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir 네이버 미소장
77 Effect of dose and dosage interval on the oral bioavailability of docetaxel in combination with a curcumin self-emulsifying drug delivery system (SEDDS). 네이버 미소장
78 Nanomedicine and the complement paradigm 네이버 미소장
79 2004. Enhanced oral absorption of paclitaxel in a novel self-microemulsifying drug delivery system with or without concomitant use of... 미소장
80 Nanomedicine book review 네이버 미소장
81 Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. 네이버 미소장
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